gene entrez_id variant disease doid phenotypes drugs drug_interaction_type evidence_type evidence_direction evidence_level clinical_significance evidence_statement citation_id source_type asco_abstract_id citation nct_ids rating evidence_status evidence_id variant_id gene_id chromosome start stop reference_bases variant_bases representative_transcript chromosome2 start2 stop2 representative_transcript2 ensembl_version reference_build variant_summary variant_origin last_review_date evidence_civic_url variant_civic_url gene_civic_url is_flagged JAK2 3717 V617F Lymphoid Leukemia 1037 Diagnostic Supports B Negative JAK2 V617F is not associated with lymphoid leukemia (B-lineage ALL, T-ALL or CLL). 16081687 PubMed Levine et al., 2005, Blood 4 accepted 1 64 28 9 5073770 5073770 G T ENST00000381652.3 75 GRCh37 JAK2 V617F is a highly recurrent mutation in myeloproliferative diseases. It is found in around 98% of patients with polycythemia vera, and just over half of the patients with essential thrombocythemia and primary myelofibrosis. While less associated with cancer, when it is seen, it is more likely to be in myeloid leukemias than lymphoid leukemias. The V617F mutation is an activating mutation, resulting in increased kinase activity. The mutation seems to be restricted to hematologic malignancies. Treatment of JAK mutant diseases with ruxolitinib has seen some clinical success. Somatic 2020-11-20 16:18:21 UTC https://civicdb.org/links/evidence_items/1 https://civicdb.org/links/variants/64 https://civicdb.org/links/genes/28 false PDGFRA 5156 D842V Gastrointestinal Stromal Tumor 9253 Diagnostic Supports B Negative GIST tumors harboring PDGFRA D842V mutation are more likely to be benign than malignant. 15146165 PubMed Lasota et al., 2004, Lab. Invest. 3 accepted 2 99 38 4 55152093 55152093 A T ENST00000257290.5 75 GRCh37 PDGFRA D842 mutations are characterized broadly as imatinib resistance mutations. This is most well characterized in gastrointestinal stromal tumors, but other cell lines containing these mutations have been shown to be resistant as well. Exogenous expression of the A842V mutation resulted in constitutive tyrosine phosphorylation of PDGFRA in the absence of ligand in 293T cells and cytokine-independent proliferation of the IL-3-dependent Ba/F3 cell line, both evidence that this is an activating mutation. In imatinib resistant cell lines, a number of other therapeutics have demonstrated efficacy. These include; crenolanib, sirolimus, and midostaurin (PKC412). Somatic 2015-06-21 16:49:38 UTC https://civicdb.org/links/evidence_items/2 https://civicdb.org/links/variants/99 https://civicdb.org/links/genes/38 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Diagnostic Supports B Positive DNMT3A R882 mutations occur most often in de novo AML patients with intermediate risk cytogenetics (39/194 intermediate risk patients vs 0/89 low and high risk). 22081665 PubMed LaRochelle et al., 2011, Oncotarget 2 accepted 3 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2016-03-26 22:10:59 UTC https://civicdb.org/links/evidence_items/3 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Diagnostic Supports B Positive Young AML patients (<60 years old) with DNMT3A mutations (60% of which were R882) were older in age, had higher white blood cell counts and had higher platelet counts than patients wildtype for DNMT3A. 22490330 PubMed Ribeiro et al., 2012, Blood 3 accepted 4 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/4 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false JAK2 3717 V617F Chronic Myeloid Leukemia 8552 Diagnostic Supports B Positive JAK2 V617F is associated with myeloid malignanices (AML, MDS, CMML/atypical CML). 16081687 PubMed Levine et al., 2005, Blood 4 accepted 5 64 28 9 5073770 5073770 G T ENST00000381652.3 75 GRCh37 JAK2 V617F is a highly recurrent mutation in myeloproliferative diseases. It is found in around 98% of patients with polycythemia vera, and just over half of the patients with essential thrombocythemia and primary myelofibrosis. While less associated with cancer, when it is seen, it is more likely to be in myeloid leukemias than lymphoid leukemias. The V617F mutation is an activating mutation, resulting in increased kinase activity. The mutation seems to be restricted to hematologic malignancies. Treatment of JAK mutant diseases with ruxolitinib has seen some clinical success. Somatic 2015-06-21 16:49:39 UTC https://civicdb.org/links/evidence_items/5 https://civicdb.org/links/variants/64 https://civicdb.org/links/genes/28 false JAK2 3717 V617F Chronic Myeloid Leukemia 8552 Diagnostic Supports B Positive JAK2 V617F is associated with myeloid neoplasms (AML, MDS, CMML/aCML). 16081687 PubMed Levine et al., 2005, Blood 4 accepted 6 64 28 9 5073770 5073770 G T ENST00000381652.3 75 GRCh37 JAK2 V617F is a highly recurrent mutation in myeloproliferative diseases. It is found in around 98% of patients with polycythemia vera, and just over half of the patients with essential thrombocythemia and primary myelofibrosis. While less associated with cancer, when it is seen, it is more likely to be in myeloid leukemias than lymphoid leukemias. The V617F mutation is an activating mutation, resulting in increased kinase activity. The mutation seems to be restricted to hematologic malignancies. Treatment of JAK mutant diseases with ruxolitinib has seen some clinical success. Somatic 2017-06-12 22:00:28 UTC https://civicdb.org/links/evidence_items/6 https://civicdb.org/links/variants/64 https://civicdb.org/links/genes/28 false JAK2 3717 V617F Bone Marrow Cancer 4960 Diagnostic Supports B Positive The SNP rs10974944 in the Jak2 locus is associated with increased predisposition for JAK2 V617F mutation and its associated cancer. 19287384 PubMed Kilpivaara et al., 2009, Nat. Genet. 4 accepted 7 64 28 9 5073770 5073770 G T ENST00000381652.3 75 GRCh37 JAK2 V617F is a highly recurrent mutation in myeloproliferative diseases. It is found in around 98% of patients with polycythemia vera, and just over half of the patients with essential thrombocythemia and primary myelofibrosis. While less associated with cancer, when it is seen, it is more likely to be in myeloid leukemias than lymphoid leukemias. The V617F mutation is an activating mutation, resulting in increased kinase activity. The mutation seems to be restricted to hematologic malignancies. Treatment of JAK mutant diseases with ruxolitinib has seen some clinical success. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/7 https://civicdb.org/links/variants/64 https://civicdb.org/links/genes/28 false KRAS 3845 G12 Acute Leukemia 12603 Diagnostic Supports B Positive Children with early age leukaemia who had second hand smoke exposure are more likely to harbor KRAS mutation. 24571676 PubMed Andrade et al., 2014, BMC Cancer 3 accepted 8 76 30 12 25398284 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2015-06-21 16:49:39 UTC https://civicdb.org/links/evidence_items/8 https://civicdb.org/links/variants/76 https://civicdb.org/links/genes/30 false NRAS 4893 Q61 Melanoma 1909 Diagnostic Supports B Positive Melanoma associated with NRAS Q61 mutation was more often associated with those at the extremity than those at the trunk. 23861977 PubMed Tschandl et al., 2013, PLoS ONE 3 accepted 10 94 36 1 115256528 115256530 ENST00000369535.4 75 GRCh37 NRAS Q61 mutations have been found in multiple myeloma, gastrointestinal stromal tumors, melanoma, and others. Two melanoma patients, each harboring mutations at this locus (Q61L and Q61R), responded to treatment with the akylating agent temozolomide. However, in colorectal cancer patients, mutations at this locus have been shown to confer resistance to cetuximab. The prognostic impact of mutations at this locus is currently under study. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/10 https://civicdb.org/links/variants/94 https://civicdb.org/links/genes/36 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Daunorubicin Predictive Does Not Support B Resistance Daunorubicin treatment resulted in similar overall survival and disease free survival in de novo AML patients with DNMT3A R882 mutation compared to those who do not harbor this mutation. 22081665 PubMed LaRochelle et al., 2011, Oncotarget 4 accepted 11 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2015-06-21 16:49:39 UTC https://civicdb.org/links/evidence_items/11 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false MAP2K1 5604 P124S Melanoma 1909 Selumetinib Predictive Supports D Resistance A375 cells expressing MAP2K1 P124S mutation conferred an approximately 5-fold increased resistance to selumetinib (AZD6244) induced growth inhibition when compared to untransduced cells, cells expressing wild-type MAP2K1 or cells expressing a constitutively active form. This mutation also attenuated pERK inhibition by selumetinib in these cells. 19915144 PubMed Emery et al., 2009, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 12 82 31 15 66729162 66729162 C T ENST00000307102.5 75 GRCh37 MAP2K1 P124S is a recurrent mutation in melanoma, and is seen in bladder and colon cancer to a lesser degree. The P124S mutation has been shown to contribute to AZD6244 resistance in melanoma cell lines, but considerably less so than its Q56P counterpart. Somatic 2016-08-19 18:23:15 UTC https://civicdb.org/links/evidence_items/12 https://civicdb.org/links/variants/82 https://civicdb.org/links/genes/31 false MAP2K1 5604 Q56P Melanoma 1909 Selumetinib Predictive Supports D Resistance A375 cells expressing MAP2K1 Q56P mutation conferred an approximately 100-fold increased resistance to selumetinib (AZD6244) induced growth inhibition when compared to untransduced cells, cells expressing wild-type MAP2K1, or cells expressing a constitutively active form. This mutation also attenuated pERK inhibition by selumetinib in these cells. 19915144 PubMed Emery et al., 2009, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 13 83 31 15 66727451 66727451 A C ENST00000307102.5 75 GRCh37 MAP2K1 Q56P is a recurrent mutation in melanoma and gastric cancer. This mutation has been shown to confer considerable resistance to AZD6244 treatment of melanoma cell lines. Somatic 2016-11-07 18:43:41 UTC https://civicdb.org/links/evidence_items/13 https://civicdb.org/links/variants/83 https://civicdb.org/links/genes/31 false NRAS 4893 Q61 Melanoma 1909 Vemurafenib Predictive Supports B Resistance Vemurafenib resistance is associated with gain of Q61 mutation in NRAS. 23569304 PubMed Trunzer et al., 2013, J. Clin. Oncol. 4 accepted 14 94 36 1 115256528 115256530 ENST00000369535.4 75 GRCh37 NRAS Q61 mutations have been found in multiple myeloma, gastrointestinal stromal tumors, melanoma, and others. Two melanoma patients, each harboring mutations at this locus (Q61L and Q61R), responded to treatment with the akylating agent temozolomide. However, in colorectal cancer patients, mutations at this locus have been shown to confer resistance to cetuximab. The prognostic impact of mutations at this locus is currently under study. Somatic 2015-06-21 16:49:39 UTC https://civicdb.org/links/evidence_items/14 https://civicdb.org/links/variants/94 https://civicdb.org/links/genes/36 false PDGFRA 5156 D842V Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports B Resistance GIST cancer with D842V mutation is resistant to imatinib. 15928335 PubMed Corless et al., 2005, J. Clin. Oncol. 4 accepted 15 99 38 4 55152093 55152093 A T ENST00000257290.5 75 GRCh37 PDGFRA D842 mutations are characterized broadly as imatinib resistance mutations. This is most well characterized in gastrointestinal stromal tumors, but other cell lines containing these mutations have been shown to be resistant as well. Exogenous expression of the A842V mutation resulted in constitutive tyrosine phosphorylation of PDGFRA in the absence of ligand in 293T cells and cytokine-independent proliferation of the IL-3-dependent Ba/F3 cell line, both evidence that this is an activating mutation. In imatinib resistant cell lines, a number of other therapeutics have demonstrated efficacy. These include; crenolanib, sirolimus, and midostaurin (PKC412). Somatic 2015-06-21 16:49:39 UTC https://civicdb.org/links/evidence_items/15 https://civicdb.org/links/variants/99 https://civicdb.org/links/genes/38 false PDGFRA 5156 D842V Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports B Resistance While cancer with PDGFRA V561D mutation is known to be sensitive to Imatinib, double mutation of V561D and D842V mutants are resistant to imatinib. 16954519 PubMed Heinrich et al., 2006, J. Clin. Oncol. 4 accepted 16 99 38 4 55152093 55152093 A T ENST00000257290.5 75 GRCh37 PDGFRA D842 mutations are characterized broadly as imatinib resistance mutations. This is most well characterized in gastrointestinal stromal tumors, but other cell lines containing these mutations have been shown to be resistant as well. Exogenous expression of the A842V mutation resulted in constitutive tyrosine phosphorylation of PDGFRA in the absence of ligand in 293T cells and cytokine-independent proliferation of the IL-3-dependent Ba/F3 cell line, both evidence that this is an activating mutation. In imatinib resistant cell lines, a number of other therapeutics have demonstrated efficacy. These include; crenolanib, sirolimus, and midostaurin (PKC412). Somatic 2016-12-01 15:26:38 UTC https://civicdb.org/links/evidence_items/16 https://civicdb.org/links/variants/99 https://civicdb.org/links/genes/38 false ARAF 369 S214C Lung Non-small Cell Carcinoma 3908 Sorafenib Predictive Supports C Sensitivity/Response In one patient with S214C mutation, the use of sorafenib has led to more than 5 years of survival and near remission. 24569458 PubMed Imielinski et al., 2014, J. Clin. Invest. 2 accepted 17 10 3 X 47426121 47426121 C G ENST00000377045.4 75 GRCh37 ARAF S214C has been found to be a recurrent oncogenic mutation in non-small cell lung cancer. It has been shown to confer sensitivity to sorafenib and trametenib in cell lines. In a case study of advanced stage lung adenocarcinoma harboring this mutation, sorafenib also acheived near-complete clinical remission. This case has brought more interest to the variant from a research and clinical perspective. Somatic 2019-02-22 15:00:44 UTC https://civicdb.org/links/evidence_items/17 https://civicdb.org/links/variants/10 https://civicdb.org/links/genes/3 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Idarubicin Predictive Supports B Sensitivity/Response Idarubicin increases the overall survival and disease free survival in de novo AML patients with DNMT3A R882 mutation compared to those who do not harbor this mutation. 22081665 PubMed LaRochelle et al., 2011, Oncotarget 4 accepted 18 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2015-06-21 16:49:39 UTC https://civicdb.org/links/evidence_items/18 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false JAK2 3717 V617F Polycythemia Vera 8997 Peginterferon Alfa-2b Predictive Supports B Sensitivity/Response In patients with JAK2 V617F, the use of pegylated IFN-alpha-2a leads to reduction in the percentage of cells harboring JAK2 V617F. 16709929 PubMed Kiladjian et al., 2006, Blood NCT00241241 4 accepted 19 64 28 9 5073770 5073770 G T ENST00000381652.3 75 GRCh37 JAK2 V617F is a highly recurrent mutation in myeloproliferative diseases. It is found in around 98% of patients with polycythemia vera, and just over half of the patients with essential thrombocythemia and primary myelofibrosis. While less associated with cancer, when it is seen, it is more likely to be in myeloid leukemias than lymphoid leukemias. The V617F mutation is an activating mutation, resulting in increased kinase activity. The mutation seems to be restricted to hematologic malignancies. Treatment of JAK mutant diseases with ruxolitinib has seen some clinical success. Somatic 2015-06-21 16:49:39 UTC https://civicdb.org/links/evidence_items/19 https://civicdb.org/links/variants/64 https://civicdb.org/links/genes/28 false JAK2 3717 V617F Polycythemia Vera 8997 Fedratinib Predictive Supports D Sensitivity/Response TG101348 effectively inhibits STAT5 signaling in JAK2 V617F cells. 18394554 PubMed Wernig et al., 2008, Cancer Cell 3 accepted 20 64 28 9 5073770 5073770 G T ENST00000381652.3 75 GRCh37 JAK2 V617F is a highly recurrent mutation in myeloproliferative diseases. It is found in around 98% of patients with polycythemia vera, and just over half of the patients with essential thrombocythemia and primary myelofibrosis. While less associated with cancer, when it is seen, it is more likely to be in myeloid leukemias than lymphoid leukemias. The V617F mutation is an activating mutation, resulting in increased kinase activity. The mutation seems to be restricted to hematologic malignancies. Treatment of JAK mutant diseases with ruxolitinib has seen some clinical success. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/20 https://civicdb.org/links/variants/64 https://civicdb.org/links/genes/28 false NRAS 4893 G13D Melanoma 1909 Tanespimycin Predictive Supports C Sensitivity/Response Likely due to increased reliance of mutant NRAS on HSP90 for stabilization, inhibition of HSP90 by 17-AAG was shown to be effective in a patient with metastatic malignant melanoma with an NRAS G13D mutation. 18375819 PubMed Banerji et al., 2008, Mol. Cancer Ther. 2 accepted 21 93 36 1 115258744 115258744 C T ENST00000369535.4 75 GRCh37 While the NRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/21 https://civicdb.org/links/variants/93 https://civicdb.org/links/genes/36 false NRAS 4893 Q61L Melanoma 1909 Temozolomide Predictive Supports C Sensitivity/Response In a melanoma patient with NRAS Q61L mutation, treatment with temozolomide resulted in disease free survival of 14 months. 21576590 PubMed Soon et al., 2011, Arch Dermatol 2 accepted 22 95 36 1 115256529 115256529 T A ENST00000369535.4 75 GRCh37 NRAS Q61 mutations have been found in multiple myeloma, gastrointestinal stromal tumors, melanoma, and others. A melanoma patient harboring a mutation at this locus responded to treatment with the akylating agent temozolomide. However, in colorectal cancer patients, mutations at this locus have been shown to confer resistance to cetuximab. The prognostic impact of mutations at this locus is currently under study. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/22 https://civicdb.org/links/variants/95 https://civicdb.org/links/genes/36 false NRAS 4893 Q61R Melanoma 1909 Temozolomide Predictive Supports C Sensitivity/Response In a melanoma patient with Q61R mutation, treatment with temozolomide resulted in overall survival of 16 months. 21576590 PubMed Soon et al., 2011, Arch Dermatol 2 accepted 23 96 36 1 115256529 115256529 T C ENST00000369535.4 75 GRCh37 NRAS Q61 mutations have been found in multiple myeloma, gastrointestinal stromal tumors, melanoma, and others. A melanoma patient harboring a mutation at this locus responded to treatment with the akylating agent temozolomide. However, in colorectal cancer patients, mutations at this locus have been shown to confer resistance to cetuximab. The prognostic impact of mutations at this locus is currently under study. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/23 https://civicdb.org/links/variants/96 https://civicdb.org/links/genes/36 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A There is no difference in the complete remission rate of de novo AML patients with DNMT3A mutation compared to those who are wild type for DNMT3A. 22081665 PubMed LaRochelle et al., 2011, Oncotarget 4 accepted 24 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2015-06-21 16:49:39 UTC https://civicdb.org/links/evidence_items/24 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome De novo AML patients with DNMT3A D882 mutation showed worse survival (event-free and overall) outcome than those without DNMT3A mutation. 21067377 PubMed Ley et al., 2010, N. Engl. J. Med. 4 accepted 25 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2015-06-21 16:49:39 UTC https://civicdb.org/links/evidence_items/25 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false KIT 3815 D816V Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In acute myloid leukemia patients, D816 mutation is associated with earlier relapse and poorer prognosis than wildtype KIT. 16384925 PubMed Cairoli et al., 2006, Blood 4 accepted 26 65 29 4 55599321 55599321 A T ENST00000288135.5 75 GRCh37 KIT D816V is a mutation observed in acute myeloid leukemia (AML). This variant has been linked to poorer prognosis and worse outcome in AML patients. Somatic 2015-08-05 18:23:35 UTC https://civicdb.org/links/evidence_items/26 https://civicdb.org/links/variants/65 https://civicdb.org/links/genes/29 false NRAS 4893 Mutation Colorectal Cancer 9256 Prognostic Supports B Poor Outcome Patients with colorectal cancer harboring NRAS mutation have poorer survival outcome and worse prognosis than patients with wildtype NRAS. 24666267 PubMed Therkildsen et al., 2014, Acta Oncol 3 accepted 27 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2015-11-10 17:17:52 UTC https://civicdb.org/links/evidence_items/27 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false BRAF 673 V600 Melanoma 1909 Diagnostic Supports B Positive BRAF mutations are associated with melanoma arising in non-chronic sun damaged skin and with superficial spreading melanoma. 21166657 PubMed Lee et al., 2011, Br. J. Dermatol. 4 accepted 30 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/30 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Diagnostic Supports B Positive DNMT3A R882 mutations were associated with older age, higher white blood cell count, and FAB M4 and M5 subtypes compared to wildtype DNMT3A in a cohort of cytogenetically normal AML patients. 24512939 PubMed El Ghannam et al., Blood Cells Mol. Dis. 3 accepted 31 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/31 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false ALK 238 F1174L Inflammatory Myofibroblastic Tumor 0050905 Crizotinib Predictive Supports D Resistance Ba/F3 cells expressing the RANBP2-ALK fusion containing an F1174L mutation were more resistant to crizotinib treatment than Ba/F3 cells expressing RANBP2-ALK without this mutation. 21030459 PubMed Sasaki et al., 2010, Cancer Res. 3 accepted 32 8 1 2 29443695 29443695 G T ENST00000389048.3 75 GRCh37 ALK F1174L has been observed as recurrent in neuroblastoma, non-small cell lung cancer (NSCLC), and other cancer types. Neuroblastoma cells containing this mutation have shown resistance to low doses of criztonib. However, increased dosage can overcome this resistance in cell lines studies. TAE684 has also proven effective in both NSCLC and neuroblastoma F1174L containing cells. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/32 https://civicdb.org/links/variants/8 https://civicdb.org/links/genes/1 false ALK 238 F1174L Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports D Resistance Ba/F3 cells expressing the EML4-ALK fusion containing an F1174L mutation were more resistant to crizotinib treatment than Ba/F3 cells expressing EML4-ALK without this mutation. 21030459 PubMed Sasaki et al., 2010, Cancer Res. 3 accepted 33 8 1 2 29443695 29443695 G T ENST00000389048.3 75 GRCh37 ALK F1174L has been observed as recurrent in neuroblastoma, non-small cell lung cancer (NSCLC), and other cancer types. Neuroblastoma cells containing this mutation have shown resistance to low doses of criztonib. However, increased dosage can overcome this resistance in cell lines studies. TAE684 has also proven effective in both NSCLC and neuroblastoma F1174L containing cells. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/33 https://civicdb.org/links/variants/8 https://civicdb.org/links/genes/1 false KIT 3815 L576P Melanoma 1909 Sorafenib,Imatinib,Nilotinib Substitutes Predictive Supports D Resistance The melanoma cell line WM3211, which harbors the L576P mutation, is not sensitive to imatinib, nilotinib, and sorafenib. Molecular modeling indicated the L576P mutation alters the conformation of KIT and reduces the binding affinity of imatinib. 19671763 PubMed Woodman et al., 2009, Mol. Cancer Ther. 3 accepted 34 72 29 4 55593661 55593661 T C ENST00000288135.5 75 GRCh37 KIT L576P is an exon 11 mutation that lies within the juxtamembrane domain. It is one of the most recurrent KIT mutations in melanoma, and both in vitro and in vivo studies have shown sensitivity to imatinib. Somatic 2017-05-31 00:09:59 UTC https://civicdb.org/links/evidence_items/34 https://civicdb.org/links/variants/72 https://civicdb.org/links/genes/29 false KRAS 3845 G12/G13 Lung Non-small Cell Carcinoma 3908 Gefitinib,Erlotinib Substitutes Predictive Supports B Resistance In 60 patients with NSCLC, Exon 2 KRAS mutations were associated with resistance to the EGFR kinase inhibitors gefitinib or erlotinib (9/38 refractory vs 0/21 sensitive patients; P=0.0201). 15696205 PubMed Pao et al., 2005, PLoS Med. 3 accepted 35 77 30 12 25398280 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2018-07-25 16:35:49 UTC https://civicdb.org/links/evidence_items/35 https://civicdb.org/links/variants/77 https://civicdb.org/links/genes/30 false NRAS 4893 Q61 Colorectal Cancer 9256 Cetuximab,Chemotherapy Combination Predictive Supports B Resistance Chemotherapy-refractory patients with KRAS wt metastatic colorectal cancer harboring NRAS mutation (primarily Q61, n=10) have a significantly lower response rate to cetuximab than patients wildtype for NRAS (7.1% [1/14] vs 38.1% [110/289]). 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 2 accepted 36 94 36 1 115256528 115256530 ENST00000369535.4 75 GRCh37 NRAS Q61 mutations have been found in multiple myeloma, gastrointestinal stromal tumors, melanoma, and others. Two melanoma patients, each harboring mutations at this locus (Q61L and Q61R), responded to treatment with the akylating agent temozolomide. However, in colorectal cancer patients, mutations at this locus have been shown to confer resistance to cetuximab. The prognostic impact of mutations at this locus is currently under study. Somatic 2020-11-25 00:10:58 UTC https://civicdb.org/links/evidence_items/36 https://civicdb.org/links/variants/94 https://civicdb.org/links/genes/36 false ALK 238 F1174L Neuroblastoma 769 Alectinib Predictive Supports D Sensitivity/Response CH5424802 (Alectinib) is effective in inhibiting the activity of the F1174L ALK mutant in a kinase activity assay and proliferation assay using neuroblastoma KELLY cells. 21575866 PubMed Sakamoto et al., 2011, Cancer Cell 3 accepted 37 8 1 2 29443695 29443695 G T ENST00000389048.3 75 GRCh37 ALK F1174L has been observed as recurrent in neuroblastoma, non-small cell lung cancer (NSCLC), and other cancer types. Neuroblastoma cells containing this mutation have shown resistance to low doses of criztonib. However, increased dosage can overcome this resistance in cell lines studies. TAE684 has also proven effective in both NSCLC and neuroblastoma F1174L containing cells. Somatic 2019-08-29 22:04:09 UTC https://civicdb.org/links/evidence_items/37 https://civicdb.org/links/variants/8 https://civicdb.org/links/genes/1 false ALK 238 F1174L Neuroblastoma 769 Crizotinib Predictive Supports D Sensitivity/Response High levels of crizotinib can overcome drug resistance of Ba/F3 cells expressing the EML4-ALK fusion containing the F1174L mutation. 21948233 PubMed Heuckmann et al., 2011, Clin. Cancer Res. 3 accepted 38 8 1 2 29443695 29443695 G T ENST00000389048.3 75 GRCh37 ALK F1174L has been observed as recurrent in neuroblastoma, non-small cell lung cancer (NSCLC), and other cancer types. Neuroblastoma cells containing this mutation have shown resistance to low doses of criztonib. However, increased dosage can overcome this resistance in cell lines studies. TAE684 has also proven effective in both NSCLC and neuroblastoma F1174L containing cells. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/38 https://civicdb.org/links/variants/8 https://civicdb.org/links/genes/1 false ALK 238 R1275Q Neuroblastoma 769 TAE684 Predictive Supports D Sensitivity/Response TAE684 inhibits growth of Ba/F3 cells expressing ALK mutations; however, cells with the R1275Q mutation were inhibited at a higher IC50 than those expressing F1174L. 18923525 PubMed George et al., 2008, Nature 3 accepted 39 9 1 2 29432664 29432664 C T ENST00000389048.3 75 GRCh37 ALK R1275Q has been observed as a recurrent mutation in neuroblastoma, non-small cell lung cancer (NSCLC), as well as other cancer types. Neuroblastoma cells with this mutation have shown sensitivity to the ALK-inhibitor TAE684. This and the geldanamycin deriviative 17-DMAG have been shown to be effective in NSCLC cell lines. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/39 https://civicdb.org/links/variants/9 https://civicdb.org/links/genes/1 false ARAF 369 S214C Lung Non-small Cell Carcinoma 3908 Sorafenib Predictive Supports D Sensitivity/Response Sorafenib can inhibit ARF-mediated MEK phosphorylation and soft agar colony formation of AALE cells expressing ARAF S214C in vitro. 24569458 PubMed Imielinski et al., 2014, J. Clin. Invest. 3 accepted 40 10 3 X 47426121 47426121 C G ENST00000377045.4 75 GRCh37 ARAF S214C has been found to be a recurrent oncogenic mutation in non-small cell lung cancer. It has been shown to confer sensitivity to sorafenib and trametenib in cell lines. In a case study of advanced stage lung adenocarcinoma harboring this mutation, sorafenib also acheived near-complete clinical remission. This case has brought more interest to the variant from a research and clinical perspective. Somatic 2019-02-22 15:00:56 UTC https://civicdb.org/links/evidence_items/40 https://civicdb.org/links/variants/10 https://civicdb.org/links/genes/3 false ARAF 369 S214C Lung Non-small Cell Carcinoma 3908 Trametinib Predictive Supports D Sensitivity/Response Trametinib can inhibit ARF-mediated ERK phosphorylation and soft agar colony formation of AALE cells expressing ARAF S214C in vitro. 24569458 PubMed Imielinski et al., 2014, J. Clin. Invest. 3 accepted 41 10 3 X 47426121 47426121 C G ENST00000377045.4 75 GRCh37 ARAF S214C has been found to be a recurrent oncogenic mutation in non-small cell lung cancer. It has been shown to confer sensitivity to sorafenib and trametenib in cell lines. In a case study of advanced stage lung adenocarcinoma harboring this mutation, sorafenib also acheived near-complete clinical remission. This case has brought more interest to the variant from a research and clinical perspective. Somatic 2019-02-22 15:01:05 UTC https://civicdb.org/links/evidence_items/41 https://civicdb.org/links/variants/10 https://civicdb.org/links/genes/3 false KIT 3815 L576P Melanoma 1909 Dasatinib Predictive Supports D Sensitivity/Response The melanoma cell line WM3211, which harbors the L576P mutation, is sensitive to dasatinib. Molecular modeling indicated the L576P mutation alters the conformation of KIT but did not alter the binding affinity of dasatinib. 19671763 PubMed Woodman et al., 2009, Mol. Cancer Ther. 3 accepted 42 72 29 4 55593661 55593661 T C ENST00000288135.5 75 GRCh37 KIT L576P is an exon 11 mutation that lies within the juxtamembrane domain. It is one of the most recurrent KIT mutations in melanoma, and both in vitro and in vivo studies have shown sensitivity to imatinib. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/42 https://civicdb.org/links/variants/72 https://civicdb.org/links/genes/29 false PDGFRA 5156 D842I Gastrointestinal Stromal Tumor 9253 Crenolanib Predictive Supports D Sensitivity/Response In CHO cells with PDGFRA D842I mutation that have shown imatinib resistance, crenolanib was significantly more potent at inhibiting kinase activity than imatinib. 22745105 PubMed Heinrich et al., 2012, Clin. Cancer Res. 4 accepted 43 98 38 4 55152092 55152093 GA AT ENST00000257290.5 75 GRCh37 PDGFRA D842 mutations are characterized broadly as imatinib resistance mutations. This is most well characterized in gastrointestinal stromal tumors, but other cell lines containing these mutations have been shown to be resistant as well. In imatinib resistant cell lines, a number of other therapeutics have demonstrated efficacy. These include; crenolanib, sirolimus, and midostaurin (PKC412). Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/43 https://civicdb.org/links/variants/98 https://civicdb.org/links/genes/38 false PDGFRA 5156 D842V Gastrointestinal Stromal Tumor 9253 Crenolanib Predictive Supports D Sensitivity/Response In CHO cells with PDGFRA D842V mutation that have shown imatinib resistance, crenolanib was significantly more potent at inhibiting kinase activity than imatinib. 22745105 PubMed Heinrich et al., 2012, Clin. Cancer Res. 4 accepted 44 99 38 4 55152093 55152093 A T ENST00000257290.5 75 GRCh37 PDGFRA D842 mutations are characterized broadly as imatinib resistance mutations. This is most well characterized in gastrointestinal stromal tumors, but other cell lines containing these mutations have been shown to be resistant as well. Exogenous expression of the A842V mutation resulted in constitutive tyrosine phosphorylation of PDGFRA in the absence of ligand in 293T cells and cytokine-independent proliferation of the IL-3-dependent Ba/F3 cell line, both evidence that this is an activating mutation. In imatinib resistant cell lines, a number of other therapeutics have demonstrated efficacy. These include; crenolanib, sirolimus, and midostaurin (PKC412). Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/44 https://civicdb.org/links/variants/99 https://civicdb.org/links/genes/38 false PDGFRA 5156 D842Y Gastrointestinal Stromal Tumor 9253 Crenolanib Predictive Supports D Sensitivity/Response In CHO cells with PDGFRA D842Y mutation that have shown imatinib resistance, crenolanib was significantly more potent at inhibiting kinase activity than imatinib. 22745105 PubMed Heinrich et al., 2012, Clin. Cancer Res. 4 accepted 45 100 38 4 55152092 55152092 G T ENST00000257290.5 75 GRCh37 PDGFRA D842 mutations are characterized broadly as imatinib resistance mutations. This is most well characterized in gastrointestinal stromal tumors, but other cell lines containing these mutations have been shown to be resistant as well. In imatinib resistant cell lines, a number of other therapeutics have demonstrated efficacy. These include; crenolanib, sirolimus, and midostaurin (PKC412). Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/45 https://civicdb.org/links/variants/100 https://civicdb.org/links/genes/38 false PDGFRA 5156 I843DEL Gastrointestinal Stromal Tumor 9253 Crenolanib Predictive Supports D Sensitivity/Response In CHO cells with the PDGFRA deletion I843 mutation that have shown imatinib sensitivity, crenolanib showed no significant difference from imatinib in kinase activity inhibition. 22745105 PubMed Heinrich et al., 2012, Clin. Cancer Res. 3 accepted 46 101 38 4 55152095 55152097 ATC ENST00000257290.5 75 GRCh37 PDGFRA D842 mutations are characterized broadly as imatinib resistance mutations. This is most well characterized in gastrointestinal stromal tumors, but other cell lines containing these mutations have been shown to be resistant as well. In imatinib resistant cell lines, a number of other therapeutics have demonstrated efficacy. These include; crenolanib, sirolimus, and midostaurin (PKC412). Somatic 2016-11-04 16:27:48 UTC https://civicdb.org/links/evidence_items/46 https://civicdb.org/links/variants/101 https://civicdb.org/links/genes/38 false PDGFRA 5156 D842_I843delinsVM Gastrointestinal Stromal Tumor 9253 Crenolanib Predictive Supports D Sensitivity/Response In CHO cells with PDGFRA DI842-843VM mutation that have shown imatinib resistance, crenolanib was significantly more potent at inhibiting kinase activity than imatinib. 22745105 PubMed Heinrich et al., 2012, Clin. Cancer Res. 4 accepted 47 102 38 4 55152093 55152097 ACATC TCATG ENST00000257290.5 75 GRCh37 PDGFRA D842 mutations are characterized broadly as imatinib resistance mutations. The DI842-843VM variant is the result of a double point mutation. This is most well characterized in gastrointestinal stromal tumors, but other cell lines containing these mutations have been shown to be resistant as well. In imatinib resistant cell lines, a number of other therapeutics have demonstrated efficacy. These include; crenolanib, sirolimus, and midostaurin (PKC412). Somatic 2016-02-18 18:22:03 UTC https://civicdb.org/links/evidence_items/47 https://civicdb.org/links/variants/102 https://civicdb.org/links/genes/38 false ALK 238 R1275Q Neuroblastoma 769 TAE684 Predictive Supports D Resistance The SMS-KCNR cell line harboring the R1275Q mutation was resistant to TAE684. 18923525 PubMed George et al., 2008, Nature 3 accepted 48 9 1 2 29432664 29432664 C T ENST00000389048.3 75 GRCh37 ALK R1275Q has been observed as a recurrent mutation in neuroblastoma, non-small cell lung cancer (NSCLC), as well as other cancer types. Neuroblastoma cells with this mutation have shown sensitivity to the ALK-inhibitor TAE684. This and the geldanamycin deriviative 17-DMAG have been shown to be effective in NSCLC cell lines. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/48 https://civicdb.org/links/variants/9 https://civicdb.org/links/genes/1 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A In a large cohort of AML patients (mean = 48 years), DNMT3A mutation (64.5% of which were R882) had no prognostic value on overall, relapse free and event free survival. 23632886 PubMed Gaidzik et al., 2013, Blood 3 accepted 49 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2015-06-21 16:49:40 UTC https://civicdb.org/links/evidence_items/49 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Does Not Support B Poor Outcome In a large cohort (n=1770) of AML patients (18-60 years old), DNMT3A mutation status (65.4% of which were R882) had no prognostic value for overall, relapse free and event free survival. This was true for cytogenetically normal AML and the entire cohort. 23632886 PubMed Gaidzik et al., 2013, Blood 3 accepted 50 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2016-02-12 23:17:24 UTC https://civicdb.org/links/evidence_items/50 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A In young AML patients (<60 years old), DNMT3A mutation status (60% of which were R882) was not predictive of overall and relapse free survival in patients with NPM1 mutations and wildtype FLT3 or wildtype NPM1 and FLT3-ITD. 22490330 PubMed Ribeiro et al., 2012, Blood 4 accepted 51 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/51 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A In young AML patients (<60 years old), DNMT3A mutation status was not predictive of overall and relapse free survival in patients with NPM1 mutations and wildtype FLT3 or wildtype NPM1 and FLT3-ITD. 22490330 PubMed Ribeiro et al., 2012, Blood 4 accepted 52 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/52 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false KIT 3815 Exon 11 Mutation Gastrointestinal Stromal Tumor 9253 Prognostic Does Not Support B N/A There is no significant association between wildtype KIT or KIT mutations in exon 9 or 11 in survival among GIST patients. 16551858 PubMed Wardelmann et al., 2006, Clin. Cancer Res. 3 accepted 53 66 29 4 55593582 55593708 ENST00000288135.5 75 GRCh37 c-KIT mutations in exon 11 lie within the juxtamembrane domain, and are very recurrent in gastrointestinal stromal tumors, often bearing a poorer prognosis than other KIT mutations. Cells harboring exon 11 mutations have shown sensitivity to the tyrosine kinase inhibitor imatinib, offering a better prognosis to patients treated with the drug in the first year. Small cohorts of melanoma patients harboring exon 11 KIT mutations have shown response to imatinib and sunitinib. Somatic 2015-08-05 18:28:35 UTC https://civicdb.org/links/evidence_items/53 https://civicdb.org/links/variants/66 https://civicdb.org/links/genes/29 false NRAS 4893 Mutation Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A The presence of NRAS mutation in AML patients does not impact diease prognosis (resistant disease, disease-free survival, complete remission rate, relapse rate, induction death). 15951308 PubMed Bowen et al., 2005, Blood 3 accepted 56 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2016-06-21 19:06:50 UTC https://civicdb.org/links/evidence_items/56 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false NRAS 4893 G12 Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A NRAS mutation status does not impact overall, event-free or disease-free survival in patients with AML. 16434492 PubMed Bacher et al., 2006, Blood 3 accepted 57 92 36 1 115258747 115258748 ENST00000369535.4 75 GRCh37 While the NRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/57 https://civicdb.org/links/variants/92 https://civicdb.org/links/genes/36 false KIT 3815 Exon 11 Mutation Melanoma 1909 Imatinib Predictive Supports B Sensitivity/Response Melanoma patients with KIT mutation but not KIT amplification showed response to imatinib treatment in a small cohort of patients. 23775962 PubMed Hodi et al., 2013, J. Clin. Oncol. NCT00424515 3 accepted 58 66 29 4 55593582 55593708 ENST00000288135.5 75 GRCh37 c-KIT mutations in exon 11 lie within the juxtamembrane domain, and are very recurrent in gastrointestinal stromal tumors, often bearing a poorer prognosis than other KIT mutations. Cells harboring exon 11 mutations have shown sensitivity to the tyrosine kinase inhibitor imatinib, offering a better prognosis to patients treated with the drug in the first year. Small cohorts of melanoma patients harboring exon 11 KIT mutations have shown response to imatinib and sunitinib. Somatic 2016-10-02 15:11:12 UTC https://civicdb.org/links/evidence_items/58 https://civicdb.org/links/variants/66 https://civicdb.org/links/genes/29 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In a large cohort of young AML patients (18-60 years old), DNMT3A R882 mutations were associated with reduced relapse free survival in the entire cohort as well as the subset of patients with cytogenetically normal AML. 23632886 PubMed Gaidzik et al., 2013, Blood 3 accepted 61 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2021-02-24 19:52:43 UTC https://civicdb.org/links/evidence_items/61 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome AML patients with DNMT3A mutations (59% of which were R882) showed worse survival (event-free and overall) outcome than those without DNMT3A mutation. 21067377 PubMed Ley et al., 2010, N. Engl. J. Med. 5 accepted 62 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2015-06-21 16:49:41 UTC https://civicdb.org/links/evidence_items/62 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome DNMT3A R882 mutation was associated with reduced relapse free and overall survival in ELN-unfavorable, cytogenetically normal AMLs. 23632886 PubMed Gaidzik et al., 2013, Blood 3 accepted 63 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/63 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In AML patients with FLT3-ITD mutations, concurrent DNMT3A mutations (including R882) were associated with worse overall survival compared to those without DNMT3A mutation. 21067377 PubMed Ley et al., 2010, N. Engl. J. Med. 5 accepted 64 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2015-06-21 16:49:41 UTC https://civicdb.org/links/evidence_items/64 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In cytogenetically normal AML patients, DNMT3A R882 mutations are associated with lower overall and disease free survival as compared to patients with wild type DNMT3A. 24512939 PubMed El Ghannam et al., Blood Cells Mol. Dis. 5 accepted 65 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2015-06-21 16:49:41 UTC https://civicdb.org/links/evidence_items/65 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In older cytogenetically normal AML patients (>59 years), DNMT3A R882 mutation is prognostic for shorter disease free survival and overall survival compared to patients without the mutation. 22291079 PubMed Marcucci et al., 2012, J. Clin. Oncol. 4 accepted 66 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2015-06-21 16:49:41 UTC https://civicdb.org/links/evidence_items/66 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In young AML patients (<60 years old), DNMT3A mutations were associated with significantly reduced overall survival and relapse free survival in patients wildtype for NPM1 and FLT3. 22490330 PubMed Ribeiro et al., 2012, Blood 4 accepted 67 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/67 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In younger cytogenetically normal AML patients (<60 years), DNMT3A mutations other than R882 are prognostic for shorter disease free survival and overall survival compared to patients without the mutation. 22291079 PubMed Marcucci et al., 2012, J. Clin. Oncol. 4 accepted 68 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2015-06-21 16:49:41 UTC https://civicdb.org/links/evidence_items/68 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In AML patients with FLT3-ITD mutations, concurrent DNMT3A mutations were associated with worse overall survival compared to those without DNMT3A mutation. 21067377 PubMed Ley et al., 2010, N. Engl. J. Med. 5 accepted 69 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2015-06-21 16:49:41 UTC https://civicdb.org/links/evidence_items/69 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false KIT 3815 Exon 14 Mutation Gastrointestinal Stromal Tumor 9253 Prognostic Supports B Poor Outcome GIST patients with exon 14 KIT mutations had reduced overall survival compared to patients wiltype for KIT. 16551858 PubMed Wardelmann et al., 2006, Clin. Cancer Res. 3 accepted 70 69 29 4 55595501 55595651 ENST00000288135.5 75 GRCh37 c-KIT exon 14 mutations lie within the tyrosine kinase domain of the protein. While relatively rare in primary gastrointestinal tumors, they are notably more prevalent in refractory disease, suggesting a role in imatinib resistance. Unlike mutations in other KIT exons, exon 14 mutations seem relatively rare in melanoma. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/70 https://civicdb.org/links/variants/69 https://civicdb.org/links/genes/29 false NRAS 4893 Mutation Melanoma 1909 Prognostic Supports B Poor Outcome In patients with stage IV melanoma, NRAS mutation was associated with reduced median survival compared to patients with wildtype NRAS. 22180178 PubMed Jakob et al., 2012, Cancer 3 accepted 71 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2016-06-21 19:08:26 UTC https://civicdb.org/links/evidence_items/71 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false BRAF 673 V600E and V600M Melanoma 1909 Dabrafenib Predictive Supports C Sensitivity/Response A single 66-year old male patient with advanced melanoma thought to have concomitant BRAF V600E and V600M mutations responded rapidly to dabrafenib. His shoulder lesion reduced by 60% after 1 week of therapy and was gone after 1 month. 23031422 PubMed Ponti et al., 2012, J Hematol Oncol 1 accepted 73 13 5 7 140453135 140453137 ENST00000288602.6 75 GRCh37 A case study of a single patient harboring both a V600E and a V600M mutation, dabrafenib was shown to acheive clinical response. Somatic 2021-04-14 17:31:44 UTC https://civicdb.org/links/evidence_items/73 https://civicdb.org/links/variants/13 https://civicdb.org/links/genes/5 false RET 5979 M918T Thyroid Gland Medullary Carcinoma 3973 Diagnostic Supports B Positive In patients with medullary carcinoma, the presence of RET M918T mutation is associated with increased probability of lymph node metastases. 18073307 PubMed Elisei et al., 2008, J. Clin. Endocrinol. Metab. 5 accepted 74 113 42 10 43617416 43617416 T C ENST00000355710.3 75 GRCh37 RET M819T is the most common somatically acquired mutation in medullary thyroid cancer (MTC). While there currently are no RET-specific inhibiting agents, promiscuous kinase inhibitors have seen some success in treating RET overactivity. Data suggests however, that the M918T mutation may lead to drug resistance, especially against the VEGFR-inhibitor motesanib. It has also been suggested that RET M819T leads to more aggressive MTC with a poorer prognosis. Somatic 2019-02-22 15:10:22 UTC https://civicdb.org/links/evidence_items/74 https://civicdb.org/links/variants/113 https://civicdb.org/links/genes/42 false RET 5979 C634W Thyroid Gland Medullary Carcinoma 3973 Motesanib Predictive Supports D Resistance Medullary thyroid cancer cells with RET C634W mutation are insensitive to motesanib, compared to wild-type RET. 21422803 PubMed Coxon et al., 2012, J. Endocrinol. Invest. 3 accepted 75 112 42 10 43609950 43609950 C G ENST00000355710.3 75 GRCh37 RET C634W has been implicated as an alternate mechanism of activating RET in medullary thyroid cancer. While there currently are no RET-specific inhibiting agents, promiscuous kinase inhibitors have seen some success in treating RET overactivity. Data suggests however, that the C634W mutation may lead to drug resistance, especially against the VEGFR-inhibitor motesanib. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/75 https://civicdb.org/links/variants/112 https://civicdb.org/links/genes/42 false RET 5979 M918T Thyroid Gland Medullary Carcinoma 3973 Motesanib Predictive Supports D Resistance Medullary thyroid cancer cells with RET M918T mutation are insensitive to motesanib, compared to wild-type RET. 21422803 PubMed Coxon et al., 2012, J. Endocrinol. Invest. 3 accepted 76 113 42 10 43617416 43617416 T C ENST00000355710.3 75 GRCh37 RET M819T is the most common somatically acquired mutation in medullary thyroid cancer (MTC). While there currently are no RET-specific inhibiting agents, promiscuous kinase inhibitors have seen some success in treating RET overactivity. Data suggests however, that the M918T mutation may lead to drug resistance, especially against the VEGFR-inhibitor motesanib. It has also been suggested that RET M819T leads to more aggressive MTC with a poorer prognosis. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/76 https://civicdb.org/links/variants/113 https://civicdb.org/links/genes/42 false RET 5979 M918T Thyroid Gland Medullary Carcinoma 3973 JAK2 Inhibitor AZD1480 Predictive Supports D Sensitivity/Response The use of AZD1480 on RET-mutated/rearranged cell lines in vitro led to strong repression of tyroid cancer cell growth. 23056499 PubMed Couto et al., 2012, PLoS ONE 3 accepted 77 113 42 10 43617416 43617416 T C ENST00000355710.3 75 GRCh37 RET M819T is the most common somatically acquired mutation in medullary thyroid cancer (MTC). While there currently are no RET-specific inhibiting agents, promiscuous kinase inhibitors have seen some success in treating RET overactivity. Data suggests however, that the M918T mutation may lead to drug resistance, especially against the VEGFR-inhibitor motesanib. It has also been suggested that RET M819T leads to more aggressive MTC with a poorer prognosis. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/77 https://civicdb.org/links/variants/113 https://civicdb.org/links/genes/42 false RET 5979 M918T Thyroid Gland Medullary Carcinoma 3973 Prognostic Supports B Poor Outcome Compared to those who harbor a wild type RET, patients with RET M918T mutation develop larger and more aggressive medullary thyroid cancer. 9839497 PubMed Egawa et al., 1998, Jpn. J. Clin. Oncol. 4 accepted 78 113 42 10 43617416 43617416 T C ENST00000355710.3 75 GRCh37 RET M819T is the most common somatically acquired mutation in medullary thyroid cancer (MTC). While there currently are no RET-specific inhibiting agents, promiscuous kinase inhibitors have seen some success in treating RET overactivity. Data suggests however, that the M918T mutation may lead to drug resistance, especially against the VEGFR-inhibitor motesanib. It has also been suggested that RET M819T leads to more aggressive MTC with a poorer prognosis. Somatic 2015-06-21 16:49:42 UTC https://civicdb.org/links/evidence_items/78 https://civicdb.org/links/variants/113 https://civicdb.org/links/genes/42 false BRAF 673 V600E Thyroid Gland Cancer 1781 Diagnostic Supports B Positive BRAF V600E is shown to be associated with the tall-cell variant of papillary thyroid cancer. 21594703 PubMed Howell et al., 2011, Ann. Surg. Oncol. 3 accepted 79 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/79 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Thyroid Gland Papillary Carcinoma 3969 Diagnostic Supports B Positive Thyroid nodule with BRAF V600E mutation is highly correlated with papillary thyroid cancer. 24570209 PubMed Crescenzi et al., 2014, Horm. Metab. Res. 5 accepted 80 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-10-24 15:29:05 UTC https://civicdb.org/links/evidence_items/80 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Melanoma 1909 Prognostic Does Not Support B Poor Outcome BRAF status does not predict outcome in patients treated with dacarbazine or temozolomide. 24586605 PubMed Meckbach et al., 2014, PLoS ONE 2 accepted 82 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2019-03-22 01:52:45 UTC https://civicdb.org/links/evidence_items/82 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false PIK3CA 5290 E542K Colorectal Cancer 9256 Regorafenib Predictive Does Not Support B Resistance This was a retrospective analysis of genetic markers in 503 metastatic colorectal cancer patients who participated in the CORRECT phase III trial of regorafenib. PIK3CA mutations were identified in the tumors of 84 patients, including 27 with PIK3CA E542K. Authors found a clinical benefit of regorafenib across PIK3CA mutated and wildtype subgroups (progression free survival with regorafenib vs placebo: mutant HR: 0.54, wildtype HR: 0.50, P=0.85). Authors do not provide direct comparison between patients with wildtype and PIK3CA E542K patients. Note that it's unclear how many PIK3CA wildtype patients harbor KRAS mutations, though authors' suggest that regorafenib induces clinical benefit regardless of KRAS or PIK3CA mutation status. 26184520 PubMed Tabernero et al., 2015, Lancet Oncol NCT01103323 3 accepted 83 103 37 3 178936082 178936082 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K variants are the second most recurrent PIK3CA mutations in breast cancer and are highly recurrent mutations in many other cancer types. Colorectal cancer patients with the PIK3CA E545K variant, and possibly other variants in the E545 region, may indicate poor prognosis relative to patients with other PIK3CA variants or wild-type PIK3CA. The literature also suggests that E545/E542 variants may confer resistance to EGFR inhibitors (e.g., cetuximab). An FDA approved treatment regimen including a targeted PIK3CA inhibitor is available for specific subtypes of breast cancer. While PIK3CA variants are highly prevalent in many other cancer types, targeted therapies for PIK3CA variants are still in early clinical trial phases in other cancer types. Somatic 2021-07-26 20:05:02 UTC https://civicdb.org/links/evidence_items/83 https://civicdb.org/links/variants/103 https://civicdb.org/links/genes/37 false BRAF 673 V600E Melanoma 1909 Mirdametinib,Trametinib Substitutes Predictive Does Not Support D Resistance In the setting of BRAF(V600E), NF1 loss resulted in elevated activation of RAS-GTP but does not show resistance to MEK inhibitors. 24576830 PubMed Nissan et al., 2014, Cancer Res. 3 accepted 86 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-02-18 18:20:58 UTC https://civicdb.org/links/evidence_items/86 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false KRAS 3845 Exon 2 Mutation Colorectal Cancer 9256 Regorafenib Predictive Does Not Support B Sensitivity/Response KRAS mutation status was not predictive of response to regorafenib treatment in patients that had received standard therapy and progressed within 3 months of their last treatment. KRAS exon 2 variants (G12A, C, D, R, S, V; G13D) were sequenced, among variants in other KRAS exons. 24559322 PubMed Sartore-Bianchi et al., 2014, Expert Rev Anticancer Ther 1 accepted 87 75 30 12 25398208 25398329 ENST00000256078.4 75 GRCh37 Exon 2 mutations have been associated with reduced response rates or resistance to EGFR inhibitors in non-small cell lung and colorectal cancer. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. Somatic 2021-04-24 00:32:35 UTC https://civicdb.org/links/evidence_items/87 https://civicdb.org/links/variants/75 https://civicdb.org/links/genes/30 false BRAF 673 V600 Colorectal Cancer 9256 Panitumumab Predictive Supports B Resistance In metastatic colorectal cancer patients with wildtype KRAS, BRAF mutations were associated with poor progression free survival regardless of treatment (panitumumab with best supportive care or best supportive care alone). 23325582 PubMed Peeters et al., 2013, Clin. Cancer Res. 3 accepted 88 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/88 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Sorafenib,Panitumumab Combination Predictive Supports D Sensitivity/Response Cetuximab or panitumumab may be ineffective in patients with BRAF mutation unless BRAF inhibitor such as Sorafenib is introduced. 19001320 PubMed Di Nicolantonio et al., 2008, J. Clin. Oncol. 3 accepted 89 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2017-09-16 01:20:46 UTC https://civicdb.org/links/evidence_items/89 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Melanoma 1909 Vemurafenib Predictive Supports D Resistance In the setting of BRAF(V600E), NF1 loss resulted in elevated activation of RAS-GTP and resistance to RAF inhibitors. 24576830 PubMed Nissan et al., 2014, Cancer Res. 3 accepted 90 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/90 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Lung Non-small Cell Carcinoma 3908 Dabrafenib Predictive Supports C Resistance In a patient with V600E-positive NSCLC, KRAS G12D seemed to confer resistance to dabrafenib. 23524406 PubMed Rudin et al., 2013, J Thorac Oncol 2 accepted 91 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/91 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E and Amplification Colorectal Cancer 9256 Selumetinib Predictive Supports E Resistance COLO201 and COLO206F cells harboring BRAF V600E mutations were cloned to be MEK inhibitor (AZD6244 [selumetinib]) resistant. The mechanism of this resistance was shown to be amplification of the BRAF V600E gene. BRAF V600E amplification was observed in 1/11 colorectal cancer patient samples evaluated, indicating this subclone (28% of cells) would be MEK inhibitor resistant. 21098728 PubMed Corcoran et al., 2010, Sci Signal 4 accepted 92 14 5 7 140434279 140624564 ENST00000288602.6 75 GRCh37 Amplification of BRAF V600E has been shown to confer resistance to MEK inhibitors. For more information on the V600 locus, see the V600E entry. Somatic 2019-06-12 12:28:56 UTC https://civicdb.org/links/evidence_items/92 https://civicdb.org/links/variants/14 https://civicdb.org/links/genes/5 false BRAF 673 V600 Melanoma 1909 Dabrafenib,Trametinib Combination Predictive Supports B Sensitivity/Response This was a Phase I and II study (NCT01072175) of dabrafenib and trametinib combination therapy vs. dabrafenib monotherapy in patients with metastatic melanoma. Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination therapy in contrast to 19% in those receiving monotherapy (P = 0.09). Of 162 patients with V600E or V600K mutation, 108 were given combination therapy and 54 monotherapy. After 1 year, 41% of patients in the combination group were alive and progression free whereas this was 9% in the monotherapy group (P<0.001). Median progression-free survival was 9.4 months with combination and 5.8 months with monotherapy. Hazard ratio for progression or death was 0.39 (95% CI, 0.25 to 0.62; P<0.001). 23020132 PubMed Flaherty et al., 2012, N. Engl. J. Med. NCT01072175 3 accepted 93 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2018-11-08 17:21:37 UTC https://civicdb.org/links/evidence_items/93 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false BRAF 673 V600D Melanoma 1909 Dabrafenib Predictive Supports B Sensitivity/Response Patients with other BRAF V600 mutations also respond well to the V600E drug dabrafenib. 23463675 PubMed Ponti et al., 2013, J. Clin. Pathol. 5 accepted 94 11 5 7 140453135 140453136 CA AT ENST00000288602.6 75 GRCh37 Patients harboring mutations in valine 600 residue of BRAF have been shown to be sensitive to dabrafenib. For more information on the V600 locus, see the V600E entry. Somatic 2015-06-21 16:49:42 UTC https://civicdb.org/links/evidence_items/94 https://civicdb.org/links/variants/11 https://civicdb.org/links/genes/5 false BRAF 673 V600E Melanoma 1909 Dabrafenib,Trametinib Combination Predictive Supports B Sensitivity/Response Dabrafenib with trametinib provides higher response rate and lower toxicity (as compared to chemotherapy) in patients with melanoma. 24583796 PubMed Menzies et al., 2014, Clin. Cancer Res. 5 accepted 95 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-02-18 21:13:57 UTC https://civicdb.org/links/evidence_items/95 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Pictilisib Bismesylate,PLX4720 Combination Predictive Supports D Sensitivity/Response Combined PI3K inhibitor GDC0941 and BRAF inhibitor PLX4720 administration to NSG mice subcutanousely injected with colorectal cell lines with a BRAF V600E mutation effectively inhibited tumor growth and reduced cellular proliferation. 23845441 PubMed Rad et al., 2013, Cancer Cell 3 accepted 96 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2019-08-22 21:32:55 UTC https://civicdb.org/links/evidence_items/96 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Nutlin-3,PLX4720 Combination Predictive Supports D Sensitivity/Response Combined nutlin-3 and PLX4720 administration to athymic nude mice subcutanousely injected with the A357 colorectal cell line with a BRAF V600E mutation effectively inhibited tumor growth significantly more than single agent therapy. 23812671 PubMed Ji et al., 2013, Clin. Cancer Res. 2 accepted 97 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2017-05-31 00:11:36 UTC https://civicdb.org/links/evidence_items/97 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Capecitabine,Bevacizumab,Vemurafenib Combination Predictive Supports D Sensitivity/Response This in vivo study examined the efficacy of various treatments on athymic nude mice xenografted with colorectal cancer HT29 cells, which harbor BRAF V600E. The authors sought to understand whether the addition of vemurafenib (a BRAF V600E inhibitor) to agents approved for the treatment of metastatic colorectal cancer increased therapeutic efficacy, and which combinations worked best. Capecitabine, bevacizumab and vemurafenib combination therapy resulted in 100% tumor growth inhibition (TGI) and 190% increased lifespan (ILS) compared to vehicle treated controls. Seven mice experienced partial response and two experienced complete response. Triplet therapy resulted in better TGI and ILS compared to any agent in isolation or capecitabine + vemurafenib doublet therapy (p <0.05, p <0.0001, for all comparisons). 22180495 PubMed Yang et al., 2012, Cancer Res. 3 accepted 98 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-07-09 21:26:14 UTC https://civicdb.org/links/evidence_items/98 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Vemurafenib Predictive Supports D Sensitivity/Response This preclinical study examined vemurafenib efficacy on various colorectal cancer cell lines and in mouse xenograft experiments. Of the cell lines tested, six harbored BRAF V600E (and WT KRAS) and three harbored BRAF WT (but mutant KRAS). Of the six BRAF V600E expressing cell lines, four were sensitive to vemurafenib (IC50 ranging between 0.025 and 0.35 uM; HT29, Colo205, Colo741, LS411N). Cell lines expressing the BRAF V600E mutation responded better to vemurafenib treatment than cells wildtype for BRAF as measured by reduced cellular proliferation and inhibition of MET and ERK phosphorylation (none of the three BRAF wt cell lines had IC50s less than 10uM). Authors note that one of the vemurafenib-resistant cell lines harboring BRAF V600E (RKO) harbored a concurrent activating PIK3CA H1047R mutation. Nude, athymic mice with HT29 xenografts treated with vemurafenib experienced substantial tumor inhibition and increased lifespan at every dose tested, though authors found 75 mg/kg twice daily to be optimal (95% tumor growth inhibition, 90% increased lifespan compared to vehicle treated controls). 22180495 PubMed Yang et al., 2012, Cancer Res. 2 accepted 99 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-06-18 21:56:48 UTC https://civicdb.org/links/evidence_items/99 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Thyroid Gland Papillary Carcinoma 3969 Prognostic Does Not Support B Poor Outcome Unlike other studies that suggest a poorer outcome, BRAF mutation in this study was not correlated with poorer prognosis in papillary thyroid cancer. 24354346 PubMed Walczyk et al., 2014, Clin. Endocrinol. (Oxf) 5 accepted 102 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-10-24 15:28:30 UTC https://civicdb.org/links/evidence_items/102 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Prognostic Supports B Poor Outcome V600E is associated with adverse pathological features of colorectal cancer. This can be concluded as a marker of poor prognosis. 24594804 PubMed Chen et al., 2014, PLoS ONE 5 accepted 103 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-07-17 22:57:55 UTC https://civicdb.org/links/evidence_items/103 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Melanoma 1909 Prognostic Supports B Poor Outcome BRAF V600E is correlated with shorter disease-free and overall Survival in a Spanish cohort of melanoma patients. 24388723 PubMed Nagore et al., 2014, J. Am. Acad. Dermatol. 3 accepted 104 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2015-06-21 16:49:43 UTC https://civicdb.org/links/evidence_items/104 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Thyroid Gland Papillary Carcinoma 3969 Prognostic Supports B Poor Outcome BRAF mutation correlated with poor prognosis in papillary thyroid cancer in both older (>65 yo) and younger (<65 yo) cohorts. 21594703 PubMed Howell et al., 2011, Ann. Surg. Oncol. 3 accepted 105 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-10-24 15:31:06 UTC https://civicdb.org/links/evidence_items/105 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Thyroid Gland Papillary Carcinoma 3969 Prognostic Supports B Poor Outcome BRAF V600E is correlated with poor prognosis in papillary thyroid cancer in a study of 187 patients with PTC and other thyroid diseases. 24396464 PubMed He et al., 2014, Oncol Lett 3 accepted 106 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-10-24 15:30:00 UTC https://civicdb.org/links/evidence_items/106 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Thyroid Gland Papillary Carcinoma 3969 Prognostic Supports B Poor Outcome V600E is correlated with disease recurrence in both age cohorts (>65 and <65 yo). 21594703 PubMed Howell et al., 2011, Ann. Surg. Oncol. 3 accepted 107 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-10-24 15:30:48 UTC https://civicdb.org/links/evidence_items/107 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Diagnostic Does Not Support B Positive NPM1 mutations were not associated with the M3 acute myeloid leukemia FAB subtype (0/55). 16455956 PubMed Thiede et al., 2006, Blood 3 accepted 108 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2015-06-21 16:49:43 UTC https://civicdb.org/links/evidence_items/108 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 W288FS Acute Myeloid Leukemia 9119 Diagnostic Does Not Support B Positive No NPM1 mutations were identified in patients with favorable risk cytogenetics (79/215 patients). 21067377 PubMed Ley et al., 2010, N. Engl. J. Med. 4 accepted 109 87 35 5 170837547 170837548 TCTG ENST00000517671.1 75 GRCh37 NPM1 W288fs (aka NPM1-A) is located in exon 12 of NPM1 and is the most common NPM1 mutation identified in acute myeloid leukemia. This mutation results in cytoplasmic localization of NPM1 (NPM1c) which is associated with a good response to induction therapy. Although it is the most extensively studied NPM1 exon 12 mutation, it is generally grouped with other exon 12 mutations for patient analysis (see NPM1 Exon 12 variants for more information). Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/109 https://civicdb.org/links/variants/87 https://civicdb.org/links/genes/35 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Diagnostic Supports B Negative Therapy-related AML was less common in patients with DNMT3A mutations (64.5% of which were R882) than patients wildtype for DNMT3A in a large cohort of younger (18-60) AML patients. 23632886 PubMed Gaidzik et al., 2013, Blood 3 accepted 110 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/110 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Diagnostic Supports B Negative NPM1 mutations were not associated with the M2 FAB subtype of acute myeloid leukemia. 16076867 PubMed Schnittger et al., 2005, Blood 4 accepted 111 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2015-06-21 16:49:43 UTC https://civicdb.org/links/evidence_items/111 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Diagnostic Supports B Positive DNMT3A mutations (59% of which were R882) were associated with an intermediate risk cytogenetic profile, normal cytogenetic profile, and M4 and M5 FAB subtypes. 21067377 PubMed Ley et al., 2010, N. Engl. J. Med. 5 accepted 112 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/112 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Diagnostic Supports B Positive DNMT3A mutations (59% of which were R882) were associated with intermediate risk cytogenetics (including normal karyotype). 21067377 PubMed Ley et al., 2010, N. Engl. J. Med. 4 accepted 113 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/113 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Diagnostic Supports B Positive DNMT3A mutations (64.5% R882) were associated with older age, higher white blood cell count and cytogenetically normal AML in a large cohort of younger (18-60) AML patients. 23632886 PubMed Gaidzik et al., 2013, Blood 3 accepted 114 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/114 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Diagnostic Supports B Positive DNMT3A R882 mutations were associated with cytogenetically normal AML in a large cohort of younger (18-60) AML patients. 23632886 PubMed Gaidzik et al., 2013, Blood 3 accepted 115 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/115 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Diagnostic Supports A Positive AML with mutated NPM1 is a provisional entity in the World Health Organization (WHO) classification of acute myeloid leukemia (AML). This mutation should be tested for in clinical trials and is recommended for testing in patients with cytogentically normal AML. 19357394 PubMed Vardiman et al., 2009, Blood 5 accepted 116 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-07-01 17:25:30 UTC https://civicdb.org/links/evidence_items/116 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Diagnostic Supports B Positive NPM1 mutations were associated with de novo AML as well as M4 and M5 FAB subtypes. 17957027 PubMed Gale et al., 2008, Blood 2 accepted 117 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/117 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Diagnostic Supports B Positive NPM1 mutations were associated with M4, M5a and M5b FAB subtypes of acute myeloid leukemia. 16076867 PubMed Schnittger et al., 2005, Blood 4 accepted 118 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2015-06-21 16:49:43 UTC https://civicdb.org/links/evidence_items/118 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Diagnostic Supports B Positive NPM1 mutations were associated with M5a and M5b FAB subtypes of acute myeloid leukemia. 16455956 PubMed Thiede et al., 2006, Blood 3 accepted 119 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/119 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Diagnostic Supports B Positive NPM1 mutations were associated with normal karyotype in older (>60) patients. 19059939 PubMed Schlenk et al., 2009, Haematologica NCT00151242 3 accepted 120 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/120 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 W288FS Acute Myeloid Leukemia 9119 Diagnostic Supports B Positive NPM1 mutations were associated with intermediate risk cytogenetics (including normal karyotype). 21067377 PubMed Ley et al., 2010, N. Engl. J. Med. 4 accepted 121 87 35 5 170837547 170837548 TCTG ENST00000517671.1 75 GRCh37 NPM1 W288fs (aka NPM1-A) is located in exon 12 of NPM1 and is the most common NPM1 mutation identified in acute myeloid leukemia. This mutation results in cytoplasmic localization of NPM1 (NPM1c) which is associated with a good response to induction therapy. Although it is the most extensively studied NPM1 exon 12 mutation, it is generally grouped with other exon 12 mutations for patient analysis (see NPM1 Exon 12 variants for more information). Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/121 https://civicdb.org/links/variants/87 https://civicdb.org/links/genes/35 false CEBPA 1050 Mutation Acute Myeloid Leukemia 9119 Tretinoin Predictive Does Not Support B Sensitivity/Response In a randomized trial of previously untreated younger (<60) patients with acute myeloid leukemia (excluding acute promyelocytic leukemia) and high-risk myelodysplastic syndrome CEBPA mutation status had no significant impact on patient response to ATRA (N=20) compared to randomized control (N=15). 19965647 PubMed Burnett et al., 2010, Blood 3 accepted 122 29 15 19 33790840 33793470 ENST00000498907.2 75 GRCh37 CEBPA mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) and a favorable prognosis. However, NPM1 and FLT3 mutations should also be assessed in CN-AML patients as concurrent mutations may have prognostic implications. Somatic 2016-02-25 20:53:44 UTC https://civicdb.org/links/evidence_items/122 https://civicdb.org/links/variants/29 https://civicdb.org/links/genes/15 false PIK3CA 5290 Exon 10 Mutation Colorectal Cancer 9256 Cetuximab,Chemotherapy Combination Predictive Does Not Support B Resistance In chemotherapy-refractory patients with metastatic colorectal cancer and KRAS wt tumors, Exon 10 PIK3CA mutations (listed as Exon 9 in the source) had no significant impact on response rate (6/21 [28.6%] vs 115/317 [36.3%]; OR: 0.70; p = 0.47), disease control rate, median progression free survival or median overall survival (46 vs 51 weeks, HR: 1.30, p=0.28) following cetuximab + chemotherapy than wildtype PIK3CA. In multivariate analysis of KRAS wildtype patients, PIK3CA was not significantly associated with patient outcome. Authors conclude that PIK3CA exon 10 mutation status does not appear relevant to treatment response. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 123 106 37 3 178935998 178936122 ENST00000263967.3 75 GRCh37 PIK3CA Exon 10 Mutations (e.g. E545K/E542K; often referred to as Exon 9 mutations if counting only coding exons) are the second most recurrent PIK3CA mutations in breast cancer, and highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that exon 10 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2020-12-02 00:31:46 UTC https://civicdb.org/links/evidence_items/123 https://civicdb.org/links/variants/106 https://civicdb.org/links/genes/37 false NRAS 4893 Q61 Colorectal Cancer 9256 Cetuximab Predictive Does Not Support B Resistance In chemotherapy-refractory patients with colorectal cancer, NRAS mutation status (primarily Q61, N=13) was not informative for disease control rate, progression free survival or overall survival following cetuximab plus chemotherapy (N=480). 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 124 94 36 1 115256528 115256530 ENST00000369535.4 75 GRCh37 NRAS Q61 mutations have been found in multiple myeloma, gastrointestinal stromal tumors, melanoma, and others. Two melanoma patients, each harboring mutations at this locus (Q61L and Q61R), responded to treatment with the akylating agent temozolomide. However, in colorectal cancer patients, mutations at this locus have been shown to confer resistance to cetuximab. The prognostic impact of mutations at this locus is currently under study. Somatic 2020-11-10 22:05:07 UTC https://civicdb.org/links/evidence_items/124 https://civicdb.org/links/variants/94 https://civicdb.org/links/genes/36 false ALK 238 F1174L Neuroblastoma 769 Crizotinib Predictive Supports D Resistance Cells lines expressing ALK harboring the F1174L mutation are less sensitive to growth inhibition by crizotinib than cells expressing the R1275Q mutation. The authors conclude that this effect should be surmountable with higher doses of crizotinib and/or with higher-affinity inhibitors. 22072639 PubMed Bresler et al., 2011, Sci Transl Med 3 accepted 125 8 1 2 29443695 29443695 G T ENST00000389048.3 75 GRCh37 ALK F1174L has been observed as recurrent in neuroblastoma, non-small cell lung cancer (NSCLC), and other cancer types. Neuroblastoma cells containing this mutation have shown resistance to low doses of criztonib. However, increased dosage can overcome this resistance in cell lines studies. TAE684 has also proven effective in both NSCLC and neuroblastoma F1174L containing cells. Somatic 2017-10-19 15:58:24 UTC https://civicdb.org/links/evidence_items/125 https://civicdb.org/links/variants/8 https://civicdb.org/links/genes/1 false BRAF 673 V600E Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance This was a retrospective study of 691 cetuximab treated patients with metastatic, chemotherapy refractory colorectal cancer. Of those, 30 patients harbored BRAF V600E, were KRAS, NRAS and PIK3CA wt, and had individual response data. One patient (who harbored BRAF V600E in low copy number) responded, 11 had stable disease, and 18 progressed. Treatments included cetuximab + irinotecan (n=20), cetuximab monotherapy (n=5), cetuximab + FOLFIRI (n=4), and cetuximab + oxaliplatin + 5FU (n=1). Median PFS was 8 weeks (2-32 weeks), median OS was 25 weeks (4-237 weeks), and median number of previous chemotherapy lines was 2 (0-4). Median age was 61 years old (42-78) and there were 16 males and 14 females. Authors concluded that BRAF mutation (23/24 of mutants were BRAF V600E) was strongly associated with poor response to cetuximab and suggested that mutation status of BRAF is more informative than those of NRAS and PIK3CA exon 20 for predicting cetuximab response (second only to KRAS). 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 126 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-11-13 22:27:02 UTC https://civicdb.org/links/evidence_items/126 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Tretinoin Predictive Supports B Resistance ATRA treatment did not effect overall survival in patients <60 years old with FLT3-ITD mutation. 19965647 PubMed Burnett et al., 2010, Blood 3 accepted 127 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2019-02-22 15:12:18 UTC https://civicdb.org/links/evidence_items/127 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome FLT3-ITD mutation without NPM1 was associated with increased relapse risk and reduced overall survival in young adult AML patients (median age 43). 17957027 PubMed Gale et al., 2008, Blood 4 accepted 128 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/128 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Increasing level of FLT3-ITD mutant correlated with reduced disease-free and overall survival as well as increased relapse rate. 17957027 PubMed Gale et al., 2008, Blood 3 accepted 129 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-03-16 22:09:25 UTC https://civicdb.org/links/evidence_items/129 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Daunorubicin Predictive Supports D Resistance Ba/F3 cells with both FLT3-ITD and TKD mutations on the same allele have more resistance to daunorubicin than cells with FLT3-ITD alone. 15626738 PubMed Bagrintseva et al., 2005, Blood 3 accepted 130 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/130 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 SU5614 Predictive Supports D Resistance Ba/F3 cells with both FLT3-ITD and TKD mutations on the same allele have more resistance to the protein tyrosine kinase (PTK) inhibitor SU5614 than cells with FLT3-ITD alone or FLT3 ITD and TKD mutations on opposing alleles. 15626738 PubMed Bagrintseva et al., 2005, Blood 3 accepted 131 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/131 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false KRAS 3845 G12/G13 Colorectal Cancer 9256 Cetuximab,Chemotherapy Combination Predictive Supports B Resistance Chemotherapy-refractory patients with metastatic colorectal cancer harboring KRAS mutations (primarily G12/G13; n=230 out of 253 total KRAS mutant patients) had lower response rates (17/253; 6.7% vs KRAS wt 126/352; 35.8%; P < .0001), disease control rates and shorter progression free and overall survival following cetuximab plus chemotherapy than those with wildtype KRAS. Authors note that these patients were treated with cetuximab prior to widespead adoption of regular KRAS mutational status screening. Patients treated with cetuximab or panitumumab monotherapy were not included. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 134 77 30 12 25398280 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2020-01-29 01:12:03 UTC https://civicdb.org/links/evidence_items/134 https://civicdb.org/links/variants/77 https://civicdb.org/links/genes/30 false KRAS 3845 G12/G13 Colorectal Cancer 9256 Cetuximab Predictive Supports D Resistance KRAS mutations were significantly associated with lack of response to cetuximab in patients with advanced colorectal cancer. 18202412 PubMed Lièvre et al., 2008, J. Clin. Oncol. 3 accepted 135 77 30 12 25398280 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/135 https://civicdb.org/links/variants/77 https://civicdb.org/links/genes/30 false KRAS 3845 G12V Colorectal Cancer 9256 Cetuximab Predictive Supports D Resistance Cells harboring KRAS G12V mutation were insensitive to cetuximab treatment in isogenic SW48 cells and in a mouse xenograft model. 20978259 PubMed De Roock et al., 2010, JAMA 4 accepted 136 425 30 12 25398284 25398284 C A ENST00000256078.4 75 GRCh37 KRAS mutations are the most common mutations in pancreatic cancer occurring in > 90% of cases. Of these the G12D activating mutation is the most prevalent and results in a loss of GTPase activity which in turn leads to a constitutively active form of KRAS. This is enough to cause pre-cancerous pancreatic intraepithelial lesions Somatic 2016-09-27 17:34:47 UTC https://civicdb.org/links/evidence_items/136 https://civicdb.org/links/variants/425 https://civicdb.org/links/genes/30 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Tretinoin Predictive Does Not Support B Sensitivity/Response ATRA treatment plus chemotherapy (daunorubicin, Ara-C, and thioguanine, N=113) did not effect overall survival in patients <60 years old with NPM1 mutation regardless of FLT3-ITD status compared to chemotherapy alone (N=94). 19965647 PubMed Burnett et al., 2010, Blood 3 accepted 137 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2022-03-04 20:25:57 UTC https://civicdb.org/links/evidence_items/137 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false PIK3CA 5290 Exon 21 Mutation Colorectal Cancer 9256 Chemotherapy,Cetuximab Combination Predictive Supports B Resistance Chemotherapy-refractory patients with metastatic colorectal cancer harboring wildtype KRAS and Exon 21 (listed as exon 20 in the source) PIK3CA mutations had lower response rates (0/9 vs 121/329; OR: 0.00; p=0.029) and disease control rates as well as shorter progression free and overall survival (median 34 vs 51 weeks; HR: 3.29, p=0.0057) following cetuximab plus chemotherapy than those with wildtype PIK3CA. In multivariate analysis of the KRAS wildtype population, significant associations between PIK3CA exon 21 mutations and poor response to cetuximab were retained. The authors concluded that PIK3CA exon 21 mutation status is more predictive of poor response to cetuximab than PIK3CA mutation status as a whole. They also recommended screening for mutations in the following gene order: KRAS, BRAF, NRAS, PIK3CA exon 21. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 138 105 37 3 178951882 178952495 ENST00000263967.3 75 GRCh37 PIK3CA Exon 21 Mutations (e.g., H1047R; often referred to as Exon 20 mutations if counting only coding exons) are among the most recurrent mutations in cancer, especially breast cancer. Of PIK3CA mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between Exon 21 and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2020-12-07 02:27:22 UTC https://civicdb.org/links/evidence_items/138 https://civicdb.org/links/variants/105 https://civicdb.org/links/genes/37 false WT1 7490 EXON 7 MUTATION Acute Myeloid Leukemia 9119 Daunorubicin,Cytarabine Combination Predictive Supports B Resistance WT1 mutations were associated with an inferior response to induction chemotherapy with a higher rate of resistant disease in young (15-60+, median 45) patients with cytogenetically normal AML. 18591546 PubMed Virappane et al., 2008, J. Clin. Oncol. 3 accepted 139 129 49 11 32417803 32417953 ENST00000332351.3 75 GRCh37 WT1 exon 7 mutations have been shown to be recurrent in acute myeloid leukemia. Many sources have examined the prognostic impact of these, agreeing that the mutant exon 7 cohort is correlated with worse overall survival and a number of poor prognistic outcomes. This may be the result of an overall poor response to chemotherapy from WT1 mutant tumors. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/139 https://civicdb.org/links/variants/129 https://civicdb.org/links/genes/49 false ALK 238 EML4::ALK L1196M Lung Non-small Cell Carcinoma 3908 Alectinib Predictive Supports D Sensitivity/Response CH5424802 treatment resulted in significant tumor regression in xenograft models produced from Ba/F3 cells expressing EML4-ALK or EML4-ALK with the L1196M mutation. 21575866 PubMed Sakamoto et al., 2011, Cancer Cell 3 accepted 141 7 1 2 29443631 29443631 G T ENST00000389048.3 75 GRCh37 In patients with non-small cell lung cancer exhibiting EML4-ALK fusion, L1196M has been shown to confer resistance to crizotinib. This was also true in a patient with both EML4-ALK C1156Y & L1196M. Somatic 2016-06-29 21:04:30 UTC https://civicdb.org/links/evidence_items/141 https://civicdb.org/links/variants/7 https://civicdb.org/links/genes/1 false ALK 238 F1174L Neuroblastoma 769 TAE684 Predictive Supports D Sensitivity/Response SH-SY5Y and Kelly cells with mutant ALK (F1174L) and Ba/F3 cells overexpressing ALK harboring the F1174L mutation are sensitive to TAE684-mediated growth inhibition. 18923525 PubMed George et al., 2008, Nature 4 accepted 142 8 1 2 29443695 29443695 G T ENST00000389048.3 75 GRCh37 ALK F1174L has been observed as recurrent in neuroblastoma, non-small cell lung cancer (NSCLC), and other cancer types. Neuroblastoma cells containing this mutation have shown resistance to low doses of criztonib. However, increased dosage can overcome this resistance in cell lines studies. TAE684 has also proven effective in both NSCLC and neuroblastoma F1174L containing cells. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/142 https://civicdb.org/links/variants/8 https://civicdb.org/links/genes/1 false ALK 238 R1275Q Neuroblastoma 769 Crizotinib Predictive Supports D Sensitivity/Response Cells lines expressing ALK harboring the F1174L mutation are less sensitive to growth inhibition by crizotinib than cells expressing the R1275Q mutation. 22072639 PubMed Bresler et al., 2011, Sci Transl Med 3 accepted 143 9 1 2 29432664 29432664 C T ENST00000389048.3 75 GRCh37 ALK R1275Q has been observed as a recurrent mutation in neuroblastoma, non-small cell lung cancer (NSCLC), as well as other cancer types. Neuroblastoma cells with this mutation have shown sensitivity to the ALK-inhibitor TAE684. This and the geldanamycin deriviative 17-DMAG have been shown to be effective in NSCLC cell lines. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/143 https://civicdb.org/links/variants/9 https://civicdb.org/links/genes/1 false FGFR3 2261 FGFR3::BAIAP2L1 Bladder Carcinoma 4007 PD173074 Predictive Supports D Sensitivity/Response Following identification of this fusion in a patient, this fusion was expressed in HEK 293T cells leading to oligomerization in the absence of ligand, induced morphologic changes in the cell and increased cellular proliferation consistent with FGFR activation. Mouse xenografts using the bladder cell line SW780 which harbors an FGFR3-BAIAP2L1 fusion showed reduced tumor burden when treated with the FGFR inhibitor PD173074. 23558953 PubMed Wu et al., 2013, Cancer Discov 3 accepted 144 53 23 4 1795039 1810599 ENST00000340107.4 7 97991744 97920963 ENST00000005260.8 75 GRCh37 In a clinical sequencing program for advanced stage cancers, Wu et al (2013, Cancer Discovery) has identified a number of FGFR fusions in patients with many different cancer types. These fusions were also found to retain oligomerization capability, and result in enhanced cell proliferation. These fusions were shown to respond to pazopanib. The authors use these cases to highlight the need for enhanced clinical sequencing efforts. Somatic 2019-02-22 15:05:44 UTC https://civicdb.org/links/evidence_items/144 https://civicdb.org/links/variants/53 https://civicdb.org/links/genes/23 false KRAS 3845 G13D Colorectal Cancer 9256 Cetuximab Predictive Supports D Sensitivity/Response Cells harboring KRAS G13D mutation were sensitive to cetuximab treatment in isogenic SW48 cells and in a mouse xenograft model. 20978259 PubMed De Roock et al., 2010, JAMA 4 accepted 145 81 30 12 25398281 25398281 C T ENST00000256078.4 75 GRCh37 While the KRAS G13 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort. This mutation, along with the mutations affecting the neighboring G12 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, results are conflicting with retrospective analyses suggesting a better response to EGFR-Inhibition. A recent prospective phase-II study (12 patients, Schirripa et. al. 2015) could not reproduce this finding and another prospective phase II trial is currently ongoing. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/145 https://civicdb.org/links/variants/81 https://civicdb.org/links/genes/30 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Tretinoin Predictive Supports B Sensitivity/Response ATRA treatment improved overall and relapse-free survival in older (>60) patients with mutant NPM1 and without FLT3-ITD. 19059939 PubMed Schlenk et al., 2009, Haematologica NCT00151242 2 accepted 146 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/146 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Daunorubicin Predictive Supports B Sensitivity/Response Young patients (18-60) with NPM1 mutations had improved overall survival following high-dose versus standard dose daunorubicin (p=0.01) in univariate analysis. However, the adjusted p-value for multiple testing is 0.11. 22417203 PubMed Patel et al., 2012, N. Engl. J. Med. 2 accepted 147 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2019-02-22 15:08:41 UTC https://civicdb.org/links/evidence_items/147 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Valproic Acid Predictive Supports B Sensitivity/Response For patients with NPM1 mutation that achieved CR following induction therapy, relapse-free survival was improved following treatment with valproic acid. 24797300 PubMed Tassara et al., 2014, Blood NCT00151255 2 accepted 148 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/148 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Tretinoin,NSC348884 Combination Predictive Supports D Sensitivity/Response NSC348884 combined with ATRA treatment induces apoptosis in primary AML cells harboring mutant NPM1 but not in cells with wildtype NPM1 or both mutant NPM1 and FLT3-ITD. 21719597 PubMed Balusu et al., 2011, Blood 3 accepted 149 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2017-05-31 15:38:16 UTC https://civicdb.org/links/evidence_items/149 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Anti-CD33,Anti-CD123 Combination Predictive Supports E Sensitivity/Response CD33 and CD123 expression was significantly increased in patients with NPM1 mutation with FLT3-ITD, indicating these patients may respond to combined anti-CD33 and anti-CD123 therapy. 24927407 PubMed Ehninger et al., 2014, Blood Cancer J 2 accepted 150 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2021-09-02 23:08:02 UTC https://civicdb.org/links/evidence_items/150 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 true NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Anti-CD33 Predictive Supports E Sensitivity/Response CD33 expression was significantly increased in patients with NPM1 mutation with or without FLT3-ITD, indicating these patients may respond to anti-CD33 therapy. 24927407 PubMed Ehninger et al., 2014, Blood Cancer J 2 accepted 151 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/151 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 W288FS Acute Myeloid Leukemia 9119 NSC348884 Predictive Supports D Sensitivity/Response NSC348884 induced apoptosis in OPI-AML3 cells harboring an NPM1 mutation. 21719597 PubMed Balusu et al., 2011, Blood 3 accepted 152 87 35 5 170837547 170837548 TCTG ENST00000517671.1 75 GRCh37 NPM1 W288fs (aka NPM1-A) is located in exon 12 of NPM1 and is the most common NPM1 mutation identified in acute myeloid leukemia. This mutation results in cytoplasmic localization of NPM1 (NPM1c) which is associated with a good response to induction therapy. Although it is the most extensively studied NPM1 exon 12 mutation, it is generally grouped with other exon 12 mutations for patient analysis (see NPM1 Exon 12 variants for more information). Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/152 https://civicdb.org/links/variants/87 https://civicdb.org/links/genes/35 false NPM1 4869 W288FS Acute Myeloid Leukemia 9119 Cytarabine,Daunorubicin,Etoposide Combination Predictive Supports E Sensitivity/Response NPM1 mutation (Type A, W288fs) causes cytoplasmic localization of NPM when transfected into a non-hematopoietic cell line (293T cells). Cytoplasmic localization of NPM in AML patients was associated with good response to induction therapy. 15659725 PubMed Falini et al., 2005, N. Engl. J. Med. 3 accepted 153 87 35 5 170837547 170837548 TCTG ENST00000517671.1 75 GRCh37 NPM1 W288fs (aka NPM1-A) is located in exon 12 of NPM1 and is the most common NPM1 mutation identified in acute myeloid leukemia. This mutation results in cytoplasmic localization of NPM1 (NPM1c) which is associated with a good response to induction therapy. Although it is the most extensively studied NPM1 exon 12 mutation, it is generally grouped with other exon 12 mutations for patient analysis (see NPM1 Exon 12 variants for more information). Somatic 2021-06-08 01:27:33 UTC https://civicdb.org/links/evidence_items/153 https://civicdb.org/links/variants/87 https://civicdb.org/links/genes/35 false TSC1 7248 Frameshift Truncation Lung Non-small Cell Carcinoma 3908 Sirolimus Predictive Supports D Sensitivity/Response Following rapamycin treatment of mice with KrasG12D-induced lung tumors, mice with Tsc1 deletion (exon17/18 deletion resulting in frameshift) in the lung exhibit increased overall survival, increased apoptosis, reduced proliferation and reduced tumor burden compared to Tsc1 wildtype mice. 19966866 PubMed Liang et al., 2010, Oncogene 3 accepted 154 124 46 9 135766735 135820008 ENST00000298552.3 75 GRCh37 In a small cohort study of bladder cancer, patients with TSC1 mutations showed better responses to and increased treatment duration tolerance with the mTOR inhibitor everolimus. Additionally, patient-derived bladder cancer cell lines with TSC1 or TSC2 mutations are much more sensitive to everolimus treatment than TSC1/TSC2 wildtype cells. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/154 https://civicdb.org/links/variants/124 https://civicdb.org/links/genes/46 false TSC1 7248 Loss-of-function Bladder Carcinoma 4007 Everolimus Predictive Supports B Sensitivity/Response Tumors expressing TSC1 or TSC2 mutations show notably more sensitivity to everolimus than their wild-type counterparts. 22923433 PubMed Iyer et al., 2012, Science NCT00805129 3 accepted 155 125 46 9 135766735 135820008 ENST00000298552.3 75 GRCh37 In a small cohort study of bladder cancer, patients with TSC1 mutations showed better responses to and increased treatment duration tolerance with the mTOR inhibitor everolimus. Additionally, patient-derived bladder cancer cell lines with TSC1 or TSC2 mutations are much more sensitive to everolimus treatment than TSC1/TSC2 wildtype cells. Somatic 2015-06-21 16:49:45 UTC https://civicdb.org/links/evidence_items/155 https://civicdb.org/links/variants/125 https://civicdb.org/links/genes/46 false FLT3 2322 Mutation Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A FLT3 mutations did not alter overall survival or remission duration in younger (16-60), cytogenetically normal AML patients with CEBPA mutations. 10/36 patients with CEBPA mutations also had FLT3 mutations (8 FLT3-ITD, 2 FLT3-D835). 14726504 PubMed Fröhling et al., 2004, J. Clin. Oncol. 2 accepted 156 519 24 13 28577411 28674729 ENST00000241453.7 75 GRCh37 Somatic 2016-04-12 22:51:01 UTC https://civicdb.org/links/evidence_items/156 https://civicdb.org/links/variants/519 https://civicdb.org/links/genes/24 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A Complete remission rates did not differ between patients with wildtype or mutant DNMT3A (62% of which affected R882) and cytogenetically normal AML. 22291079 PubMed Marcucci et al., 2012, J. Clin. Oncol. 4 accepted 157 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/157 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A FLT3-ITD duplication length did not effect prognosis in patients with an NPM1 mutation. 21537333 PubMed Schnittger et al., 2011, Leukemia 4 accepted 158 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/158 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A Size of the FLT3-ITD mutant duplication had no impact on overall survival or relapse rate. 17957027 PubMed Gale et al., 2008, Blood 2 accepted 159 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/159 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false IDH1 3417 R132 Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A Mutation status of IDH1 did not change event-free survival of patients with an NPM1 mutation. 20805365 PubMed Schnittger et al., 2010, Blood 3 accepted 160 58 26 2 209113111 209113113 ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes, IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/160 https://civicdb.org/links/variants/58 https://civicdb.org/links/genes/26 false WT1 7490 EXON 7 MUTATION Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A No differences in relapse-free or overall survival were identified between young (16-60) patients with or without WT1 mutations (69% exon 7, 15% exon 9) in cytogenetically normal AML. 19221039 PubMed Gaidzik et al., 2009, Blood 3 accepted 162 129 49 11 32417803 32417953 ENST00000332351.3 75 GRCh37 WT1 exon 7 mutations have been shown to be recurrent in acute myeloid leukemia. Many sources have examined the prognostic impact of these, agreeing that the mutant exon 7 cohort is correlated with worse overall survival and a number of poor prognistic outcomes. This may be the result of an overall poor response to chemotherapy from WT1 mutant tumors. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/162 https://civicdb.org/links/variants/129 https://civicdb.org/links/genes/49 false WT1 7490 EXON 7 MUTATION Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A Rates of complete remission and refractory disease are not different in patients with WT1 mutations (69% exon 7, 15% exon 9) than those without in young (16-60) patients with cytogenetically normal AML. 19221039 PubMed Gaidzik et al., 2009, Blood 4 accepted 163 129 49 11 32417803 32417953 ENST00000332351.3 75 GRCh37 WT1 exon 7 mutations have been shown to be recurrent in acute myeloid leukemia. Many sources have examined the prognostic impact of these, agreeing that the mutant exon 7 cohort is correlated with worse overall survival and a number of poor prognistic outcomes. This may be the result of an overall poor response to chemotherapy from WT1 mutant tumors. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/163 https://civicdb.org/links/variants/129 https://civicdb.org/links/genes/49 false WT1 7490 EXON 9 MUTATION Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A Rates of complete remission and refractory disease are not different in patients with WT1 mutations (69% exon 7, 15% exon 9) than those without in young (16-60) patients with cytogenetically normal AML. 19221039 PubMed Gaidzik et al., 2009, Blood 4 accepted 165 130 49 11 32413518 32413610 ENST00000332351.3 75 GRCh37 WT1 exon 9 mutations have been shown to be recurrent in acute myeloid leukemia, although at a less frequent rate than their exon 7 counterparts. Many sources have examined the prognostic impact of these, agreeing that the mutant exon 9 cohort is correlated with worse overall survival and a number of poor prognistic outcomes. This may be the result of an overall poor response to chemotherapy from WT1 mutant tumors. Somatic 2015-06-21 16:49:45 UTC https://civicdb.org/links/evidence_items/165 https://civicdb.org/links/variants/130 https://civicdb.org/links/genes/49 false CEBPA 1050 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome In a group of young (<60 years old) acute myeloid leukemia (exclude acute promyelocytic leukemia) and high-risk MDS patients, those with CEBPA mutations (35/423) showed marginally improved overall survival (36% vs 31%; P = .04) than those with wildtype CEBPA. 19965647 PubMed Burnett et al., 2010, Blood 3 accepted 166 29 15 19 33790840 33793470 ENST00000498907.2 75 GRCh37 CEBPA mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) and a favorable prognosis. However, NPM1 and FLT3 mutations should also be assessed in CN-AML patients as concurrent mutations may have prognostic implications. Somatic 2016-02-25 20:53:02 UTC https://civicdb.org/links/evidence_items/166 https://civicdb.org/links/variants/29 https://civicdb.org/links/genes/15 false CEBPA 1050 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome In young patients (age 16-60) with previously untreated, cytogenetically normal acute myeloid leukemia, CEBPA mutation was significantly associated with complete remission in multivariate analysis (odds ratio, 1.33; 95% confidence interval [CI], 1.01 to 1.74). Multivariate analysis was performed on all patients that were evaluated for a mutation in at least 1 gene (CEBPA, FLT3-ITD or NPM1) totaling 693/872 patients in the study. Only 509 patients in the study were evaluated for CEBPA, 67 of which had a mutation. 18450602 PubMed Schlenk et al., 2008, N. Engl. J. Med. 4 accepted 167 29 15 19 33790840 33793470 ENST00000498907.2 75 GRCh37 CEBPA mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) and a favorable prognosis. However, NPM1 and FLT3 mutations should also be assessed in CN-AML patients as concurrent mutations may have prognostic implications. Somatic 2016-02-25 20:53:53 UTC https://civicdb.org/links/evidence_items/167 https://civicdb.org/links/variants/29 https://civicdb.org/links/genes/15 false CEBPA 1050 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome Overall survival and remission duration were significantly longer (p=0.01 and p=0.05, respectively) in younger (16-60), cytogenetically normal acute myeloid leukemia patients with CEBPA mutations (21/236 patients). 14726504 PubMed Fröhling et al., 2004, J. Clin. Oncol. 3 accepted 168 29 15 19 33790840 33793470 ENST00000498907.2 75 GRCh37 CEBPA mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) and a favorable prognosis. However, NPM1 and FLT3 mutations should also be assessed in CN-AML patients as concurrent mutations may have prognostic implications. Somatic 2016-03-08 23:25:51 UTC https://civicdb.org/links/evidence_items/168 https://civicdb.org/links/variants/29 https://civicdb.org/links/genes/15 false CEBPA 1050 N-TERMINAL FRAME SHIFT Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome Remission duration was significantly longer in younger (16-60), cytogenetically normal AML patients with CEBPA 14726504 PubMed Fröhling et al., 2004, J. Clin. Oncol. 3 accepted 169 28 15 19 33792961 33793470 ENST00000498907.2 75 GRCh37 CEBPA N-terminal frame shift mutations that result in a premature stop codon are associated with cytogenetically normal acute myeloid leukemia (CN-AML). CEBPA mutations are associated with a favorable prognosis; however, NPM1 and FLT3 mutations should also be assessed in CN-AML patients as concurrent mutations may have prognostic implications. N-terminal frame shift mutations within amino acids 1-120 have been shown to disrupt expression of the full-length 42kDa isoform while maintaining expression of a 30kDa isoform (translated from the AUG at full-length protein isoform amino acid M120). This 30kDa isoform exhibits dominant negative activity. Somatic 2016-02-24 19:02:52 UTC https://civicdb.org/links/evidence_items/169 https://civicdb.org/links/variants/28 https://civicdb.org/links/genes/15 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome DNMT3A mutations were associated with achievement of complete remission in a large cohort of younger (18-60) AML patients. 23632886 PubMed Gaidzik et al., 2013, Blood 3 accepted 170 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/170 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false FLT3 2322 TKD MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome Event-free survival was significantly improved in patients with both NPM1 and FLT3-TKD mutations compared to patients with 1) FLT3-TKD mutations alone 2) either NPM1 or FLT3-TKD when FLT3-ITD patients were excluded from the analysis 3) neither FLT3-TKD or NPM1 mutations or FLT3-TKD alone when only de novo, normal karyotype patients were analyzed. 17965322 PubMed Bacher et al., 2008, Blood 3 accepted 171 56 24 13 28592642 28592642 C A ENST00000241453.7 75 GRCh37 FLT3 tyrosine kinase domain mutations (FLT3-TKD) are much less common than FLT3-ITD (internal tandem duplication) mutations and may not confer the same prognostic impact. Although the majority of mutations are point mutations effecting D835 (most frequently D835Y), a small proportion involve an in-frame deletion of I836. These mutations are within the activation loop of the second tyrosine kinase domain of FLT3 and thought to result in constitutive activation of the receptor. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/171 https://civicdb.org/links/variants/56 https://civicdb.org/links/genes/24 false MGMT 4255 Promoter Methylation Glioblastoma 3068 Prognostic Supports B Better Outcome MGMT promoter methylation was associated with increased overall and disease-free survival as well as tumor regression in patients with gliomas. 11070098 PubMed Esteller et al., 2000, N. Engl. J. Med. 4 accepted 172 85 34 10 131264495 131265656 ENST00000306010.7 75 GRCh37 MGMT promoter methylation has been observed to impact tumor progression in glioblastoma multiforme. In patients exhibiting promoter methylation, the akylating agent carmustine has shown efficacy. In patients lacking methylation, combining carmustine with the MGMT inhibitor O(6)-benzylguanine may be effective, but more experiments are required. Clinical trials have also shown selective sensitivity of promoter methylation-positive patients to temozolomide, making a case for wider methylation screening in GBM patients. Somatic 2015-06-21 16:49:45 UTC https://civicdb.org/links/evidence_items/172 https://civicdb.org/links/variants/85 https://civicdb.org/links/genes/34 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome NPM1 mutation without FLT3-ITD was associated with reduced relapse risk and increased overall survival in young adult acute myeloid leukemia patients (median age 43). 17957027 PubMed Gale et al., 2008, Blood 4 accepted 173 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/173 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome Patients with NPM1 mutations were associated with improved complete remission rates as well as overall and disease free survival when all ages and karyotype were analyzed; however, when only normal karyotype patients were analyzed, only complete remission rates were improved. 19059939 PubMed Schlenk et al., 2009, Haematologica NCT00151242 3 accepted 174 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/174 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome Complete remission rates were higher (P<0.001) and both disease-free survival (N=205 vs 352, P=0.041) and overall survival (N=372 vs 956, P=0.022) were longer for AML patients with Exon 12 NPM1 mutations (irrespective of FLT3 status) than those with wildtype NPM1. Improved CR rates were also higher for those with NPM1 exon 12 mutations and normal karyotype. In multivariate analysis, NPM1 mutation alone (FLT3 wildtype) was associated with improved overall survival (but not DFS) in the entire cohort and in normal karyotype patients <60 years old. 16455956 PubMed Thiede et al., 2006, Blood 3 accepted 175 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-06-28 23:27:18 UTC https://civicdb.org/links/evidence_items/175 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome Complete remission rates were higher (70.5% vs 54.7%, P = 0.003) and event-free survival was longer (median, 428 vs 336 days; P = 0.012) for normal karyotype AML patients (median age 60.3 years) with Exon 12 NPM1 mutations (N=212) compared to those with wildtype NPM1 (N=189). 16076867 PubMed Schnittger et al., 2005, Blood 5 accepted 176 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-06-10 19:41:01 UTC https://civicdb.org/links/evidence_items/176 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome Cytoplasmic localization of NPM in AML patients was an independent prognositic factor associated with complete remission in response to induction therapy in a multivariate analysis (p=0.019) but not in a univariate analysis (p=0.07). 15659725 PubMed Falini et al., 2005, N. Engl. J. Med. 3 accepted 177 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2015-06-21 16:49:45 UTC https://civicdb.org/links/evidence_items/177 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome Intermediate risk patients with mutant NPM1 had improved overall survival with the presence of either IDH1 or IDH2 mutations than those wildtype for both IDH1 and IDH2. 22417203 PubMed Patel et al., 2012, N. Engl. J. Med. 2 accepted 179 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2019-02-22 15:08:48 UTC https://civicdb.org/links/evidence_items/179 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome Normal karyotype patients with NPM1 mutation and without FLT3-ITD had improved overall and relapse-free survival, complete remission rates and remission duration compared to all other combinations of mutants. 19047294 PubMed Büchner et al., 2009, J. Clin. Oncol. 3 accepted 180 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/180 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome NPM1 mutation (N=724) was associated with higher complete remission rates (92% vs 82%; P < 0.0001), lower cumulative incidence of relapse (42% vs 58%; P < 0.0001) and higher overall survival (48% vs 27%; P < .0001) than NPM1 wildtype status (N=885) in intermediate risk, young adult AML patients (median age 46 years). 24855211 PubMed Linch et al., 2014, Blood 4 accepted 181 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-06-10 19:52:26 UTC https://civicdb.org/links/evidence_items/181 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome NPM1 mutation was associated with increased overall, event-free and relapse-free survival and remission after induction therapy in the entire cohort and in the cytogenetically normal subset of patients. 22430270 PubMed Gaidzik et al., 2012, J. Clin. Oncol. 3 accepted 182 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/182 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome In young patients (age 16-60) with previously untreated, cytogenetically normal acute myeloid leukemia, NPM1 mutation without FLT3-ITD was significantly associated with complete remission in multivariate analysis (odds ratio, 1.48; 95% CI, 1.21 to 1.80). Multivariate analysis was performed on all patients that were evaluated for a mutation in at least 1 gene (CEBPA, FLT3-ITD or NPM1) totaling 693/872 patients in the study. 130 patients had NPM1 mutations without FLT3-ITD. NPM1 mutations were evaluated in 570 patients (310 mutated). FLT3-ITD was evaluated in 531 patients (164 mutated). 18450602 PubMed Schlenk et al., 2008, N. Engl. J. Med. 3 accepted 183 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-03-09 21:14:53 UTC https://civicdb.org/links/evidence_items/183 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome NPM1 mutations were associated with increased complete remission rates as well as longer overall disease free survival in normal karyotype AML patients >59 years old, particularly in those >69 years old. 20026798 PubMed Becker et al., 2010, J. Clin. Oncol. 4 accepted 184 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/184 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome Younger (16-60), normal karyotype AML patients with Exon 12 NPM1 mutation and without FLT3-ITD have increased overall survival (N=74, P = .001), relapse-free survival (N=86, P < .001) and response to induction chemotherapy. Multivariate analysis identified NPM1 mutation in the absence of FLT3-ITD as a prognostic marker for the achievement of CR (P=0.004). 16051734 PubMed Döhner et al., 2005, Blood 3 accepted 185 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-06-10 20:18:47 UTC https://civicdb.org/links/evidence_items/185 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Complete remission rate was not different between young AML patients (<60 years old) with or without DNMT3A mutations (60% of which were R882). 22490330 PubMed Ribeiro et al., 2012, Blood 3 accepted 186 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/186 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome DNMT3A mutations (62% of which were R882) were associated with reduced disease-free survival in patients with cytogenetically normal AML. 22291079 PubMed Marcucci et al., 2012, J. Clin. Oncol. 4 accepted 187 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2015-06-21 16:49:46 UTC https://civicdb.org/links/evidence_items/187 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false DNMT3A 1788 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Young AML patients (415 patients; <60 years old) with any DNMT3A mutation (n=96) have shorter overall survival and relapse-free survival than patients with wildtype DNMT3A. 22490330 PubMed Ribeiro et al., 2012, Blood 3 accepted 188 189 18 2 25455845 25565459 ENST00000264709.3 75 GRCh37 DNMT3A mutations occur in a variety of myeloid malignancies. These mutations are associated with adverse prognosis in acute myeloid leukemia (AML), particularly in the context of NPM1 and FLT3-ITD mutations, which often co-occur. Early results indicate AML patients with DNMT3A mutations may respond better to decitabine than those with wild-type. Shorter survival has been indicated in patients with T-cell acute lymphoblastic leukemia and myelodysplastic syndrome, however, larger cohorts are required to verify this finding. DNMT3A mutations have been suggested as a pre-leukemic lesion and found in older individuals with clonal hematopoiesis but no overt malignancy. Somatic 2016-02-12 23:18:50 UTC https://civicdb.org/links/evidence_items/188 https://civicdb.org/links/variants/189 https://civicdb.org/links/genes/18 false DNMT3A 1788 R882 Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Young AML patients (415 patients; <60 years old) with DNMT3A R882 mutations (n=58) have shorter overall and relapse-free survival than patients with wildtype DNMT3A. 22490330 PubMed Ribeiro et al., 2012, Blood 3 accepted 189 32 18 2 25457241 25457243 ENST00000264709.3 75 GRCh37 DNMT3A R882 mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) with R882H as the most common form. Mutations in DNMT3A have largely been associated with poorer prognosis, however this is not consistent across all studies. This may be a result of patient age or combining R882 and non-R882 mutations during analysis as studies have indicated independent mechanisms of action and differential prognostic implications for these mutation types. One study that independently analyzed R882 and non-R882 mutations showed R882 mutations were associated with poorer prognosis than patients with wildtype and non-R882 mutations, but only in older patients with AML. Somatic 2016-02-16 16:49:33 UTC https://civicdb.org/links/evidence_items/189 https://civicdb.org/links/variants/32 https://civicdb.org/links/genes/18 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Prognostic Supports A Poor Outcome Meta-analysis of studies involving cytogentically normal younger (<60) patients showed reduced overall and relapse-free survival for patients with FLT3-ITD. 24801015 PubMed Port et al., 2014, Ann. Hematol. 3 accepted 190 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-08-04 05:26:40 UTC https://civicdb.org/links/evidence_items/190 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome A ratio of >0.49 FLT3-ITD/FLT3 wildtype level was associated with reduced event-free and overall survival in old (>59) and younger patients (<60) with an NPM1 mutation. 21537333 PubMed Schnittger et al., 2011, Leukemia 4 accepted 191 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/191 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Patients with NPM1 mutation and FLT3-ITD had reduced event-free survival compared to patients with wildtype FLT3. 21537333 PubMed Schnittger et al., 2011, Leukemia 4 accepted 192 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/192 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Using a ratio of FLT3-ITD/FLT3 wildtype levels as a continuous variable, a higher ratio was associated with reduced event-free survival in patients with an NPM1 mutation. 21537333 PubMed Schnittger et al., 2011, Leukemia 4 accepted 193 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/193 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false KRAS 3845 G12/G13 Colorectal Cancer 9256 Prognostic Supports D Poor Outcome KRAS mutations were significantly associated with reduced progression-free and overall survival in patients with advanced colorectal cancer. 18202412 PubMed Lièvre et al., 2008, J. Clin. Oncol. 3 accepted 194 77 30 12 25398280 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/194 https://civicdb.org/links/variants/77 https://civicdb.org/links/genes/30 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Coocurrence of FLT3-ITD mutations significantly reduced overall (N=74 vs 95, P=0.003) and disease-free survival (N=43 vs 67, P=0.02) of normal karyotype AML patients (<60 years old) compared to patients with NPM1 mutations alone. 16455956 PubMed Thiede et al., 2006, Blood 4 accepted 195 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-06-17 04:40:25 UTC https://civicdb.org/links/evidence_items/195 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Monitoring NPM1 mutation by cDNA-based RT-PCR effectively predicted relapse in 62/93 patients by >1 log increase in NPM1 levels (N=57) or lack of reduction in NPM1 levels following first line therapy (N=15). 19587375 PubMed Schnittger et al., 2009, Blood 2 accepted 196 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/196 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Patients with NPM1 mutations and low (<25%, N=63), intermediate (25-50%, N=156) or high (>50%, N=66) levels of FLT3-ITD have worse overall survival (P<0.0001 for trend) and cumulative incidence of relapse (P<0.001) than those with NPM1 mutations alone (N=387) in young adult, intermediate risk AML patients. 24855211 PubMed Linch et al., 2014, Blood 3 accepted 198 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-06-17 04:38:20 UTC https://civicdb.org/links/evidence_items/198 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome TET2 mutation reduces overall survival of normal karyotype patients with either an NPM1 mutation or NPM1 mutation without FLT3-ITD. 24859829 PubMed Tian et al., 2014, Int. J. Hematol. 3 accepted 199 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/199 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false WT1 7490 EXON 7 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Mutations in WT1 were associated with increased risk of recurrence in young patients (15-50) with cytogenetically normal AML. 19536888 PubMed Renneville et al., 2009, Cancer 2 accepted 201 129 49 11 32417803 32417953 ENST00000332351.3 75 GRCh37 WT1 exon 7 mutations have been shown to be recurrent in acute myeloid leukemia. Many sources have examined the prognostic impact of these, agreeing that the mutant exon 7 cohort is correlated with worse overall survival and a number of poor prognistic outcomes. This may be the result of an overall poor response to chemotherapy from WT1 mutant tumors. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/201 https://civicdb.org/links/variants/129 https://civicdb.org/links/genes/49 false WT1 7490 EXON 7 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Mutations in WT1 were associated with a worse overall prognosis than patients wildtype for WT1 in young patients (15-50), primarily because of increased risk of disease recurrence. 19536888 PubMed Renneville et al., 2009, Cancer 2 accepted 202 129 49 11 32417803 32417953 ENST00000332351.3 75 GRCh37 WT1 exon 7 mutations have been shown to be recurrent in acute myeloid leukemia. Many sources have examined the prognostic impact of these, agreeing that the mutant exon 7 cohort is correlated with worse overall survival and a number of poor prognistic outcomes. This may be the result of an overall poor response to chemotherapy from WT1 mutant tumors. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/202 https://civicdb.org/links/variants/129 https://civicdb.org/links/genes/49 false WT1 7490 EXON 7 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Patients with WT1 (69% exon 7, 15% exon 9) and FLT3-ITD mutations had significantly lower complete remission and higher refractory disease rates than those with wildtype WT1 and without FLT3-ITD following induction therapy in young (16-60) patients with cytogenetically normal AML. 19221039 PubMed Gaidzik et al., 2009, Blood 3 accepted 203 129 49 11 32417803 32417953 ENST00000332351.3 75 GRCh37 WT1 exon 7 mutations have been shown to be recurrent in acute myeloid leukemia. Many sources have examined the prognostic impact of these, agreeing that the mutant exon 7 cohort is correlated with worse overall survival and a number of poor prognistic outcomes. This may be the result of an overall poor response to chemotherapy from WT1 mutant tumors. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/203 https://civicdb.org/links/variants/129 https://civicdb.org/links/genes/49 false WT1 7490 EXON 7 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome WT mutations were associated with shorter overall and disease free survival in a cohort of cytogenetically normal, young (<60) AML patients. 18559874 PubMed Paschka et al., 2008, J. Clin. Oncol. 3 accepted 204 129 49 11 32417803 32417953 ENST00000332351.3 75 GRCh37 WT1 exon 7 mutations have been shown to be recurrent in acute myeloid leukemia. Many sources have examined the prognostic impact of these, agreeing that the mutant exon 7 cohort is correlated with worse overall survival and a number of poor prognistic outcomes. This may be the result of an overall poor response to chemotherapy from WT1 mutant tumors. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/204 https://civicdb.org/links/variants/129 https://civicdb.org/links/genes/49 false WT1 7490 EXON 7 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome WT1 mutations were a negative prognostic factor for overall survival in young (15-60+, median 45) patients with cytogenetically normal AML. 18591546 PubMed Virappane et al., 2008, J. Clin. Oncol. 3 accepted 205 129 49 11 32417803 32417953 ENST00000332351.3 75 GRCh37 WT1 exon 7 mutations have been shown to be recurrent in acute myeloid leukemia. Many sources have examined the prognostic impact of these, agreeing that the mutant exon 7 cohort is correlated with worse overall survival and a number of poor prognistic outcomes. This may be the result of an overall poor response to chemotherapy from WT1 mutant tumors. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/205 https://civicdb.org/links/variants/129 https://civicdb.org/links/genes/49 false WT1 7490 EXON 7 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome WT1 mutations were associated with a higher cumulative incidence of relapse and shorter relapse free survival in young (15-60+, median 45) patients with cytogenetically normal AML. 18591546 PubMed Virappane et al., 2008, J. Clin. Oncol. 3 accepted 206 129 49 11 32417803 32417953 ENST00000332351.3 75 GRCh37 WT1 exon 7 mutations have been shown to be recurrent in acute myeloid leukemia. Many sources have examined the prognostic impact of these, agreeing that the mutant exon 7 cohort is correlated with worse overall survival and a number of poor prognistic outcomes. This may be the result of an overall poor response to chemotherapy from WT1 mutant tumors. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/206 https://civicdb.org/links/variants/129 https://civicdb.org/links/genes/49 false WT1 7490 EXON 9 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome WT1 mutations were associated with shorter overall and disease free survival in a cohort of cytogenetically normal, young (<60) AML patients. 18559874 PubMed Paschka et al., 2008, J. Clin. Oncol. 3 accepted 210 130 49 11 32413518 32413610 ENST00000332351.3 75 GRCh37 WT1 exon 9 mutations have been shown to be recurrent in acute myeloid leukemia, although at a less frequent rate than their exon 7 counterparts. Many sources have examined the prognostic impact of these, agreeing that the mutant exon 9 cohort is correlated with worse overall survival and a number of poor prognistic outcomes. This may be the result of an overall poor response to chemotherapy from WT1 mutant tumors. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/210 https://civicdb.org/links/variants/130 https://civicdb.org/links/genes/49 false BRCA1 672 Loss-of-function Ovarian Cancer 2394 Olaparib Predictive Supports B Sensitivity/Response The combination of PARP inhibition (Olaparib) with BRCA mutation results in irreparable and lethal DNA damage. Response rates are higher in BRCA1 mutation positive women with high grade serous or undifferentiated ovarian cancer. 23346317 PubMed Goff, 2013, J Gynecol Oncol 4 accepted 211 131 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 BRCA1 loss of function mutations have been shown to increase risk of breast and ovarian cancer in those carrying the allele in their germline. Treating BRCA mutant patients with PARP inhibitors such as Olaparib has led to significant response. Rare Germline 2015-06-21 16:49:47 UTC https://civicdb.org/links/evidence_items/211 https://civicdb.org/links/variants/131 https://civicdb.org/links/genes/6 false BRCA2 675 Loss-of-function Ovarian Cancer 2394 Olaparib Predictive Supports B Sensitivity/Response The combination of PARP inhibition (Olaparib) with BRCA mutation results in irreparable and lethal DNA damage. Response rates are higher in BRCA2 mutation positive women with high grade serous or undifferentiated ovarian cancer. 23346317 PubMed Goff, 2013, J Gynecol Oncol 4 accepted 212 132 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 BRCA2 loss of function mutations have been shown to increase risk of breast and ovarian cancer in those carrying the allele in their germline. Treating BRCA mutant patients with PARP inhibitors such as Olaparib has led to significant response. Rare Germline 2015-06-21 16:49:47 UTC https://civicdb.org/links/evidence_items/212 https://civicdb.org/links/variants/132 https://civicdb.org/links/genes/7 false ABL1 25 BCR::ABL Chronic Myeloid Leukemia 8552 Diagnostic Does Not Support C Positive Data from deep sequencing of a Ph-negative clone of a Ph-positive CML patient has found a driving mutation in DNMT3A that preceeded the BCR-ABL fusion, and may imply the possibility that BCR-ABL is not universally the initiating event in CML. 25212276 PubMed Schmidt et al., 2014, Leukemia 2 accepted 213 1 4 22 23522397 23632600 ENST00000305877.8 9 133729451 133763063 ENST00000318560.5 75 GRCh37 The BCR-ABL fusion protein, commonly referred to as the Philadelphia chromosome, is one of the most studied fusion genes in cancer. It has widely been considered the initiating event in chronic myelogenous leukemia (CML). However, despite its ability to initiate disease in mice, its status as an initiating mutation is in dispute. In what is commonly used as the poster-child for targeted therapeutics, the development and use of imatinib in the clinic has led to profound improvements in the prognosis of the disease. However, imatinib resistance is still seen in patients with mutations in the ABL kinase domain of the fusion, most notably the T315I variant. In patients resistant to imatinib, either acquired or otherwise, second generation BCR-ABL TKI's (dasatinib and nilotinib) have seen some success in delivering a tumor response. Third generation ABL1 inhibitor ponatinib is the only FDA approved drug with activity against T315I . However due to risk of life-threatening blood clots and severe narrowing of blood vessels ponatinib is ONLY approved for T315I-positive CML or T315I-positive Ph+ ALL or in cases of CML, Ph+ ALL with resistance or intolerance to other approved ABL1 inhibitors. Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/213 https://civicdb.org/links/variants/1 https://civicdb.org/links/genes/4 false FLT3 2322 TKD MUTATION Acute Myeloid Leukemia 9119 Diagnostic Does Not Support B Positive WBC counts were not significantly different in AML patients with FLT3 D835 mutations compared to wild type. 11290608 PubMed Yamamoto et al., 2001, Blood 3 accepted 214 56 24 13 28592642 28592642 C A ENST00000241453.7 75 GRCh37 FLT3 tyrosine kinase domain mutations (FLT3-TKD) are much less common than FLT3-ITD (internal tandem duplication) mutations and may not confer the same prognostic impact. Although the majority of mutations are point mutations effecting D835 (most frequently D835Y), a small proportion involve an in-frame deletion of I836. These mutations are within the activation loop of the second tyrosine kinase domain of FLT3 and thought to result in constitutive activation of the receptor. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/214 https://civicdb.org/links/variants/56 https://civicdb.org/links/genes/24 false KRAS 3845 G12 Lung Non-small Cell Carcinoma 3908 Diagnostic Does Not Support B Positive KRAS mutations in lung cancer patients are not associated with smoking history, age or gender. 18794081 PubMed Riely et al., 2008, Clin. Cancer Res. 3 accepted 215 76 30 12 25398284 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/215 https://civicdb.org/links/variants/76 https://civicdb.org/links/genes/30 false U2AF1 7307 Q157P/R Acute Myeloid Leukemia 9119 Diagnostic Does Not Support B Positive Age, sex, FAB subtype and karyotypes were not statistically significant between AML patients with U2AF Q157P/R mutations and those who harbor wild type U2AF. 23029227 PubMed Qian et al., 2012, PLoS ONE 3 accepted 217 127 48 21 44514777 44514777 T G ENST00000291552.4 75 GRCh37 U2AF1 Q157P/R has been shown to be a recurrent mutation in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and lung adenocarcinomas. This mutation is less common than the S34F mutation, occurs in the second zinc finger domain of U2AF1 and has been demonstrated to alter splicing. The impact of U2AF1 mutations on overall survival in MDS has been debated, however, patients with U2AF1 mutations were shown to be at an increased risk of transformation to secondary AML. The presence of this mutation was not associated with a specific prognostic outcome in AML when compared to U2AF1 wildtype patients. Somatic 2016-02-13 05:33:42 UTC https://civicdb.org/links/evidence_items/217 https://civicdb.org/links/variants/127 https://civicdb.org/links/genes/48 false U2AF1 7307 S34Y/F Acute Myeloid Leukemia 9119 Diagnostic Does Not Support B Positive Age, sex, FAB subtype and karyotypes were not statistically significant between AML patients with U2AF S34Y/F mutations and those who harbor wild type U2AF. 23029227 PubMed Qian et al., 2012, PLoS ONE 3 accepted 218 128 48 21 44524456 44524456 G A ENST00000291552.4 75 GRCh37 U2AF1 S34Y/F has been shown to be a recurrent mutation in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and lung adenocarcinomas. This mutation is the most commonly identified variant in MDS, occurs in the first zinc finger domain of U2AF1 and has been demonstrated to alter splicing. The impact of U2AF1 mutations on overall survival in MDS has been debated, however, patients with U2AF1 mutations were shown to be at an increased risk of transformation to secondary AML. The presence of this mutation was not associated with a specific prognostic outcome in AML when compared to U2AF1 wildtype patients. Somatic 2016-02-13 05:37:05 UTC https://civicdb.org/links/evidence_items/218 https://civicdb.org/links/variants/128 https://civicdb.org/links/genes/48 false CCND2 894 PROMOTER DEMETHYLATION Stomach Cancer 10534 Diagnostic Supports D Negative CCND2 hypomethylation is seen to be more common in stage III and IV gastric tumors than stage I and II. 14612939 PubMed Oshimo et al., 2003, Int. J. Oncol. 3 accepted 219 22 9 12 4381437 4382937 ENST00000261254.3 75 GRCh37 Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK's) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, and range from genomic amplification to promoter methylation changes. While Cyclin D2 has only been found to be significantly misregulated in glioma, Cyclin D1 in particular seems to be a pan-cancer actor. Cyclin D misregulation has been shown to lead to poorer outcomes in a number of studies, and currently there are no FDA-approved targeted therapies. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/219 https://civicdb.org/links/variants/22 https://civicdb.org/links/genes/9 false ABL1 25 BCR::ABL Chronic Myeloid Leukemia 8552 Diagnostic Supports A Positive The presence of BCR-ABL fusion is considered the characterizing feature of chronic myeloid leukemia, and has been widely thought of as the initiating event in the disease. 20537386 PubMed An et al., 2010, Leuk. Res. 4 accepted 220 1 4 22 23522397 23632600 ENST00000305877.8 9 133729451 133763063 ENST00000318560.5 75 GRCh37 The BCR-ABL fusion protein, commonly referred to as the Philadelphia chromosome, is one of the most studied fusion genes in cancer. It has widely been considered the initiating event in chronic myelogenous leukemia (CML). However, despite its ability to initiate disease in mice, its status as an initiating mutation is in dispute. In what is commonly used as the poster-child for targeted therapeutics, the development and use of imatinib in the clinic has led to profound improvements in the prognosis of the disease. However, imatinib resistance is still seen in patients with mutations in the ABL kinase domain of the fusion, most notably the T315I variant. In patients resistant to imatinib, either acquired or otherwise, second generation BCR-ABL TKI's (dasatinib and nilotinib) have seen some success in delivering a tumor response. Third generation ABL1 inhibitor ponatinib is the only FDA approved drug with activity against T315I . However due to risk of life-threatening blood clots and severe narrowing of blood vessels ponatinib is ONLY approved for T315I-positive CML or T315I-positive Ph+ ALL or in cases of CML, Ph+ ALL with resistance or intolerance to other approved ABL1 inhibitors. Somatic 2015-06-21 16:49:47 UTC https://civicdb.org/links/evidence_items/220 https://civicdb.org/links/variants/1 https://civicdb.org/links/genes/4 false CCND1 595 Overexpression Breast Cancer 1612 Diagnostic Supports B Positive Cyclin D1 overexpression is associated with the ER-positive subtype of breast cancer. 15961768 PubMed Arnold et al., 2005, J. Clin. Oncol. 4 accepted 221 20 8 11 69455855 69469242 ENST00000227507.2 75 GRCh37 Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK's) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, and range from genomic amplification to promoter methylation changes. While Cyclin D2 has only been found to be significantly misregulated in glioma, Cyclin D1 in particular seems to be a pan-cancer actor. Cyclin D misregulation has been shown to lead to poorer outcomes in a number of studies, and currently there are no FDA-approved targeted therapies. N/A 2020-10-22 01:52:28 UTC https://civicdb.org/links/evidence_items/221 https://civicdb.org/links/variants/20 https://civicdb.org/links/genes/8 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Diagnostic Supports B Positive WBC counts were higher in AML patients with internal tandem repeat of Flt3 compared to wild type. 11290608 PubMed Yamamoto et al., 2001, Blood 3 accepted 222 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/222 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false IDH1 3417 R132 Acute Myeloid Leukemia 9119 Diagnostic Supports B Positive In leukemia patients, IDH1 R132 mutation is associated with adults and normal karyotype. 20376086 PubMed Ho et al., 2010, Leukemia 2 accepted 223 58 26 2 209113111 209113113 ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes, IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2015-06-21 16:49:47 UTC https://civicdb.org/links/evidence_items/223 https://civicdb.org/links/variants/58 https://civicdb.org/links/genes/26 false IDH1 3417 R132C Acute Myeloid Leukemia 9119 Diagnostic Supports B Positive IDH1 R132 mutation is associated with patients of older age, high platelet count during diagnosis, cytogenic normalcy and NPM1 mutation. 20538800 PubMed Abbas et al., 2010, Blood 3 accepted 224 59 26 2 209113113 209113113 G A ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes and acute myeloid leukemia (AML), IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/224 https://civicdb.org/links/variants/59 https://civicdb.org/links/genes/26 false KIT 3815 Exon 11 Mutation Gastrointestinal Stromal Tumor 9253 Diagnostic Supports B Positive KIT mutation is associated with larger, more invasive tumors, greater pathologic histology and older patients compared to tumors with wildtype KIT. 10485475 PubMed Taniguchi et al., 1999, Cancer Res. 2 accepted 225 66 29 4 55593582 55593708 ENST00000288135.5 75 GRCh37 c-KIT mutations in exon 11 lie within the juxtamembrane domain, and are very recurrent in gastrointestinal stromal tumors, often bearing a poorer prognosis than other KIT mutations. Cells harboring exon 11 mutations have shown sensitivity to the tyrosine kinase inhibitor imatinib, offering a better prognosis to patients treated with the drug in the first year. Small cohorts of melanoma patients harboring exon 11 KIT mutations have shown response to imatinib and sunitinib. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/225 https://civicdb.org/links/variants/66 https://civicdb.org/links/genes/29 false KRAS 3845 G12C Lung Cancer 1324 Diagnostic Supports B Positive KRAS G12C occur more frequently in women than men. 23014527 PubMed Dogan et al., 2012, Clin. Cancer Res. 2 accepted 227 78 30 12 25398285 25398285 C A ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/227 https://civicdb.org/links/variants/78 https://civicdb.org/links/genes/30 false KRAS 3845 G12D Lung Cancer 1324 Diagnostic Supports B Positive KRAS G12D mutation occurs in never smokers significantly more often than in smokers. 23014527 PubMed Dogan et al., 2012, Clin. Cancer Res. 3 accepted 228 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/228 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Gefitinib,Erlotinib Substitutes Predictive Supports B Sensitivity/Response There is no statistical difference in progression free survival between lung cancer patients treated with gefitinib or erlotinib with EGFR L858R mutations (N=72/242; univariate: P=0.283; multivariate: P=0.250) compared to patients with Exon 19 mutations (N=170). 24736073 PubMed Lim et al., 2014, J Thorac Oncol 3 accepted 229 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2018-02-24 00:12:24 UTC https://civicdb.org/links/evidence_items/229 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false AKT1 207 E17K Breast Cancer 1612 Akt Inhibitor MK2206 Predictive Does Not Support D Sensitivity/Response Breast cancer cell lines with the AKT1 E17K mutation did not show sensitivity to AKT inhibitor MK-2206, unlike cell lines with PIK3CA mutations. 23888070 PubMed Beaver et al., 2013, Clin. Cancer Res. 3 accepted 231 4 2 14 105246551 105246551 C T ENST00000407796.2 75 GRCh37 AKT1 E17K is a recurrent mutation that has been observed in breast, colorectal, lung, and ovarian cancer. It has been convincingly shown to be an activating mutation resulting in PI3K/AKT/mTOR pathway activity. It has been suggested that this mutation decreases the cell's sensitivity to AKT1 allosteric kinase inhibitors. This, and other AKT1 mutations, are the subject of much research and development for therapeutics. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/231 https://civicdb.org/links/variants/4 https://civicdb.org/links/genes/2 false ABL1 25 BCR::ABL Acute Myeloid Leukemia 9119 Imatinib Predictive Supports D Resistance BCR-ABL fusions have been found to contribute to imatinib resistance in AML cell lines. 12476305 PubMed Nimmanapalli et al., 2002, Oncogene 3 accepted 232 1 4 22 23522397 23632600 ENST00000305877.8 9 133729451 133763063 ENST00000318560.5 75 GRCh37 The BCR-ABL fusion protein, commonly referred to as the Philadelphia chromosome, is one of the most studied fusion genes in cancer. It has widely been considered the initiating event in chronic myelogenous leukemia (CML). However, despite its ability to initiate disease in mice, its status as an initiating mutation is in dispute. In what is commonly used as the poster-child for targeted therapeutics, the development and use of imatinib in the clinic has led to profound improvements in the prognosis of the disease. However, imatinib resistance is still seen in patients with mutations in the ABL kinase domain of the fusion, most notably the T315I variant. In patients resistant to imatinib, either acquired or otherwise, second generation BCR-ABL TKI's (dasatinib and nilotinib) have seen some success in delivering a tumor response. Third generation ABL1 inhibitor ponatinib is the only FDA approved drug with activity against T315I . However due to risk of life-threatening blood clots and severe narrowing of blood vessels ponatinib is ONLY approved for T315I-positive CML or T315I-positive Ph+ ALL or in cases of CML, Ph+ ALL with resistance or intolerance to other approved ABL1 inhibitors. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/232 https://civicdb.org/links/variants/1 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports D Resistance COS7 cell lines transfected with BCR-ABL constructs harboring E255K mutations were shown to be resistant to imatinib and exhibited increased kinase activity. 15194504 PubMed Yamamoto et al., 2004, Biochem. Biophys. Res. Commun. 4 accepted 233 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/233 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports B Resistance In chronic myeloid leukemia patients with the ABL T315I mutation, tumors have shown to be resistant to imatinib treatment. 20537386 PubMed An et al., 2010, Leuk. Res. 4 accepted 234 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2015-06-21 16:49:48 UTC https://civicdb.org/links/evidence_items/234 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports D Resistance COS7 cell lines transfected with BCR-ABL constructs harboring T315I mutations were shown to be resistant to imatinib and exhibited increased kinase activity. 15194504 PubMed Yamamoto et al., 2004, Biochem. Biophys. Res. Commun. 4 accepted 235 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/235 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ALK 238 EML4::ALK C1156Y Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Resistance A 28 year-old patient with T4N3M1 stage lung adenocarcinoma harboring an EML4-ALK variant 1 fusion was treated with crizotinib after failing conventional therapy. The patient achieved a partial response, but progressed after 5 months of treatment. Molecular analysis at relapse identified C1156Y in the ALK kinase domain of the fusion at an allele frequency of 41.8%. This variant was undetected by Sanger sequencing in the tumor collected before crizotinib treatment. Cytotoxicity assays revealed Ba/F3 cells expressing EML4-ALK C1156Y were more resistant to crizontinib than those expressing EML4-ALK wildtype. Immunoblot demonstrated crizontinib reduced tyrosine phosphorylation of the wildtype fusion, but not the EML4-ALK C1156Y fusion. 20979473 PubMed Choi et al., 2010, N. Engl. J. Med. 4 accepted 236 6 1 2 29445258 29445258 C T ENST00000389048.3 75 GRCh37 In patients with non-small cell lung cancer exhibiting EML4-ALK fusion, C1156Y has been shown to confer resistance to crizotinib. Case reports indicate that secondary mutations can modulate drug sensitivity. EML4-ALK C1156Y/L1196M maintained crizotinib resistance while the lorlatinib resistant combination EML4-ALK C1156Y/L1198F re-sensitized the tumor to crizotinib treatment. Somatic 2020-09-02 17:56:12 UTC https://civicdb.org/links/evidence_items/236 https://civicdb.org/links/variants/6 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK L1196M Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Resistance A 28 year-old patient with non-small cell lung cancer was found to harbor the EML4-ALK (E13;A20) fusion using reverse transcription PCR. Treatment with 250mg crizotinib twice daily resulted in rapid improvement of symptoms and disease control for 5 months, followed by rapid disease progression. Analysis of pleural effusion samples obtained after relapse found L1196M at an allele frequency of 14%. This variant was undetected by Sanger sequencing in the tumor collected before crizotinib treatment. Cytotoxicity assays revealed Ba/F3 cells expressing EML4-ALK L1196M were more resistant to crizontinib than those expressing EML4-ALK wildtype. Immunoblot demonstrated crizontinib reduced tyrosine phosphorylation of the wildtype fusion, but not the EML4-ALK L1196M fusion. 20979473 PubMed Choi et al., 2010, N. Engl. J. Med. 4 accepted 237 7 1 2 29443631 29443631 G T ENST00000389048.3 75 GRCh37 In patients with non-small cell lung cancer exhibiting EML4-ALK fusion, L1196M has been shown to confer resistance to crizotinib. This was also true in a patient with both EML4-ALK C1156Y & L1196M. Somatic 2020-09-02 17:28:25 UTC https://civicdb.org/links/evidence_items/237 https://civicdb.org/links/variants/7 https://civicdb.org/links/genes/1 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports A Resistance The T790M mutation in EGFR has been shown to confer resistance to the tyrosine kinase inhibitor erlotinib, and patients harboring this mutation that are placed on the drug are likely to relapse. 25668228 PubMed Denis et al., 2015, Clin. Chim. Acta 5 accepted 238 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2015-08-05 18:28:35 UTC https://civicdb.org/links/evidence_items/238 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports B Resistance In non-small cell lung cancer, the appearance of T790M mutation leads to resistance to gefitinib. 15728811 PubMed Kobayashi et al., 2005, N. Engl. J. Med. 3 accepted 239 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2015-06-21 16:49:48 UTC https://civicdb.org/links/evidence_items/239 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Dacomitinib Predictive Supports B Resistance In Lung Cancer patients with acquired resistance to Dacomitinib (PF00299804), MET amplification and EGFR T790M were found to be the primary drivers of resistance. 21430269 PubMed Sequist et al., 2011, Sci Transl Med 4 accepted 240 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2015-06-21 16:49:48 UTC https://civicdb.org/links/evidence_items/240 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false ERBB2 2064 L755S Breast Cancer 1612 Lapatinib Predictive Supports D Resistance The L755S mutation was shown to confer resistance to lapatinib in MCF10A cell lines retrovirally transduced with wildtype or mutant ERBB2. 23220880 PubMed Bose et al., 2013, Cancer Discov 5 accepted 241 39 20 17 37880220 37880220 T C ENST00000269571.5 75 GRCh37 ERBB2 L755S was one of the first ERBB2 variants to be functionally classified (Bose et al. 2013). This mutation was not shown to be an activating mutation, unlike many of the other variants queried. This mutation was also shown to confer resistance to the tyrosine kinase inhibitor lapatinib in MCF10A cell lines. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/241 https://civicdb.org/links/variants/39 https://civicdb.org/links/genes/20 false ESR1 2099 L536Q Breast Cancer 1612 Hormone Therapy Predictive Supports D Resistance MCF7 cell lines harboring the L536Q mutation in the ligand-binding domain of ESR1 have shown resistance to hormone therapy. 24185512 PubMed Toy et al., 2013, Nat. Genet. 3 accepted 242 46 21 6 152419920 152419921 TC AG ENST00000440973.1 75 GRCh37 ESR1 biology has become a central focus in breast cancer therapy. In ER+ tumors, mutations in the ESR1 ligand binding domain have been shown to confer resistance to hormone therapy. This evidence has led to an increased use of targeted sequencing of the estrogen receptor in breast and ovarian cancer. Y536Q is one of these ligand binding domain mutations, and is commonly implicated in this hormone resistance. Preliminary data suggests ER-degrading agents, such as fulvestrant, may be beneficial in treating ESR1 mutant, hormone resistant breast cancers. Somatic 2021-09-02 23:01:21 UTC https://civicdb.org/links/evidence_items/242 https://civicdb.org/links/variants/46 https://civicdb.org/links/genes/21 true ESR1 2099 D538G Breast Cancer 1612 Hormone Therapy Predictive Supports D Resistance MCF7 cell lines harboring the D538G mutation in the ligand-binding domain of ESR1 have shown resistance to hormone therapy. 24185512 PubMed Toy et al., 2013, Nat. Genet. 3 accepted 243 47 21 6 152419926 152419926 A G ENST00000206249.3 75 GRCh37 ESR1 biology has become a central focus in breast cancer therapy. In ER+ tumors, mutations in the ESR1 ligand binding domain have been shown to confer resistance to hormone therapy. This evidence has led to an increased use of targeted sequencing of the estrogen receptor in breast and ovarian cancer. D538G is one of these ligand binding domain mutations, and is commonly implicated in this hormone resistance. Preliminary data suggests ER-degrading agents, such as fulvestrant, may be beneficial in treating ESR1 mutant, hormone resistant breast cancers. Somatic 2017-04-13 16:33:01 UTC https://civicdb.org/links/evidence_items/243 https://civicdb.org/links/variants/47 https://civicdb.org/links/genes/21 false ESR1 2099 Y537C Breast Cancer 1612 Hormone Therapy Predictive Supports D Resistance MCF7 cell lines harboring the Y537C mutation in the ligand-binding domain of ESR1 have shown resistance to hormone therapy. 24185512 PubMed Toy et al., 2013, Nat. Genet. 3 accepted 244 48 21 6 152419923 152419923 A G ENST00000206249.3 75 GRCh37 ESR1 biology has become a central focus in breast cancer therapy. In ER+ tumors, mutations in the ESR1 ligand binding domain have been shown to confer resistance to hormone therapy. This evidence has led to an increased use of targeted sequencing of the estrogen receptor in breast and ovarian cancer. Y537C is one of these ligand binding domain mutations, and is commonly implicated in this hormone resistance. Preliminary data suggests ER-degrading agents, such as fulvestrant, may be beneficial in treating ESR1 mutant, hormone resistant breast cancers. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/244 https://civicdb.org/links/variants/48 https://civicdb.org/links/genes/21 false ESR1 2099 Y537N Breast Cancer 1612 Hormone Therapy Predictive Supports D Resistance MCF7 cell lines harboring the Y537N mutation in the ligand-binding domain of ESR1 have shown resistance to hormone therapy. 24185512 PubMed Toy et al., 2013, Nat. Genet. 3 accepted 245 49 21 6 152419922 152419922 T A ENST00000206249.3 75 GRCh37 ESR1 biology has become a central focus in breast cancer therapy. In ER+ tumors, mutations in the ESR1 ligand binding domain have been shown to confer resistance to hormone therapy. This evidence has led to an increased use of targeted sequencing of the estrogen receptor in breast and ovarian cancer. Y537N is one of these ligand binding domain mutations, and is commonly implicated in this hormone resistance. Preliminary data suggests ER-degrading agents, such as fulvestrant, may be beneficial in treating ESR1 mutant, hormone resistant breast cancers. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/245 https://civicdb.org/links/variants/49 https://civicdb.org/links/genes/21 false ESR1 2099 Y537S Breast Cancer 1612 Hormone Therapy Predictive Supports D Resistance MCF7 cell lines harboring the L537S mutation in the ligand-binding domain of ESR1 have shown resistance to hormone therapy. 24185512 PubMed Toy et al., 2013, Nat. Genet. 3 accepted 246 50 21 6 152419923 152419923 A C ENST00000206249.3 75 GRCh37 ESR1 biology has become a central focus in breast cancer therapy. In ER+ tumors, mutations in the ESR1 ligand binding domain have been shown to confer resistance to hormone therapy. This evidence has led to an increased use of targeted sequencing of the estrogen receptor in breast and ovarian cancer. Y537S is one of these ligand binding domain mutations, and is commonly implicated in this hormone resistance. Preliminary data suggests ER-degrading agents, such as fulvestrant, may be beneficial in treating ESR1 mutant, hormone resistant breast cancers. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/246 https://civicdb.org/links/variants/50 https://civicdb.org/links/genes/21 false FLT3 2322 TKD MUTATION Acute Myeloid Leukemia 9119 Sorafenib Predictive Supports B Resistance Emergence of D835 mutation in AML patients with FLT3 tandem repeat is associated with sorafenib resistance. 22368270 PubMed Man et al., 2012, Blood 4 accepted 247 56 24 13 28592642 28592642 C A ENST00000241453.7 75 GRCh37 FLT3 tyrosine kinase domain mutations (FLT3-TKD) are much less common than FLT3-ITD (internal tandem duplication) mutations and may not confer the same prognostic impact. Although the majority of mutations are point mutations effecting D835 (most frequently D835Y), a small proportion involve an in-frame deletion of I836. These mutations are within the activation loop of the second tyrosine kinase domain of FLT3 and thought to result in constitutive activation of the receptor. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/247 https://civicdb.org/links/variants/56 https://civicdb.org/links/genes/24 false FLT3 2322 TKD MUTATION Acute Myeloid Leukemia 9119 Sorafenib Predictive Supports B Resistance Sorafenib is effective in patients with FLT3 internal tandem repeat mutations, but not in patients with wild type or D835 mutation. 18230792 PubMed Zhang et al., 2008, J. Natl. Cancer Inst. 4 accepted 248 56 24 13 28592642 28592642 C A ENST00000241453.7 75 GRCh37 FLT3 tyrosine kinase domain mutations (FLT3-TKD) are much less common than FLT3-ITD (internal tandem duplication) mutations and may not confer the same prognostic impact. Although the majority of mutations are point mutations effecting D835 (most frequently D835Y), a small proportion involve an in-frame deletion of I836. These mutations are within the activation loop of the second tyrosine kinase domain of FLT3 and thought to result in constitutive activation of the receptor. Somatic 2015-06-21 16:49:48 UTC https://civicdb.org/links/evidence_items/248 https://civicdb.org/links/variants/56 https://civicdb.org/links/genes/24 false KIT 3815 V654A Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports D Resistance KIT V654A results in imatinib resistance in GIST patient-derived cell lines. 16954519 PubMed Heinrich et al., 2006, J. Clin. Oncol. 3 accepted 249 73 29 4 55594258 55594258 T C ENST00000288135.5 75 GRCh37 KIT V654A is an exon 13 mutation that lies within the tyrosine kinase 1 domain of the protein. It has been shown to be an activating mutation by in vitro studies. This mutation is associated with imatinib resistance in melanoma patients. However, second generation TKI's such as sunitinib and midostaurin (PKC 412) have seen success in acheiving tumor response. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/249 https://civicdb.org/links/variants/73 https://civicdb.org/links/genes/29 false KRAS 3845 Exon 2 Mutation Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance Patients with colorectal cancer who harbor KRAS mutation have low response rate to cetuximab. 16618717 PubMed Lièvre et al., 2006, Cancer Res. 3 accepted 250 75 30 12 25398208 25398329 ENST00000256078.4 75 GRCh37 Exon 2 mutations have been associated with reduced response rates or resistance to EGFR inhibitors in non-small cell lung and colorectal cancer. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/250 https://civicdb.org/links/variants/75 https://civicdb.org/links/genes/30 false KRAS 3845 G12A Lung Adenocarcinoma 3910 Gefitinib,Erlotinib Substitutes Predictive Supports B Resistance KRAS mutations (N=29 G12, N=1 G13) were the primary predictor of EGFR TKI resistance in patients with lung adenocarcinoma (N=83). Overall survival (P=0.001) and progression-free survival (P=0.005) were significantly shorter in mutated patients. 19794967 PubMed Marchetti et al., 2009, Neoplasia 3 accepted 251 148 30 12 25398284 25398284 C G ENST00000256078.4 75 GRCh37 KRAS G12A, like EGFR T790M, has been shown to be capable of driving acquired resistance to tyrosine kinase inhibitors in lung adenocarcinoma. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/251 https://civicdb.org/links/variants/148 https://civicdb.org/links/genes/30 false PIK3CA 5290 H1047R Colorectal Cancer 9256 Cetuximab,Panitumumab Substitutes Predictive Does Not Support B Resistance In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS PIK3CA and PTEN were tested for mutation; PIK3CA H1047R was the only variant noted in the primary tumor (located in rectum) of one patient who experienced partial response (patient 38; Supplemental Table 1), following treatment. In the larger cohort, patients with tumors harboring any PIK3CA mutation had significantly shorter progression free survival and decreased incidence of objective response than patients with wtPIK3CA tumors. 19223544 PubMed Sartore-Bianchi et al., 2009, Cancer Res. 2 accepted 258 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2018-11-02 21:51:42 UTC https://civicdb.org/links/evidence_items/258 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false ABL1 25 BCR::ABL Acute Myeloid Leukemia 9119 Imatinib Predictive Supports A Sensitivity/Response Treatment of Philadelphia chromosome positive leukemias with imatinib results in high rates of complete remission in patients with CML. 12476305 PubMed Nimmanapalli et al., 2002, Oncogene 5 accepted 259 1 4 22 23522397 23632600 ENST00000305877.8 9 133729451 133763063 ENST00000318560.5 75 GRCh37 The BCR-ABL fusion protein, commonly referred to as the Philadelphia chromosome, is one of the most studied fusion genes in cancer. It has widely been considered the initiating event in chronic myelogenous leukemia (CML). However, despite its ability to initiate disease in mice, its status as an initiating mutation is in dispute. In what is commonly used as the poster-child for targeted therapeutics, the development and use of imatinib in the clinic has led to profound improvements in the prognosis of the disease. However, imatinib resistance is still seen in patients with mutations in the ABL kinase domain of the fusion, most notably the T315I variant. In patients resistant to imatinib, either acquired or otherwise, second generation BCR-ABL TKI's (dasatinib and nilotinib) have seen some success in delivering a tumor response. Third generation ABL1 inhibitor ponatinib is the only FDA approved drug with activity against T315I . However due to risk of life-threatening blood clots and severe narrowing of blood vessels ponatinib is ONLY approved for T315I-positive CML or T315I-positive Ph+ ALL or in cases of CML, Ph+ ALL with resistance or intolerance to other approved ABL1 inhibitors. Somatic 2016-03-03 00:09:52 UTC https://civicdb.org/links/evidence_items/259 https://civicdb.org/links/variants/1 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports A Sensitivity/Response The clinical use of imatinib in patients with BCR-ABL fusion has resulted in drastic prognostic improvements in patients with CML. 20537386 PubMed An et al., 2010, Leuk. Res. 5 accepted 260 1 4 22 23522397 23632600 ENST00000305877.8 9 133729451 133763063 ENST00000318560.5 75 GRCh37 The BCR-ABL fusion protein, commonly referred to as the Philadelphia chromosome, is one of the most studied fusion genes in cancer. It has widely been considered the initiating event in chronic myelogenous leukemia (CML). However, despite its ability to initiate disease in mice, its status as an initiating mutation is in dispute. In what is commonly used as the poster-child for targeted therapeutics, the development and use of imatinib in the clinic has led to profound improvements in the prognosis of the disease. However, imatinib resistance is still seen in patients with mutations in the ABL kinase domain of the fusion, most notably the T315I variant. In patients resistant to imatinib, either acquired or otherwise, second generation BCR-ABL TKI's (dasatinib and nilotinib) have seen some success in delivering a tumor response. Third generation ABL1 inhibitor ponatinib is the only FDA approved drug with activity against T315I . However due to risk of life-threatening blood clots and severe narrowing of blood vessels ponatinib is ONLY approved for T315I-positive CML or T315I-positive Ph+ ALL or in cases of CML, Ph+ ALL with resistance or intolerance to other approved ABL1 inhibitors. Somatic 2015-07-07 22:48:14 UTC https://civicdb.org/links/evidence_items/260 https://civicdb.org/links/variants/1 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Chronic Myeloid Leukemia 8552 Nilotinib,Dasatinib Substitutes Predictive Supports A Sensitivity/Response The use of nilotinib and dasatinib, second-generation BCR-ABL targeted therapies, has been effective in patients resistant to imatinib, leading to their FDA-approval. 20537386 PubMed An et al., 2010, Leuk. Res. 4 accepted 261 1 4 22 23522397 23632600 ENST00000305877.8 9 133729451 133763063 ENST00000318560.5 75 GRCh37 The BCR-ABL fusion protein, commonly referred to as the Philadelphia chromosome, is one of the most studied fusion genes in cancer. It has widely been considered the initiating event in chronic myelogenous leukemia (CML). However, despite its ability to initiate disease in mice, its status as an initiating mutation is in dispute. In what is commonly used as the poster-child for targeted therapeutics, the development and use of imatinib in the clinic has led to profound improvements in the prognosis of the disease. However, imatinib resistance is still seen in patients with mutations in the ABL kinase domain of the fusion, most notably the T315I variant. In patients resistant to imatinib, either acquired or otherwise, second generation BCR-ABL TKI's (dasatinib and nilotinib) have seen some success in delivering a tumor response. Third generation ABL1 inhibitor ponatinib is the only FDA approved drug with activity against T315I . However due to risk of life-threatening blood clots and severe narrowing of blood vessels ponatinib is ONLY approved for T315I-positive CML or T315I-positive Ph+ ALL or in cases of CML, Ph+ ALL with resistance or intolerance to other approved ABL1 inhibitors. Somatic 2017-05-31 00:51:29 UTC https://civicdb.org/links/evidence_items/261 https://civicdb.org/links/variants/1 https://civicdb.org/links/genes/4 false ALK 238 EML4::ALK Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Sensitivity/Response A 28 year-old patient with non-small cell lung cancer that failed conventional therapy was found to harbor the EML4-ALK (E13;A20) fusion using reverse transcription PCR. Treatment with 250mg crizotinib twice daily resulted in rapid improvement of symptoms and disease control for 5 months. 20979473 PubMed Choi et al., 2010, N. Engl. J. Med. 4 accepted 262 5 1 2 42396490 42522656 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The EML4-ALK fusion variant 1 consisting of ALK kinase domain (exons 20-29) fused to EML4 exons 1-13 is the most common EML4-ALK variant, and was discovered in non-small cell lung cancer. Multiple EML4 breakpoint shave been described with differential sensitivity to inhibitors with variant 1 showing greater sensitivity than 3a in cell lines. EML4-ALK is crizotinib sensitive; however, several mutations that confer resistance mutations have been described in case studies. In the only clinical trial for crizotinib that included determination of EML4-ALK variant type in a subset of its participants, a very high response rate was observed, although the numbers were insufficient to validate correlation of variant type to outcome. Preclinical studies with this variant have indicated sensitivity to Hsp90 inhibitors. Somatic 2020-09-01 17:00:06 UTC https://civicdb.org/links/evidence_items/262 https://civicdb.org/links/variants/5 https://civicdb.org/links/genes/1 false CCND3 896 Loss T-cell Lymphoblastic Leukemia/lymphoma 715 Palbociclib Predictive Supports D Sensitivity/Response Treatment of Notch-driven T-cell leukemia in Ccnd3 knockout mice with Palbociclib (PD-0332991) significantly increased median survival. 23079656 PubMed Sawai et al., 2012, Cancer Cell 3 accepted 263 23 10 6 41902671 41909586 ENST00000372991.4 75 GRCh37 Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK's) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are deregulated are widely variable, and range from genomic amplification to promoter methylation changes. Cyclin D3 loss has been reported in T-cell acute lymphoblastic leukemia (T-ALL), a seemingly unique trend when compared to the amplifcations and overexpressions of the other cyclin D's. Treating cyclin D3 knockout mice with the targeted therapeutic palbociclib significantly increased the median survival of a Notch-driven model of T-ALL. Somatic 2022-06-05 00:00:11 UTC https://civicdb.org/links/evidence_items/263 https://civicdb.org/links/variants/23 https://civicdb.org/links/genes/10 true CDK4 1019 EXPRESSION Estrogen-receptor Positive Breast Cancer 0060075 Alpelisib Predictive Supports D Sensitivity/Response In mouse xenograft studies of PIK3CA mutant breast cancers, the combination of PI3K and CDK4/6 inhibitors overcomes intrinsic and adaptive resistance leading to tumor regressions. 25002028 PubMed Vora et al., 2014, Cancer Cell NCT01219699 4 accepted 264 25 13 12 58141510 58146304 ENST00000257904.6 75 GRCh37 CDK4, along with its partner CDK6, are key players in cell cycle progression. The complex has been implicated in a number of cancer types, and is the focus of therapeutic research and development. One targeted therapy for CDK inhibition is palbociclib, which may slow the growth of advanced stage breast cancers. It has also been shown, in mouse, that CDK inhibition may sensitize mutant PIK3CA tumors to PI3K inhibitors. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/264 https://civicdb.org/links/variants/25 https://civicdb.org/links/genes/13 false DDR2 4921 G253C Lung Non-small Cell Carcinoma 3908 Dasatinib Predictive Supports D Sensitivity/Response In 3T3 fibroblasts expressing the G253C mutation have to be sensitive to the tyrosine kinase inhibitor dasatinib. 22328973 PubMed Hammerman et al., 2011, Cancer Discov 4 accepted 266 141 51 1 162729671 162729671 G T ENST00000367922.3 75 GRCh37 Activating mutations in DDR2, including G253C, has been shown to be sensitive to dasatinib in cell lines. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/266 https://civicdb.org/links/variants/141 https://civicdb.org/links/genes/51 false DDR2 4921 G505S Lung Non-small Cell Carcinoma 3908 Dasatinib Predictive Supports D Sensitivity/Response In 3T3 fibroblasts expressing the G505S mutation have to be sensitive to the tyrosine kinase inhibitor dasatinib. 22328973 PubMed Hammerman et al., 2011, Cancer Discov 4 accepted 267 142 51 1 162741822 162741822 G A ENST00000367922.3 75 GRCh37 Activating mutations in DDR2, including G505S, has been shown to be sensitive to dasatinib in cell lines. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/267 https://civicdb.org/links/variants/142 https://civicdb.org/links/genes/51 false DDR2 4921 G774V Lung Non-small Cell Carcinoma 3908 Dasatinib Predictive Supports D Sensitivity/Response In 3T3 fibroblasts expressing the G774V mutation have to be sensitive to the tyrosine kinase inhibitor dasatinib. 22328973 PubMed Hammerman et al., 2011, Cancer Discov 4 accepted 268 144 51 1 162748407 162748407 G T ENST00000367922.3 75 GRCh37 Activating mutations in DDR2, including G774V, has been shown to be sensitive to dasatinib in cell lines. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/268 https://civicdb.org/links/variants/144 https://civicdb.org/links/genes/51 false DDR2 4921 I638F Lung Non-small Cell Carcinoma 3908 Dasatinib Predictive Supports D Sensitivity/Response In 3T3 fibroblasts expressing the I638F mutation have to be sensitive to the tyrosine kinase inhibitor dasatinib. 22328973 PubMed Hammerman et al., 2011, Cancer Discov 4 accepted 269 143 51 1 162745497 162745497 A T ENST00000367922.3 75 GRCh37 DDR2 I638F has been shown to be a loss of function mutation, but also confers sensitivity to dasatinib in cell lines. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/269 https://civicdb.org/links/variants/143 https://civicdb.org/links/genes/51 false DDR2 4921 L239R Lung Non-small Cell Carcinoma 3908 Dasatinib Predictive Supports D Sensitivity/Response In 3T3 fibroblasts expressing the L239R mutation have to be sensitive to the tyrosine kinase inhibitor dasatinib. 22328973 PubMed Hammerman et al., 2011, Cancer Discov 4 accepted 270 140 51 1 162729630 162729630 T G ENST00000367922.3 75 GRCh37 Activating mutations in DDR2, including L239R, has been shown to be sensitive to dasatinib in cell lines. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/270 https://civicdb.org/links/variants/140 https://civicdb.org/links/genes/51 false DDR2 4921 L63V Lung Non-small Cell Carcinoma 3908 Dasatinib Predictive Supports D Sensitivity/Response In 3T3 fibroblasts expressing the L63V mutation have to be sensitive to the tyrosine kinase inhibitor dasatinib. 22328973 PubMed Hammerman et al., 2011, Cancer Discov 4 accepted 271 139 51 1 162724415 162724415 C G ENST00000367922.3 75 GRCh37 Activating mutations in DDR2, including L63V, has been shown to be sensitive to dasatinib in cell lines. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/271 https://civicdb.org/links/variants/139 https://civicdb.org/links/genes/51 false DDR2 4921 S768R Lung Non-small Cell Carcinoma 3908 Erlotinib,Dasatinib Combination Predictive Supports C Sensitivity/Response In a patient expressing a DDR2 S768R mutation, treatment with dasatinib plus erlotinib acheived a partial response. 22328973 PubMed Hammerman et al., 2011, Cancer Discov 3 accepted 272 145 51 1 162748390 162748390 T A ENST00000367922.3 75 GRCh37 Activating mutations in DDR2, including S768R, has been shown to be sensitive to dasatinib in cell lines. Somatic 2017-05-31 00:13:21 UTC https://civicdb.org/links/evidence_items/272 https://civicdb.org/links/variants/145 https://civicdb.org/links/genes/51 false EGFR 1956 Exon 19 Deletion Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports D Sensitivity/Response Exon 19 deletion has been shown to be correlated with gefitinib response. 16730237 PubMed Ji et al., 2006, Cancer Cell 4 accepted 273 133 19 7 55242415 55242513 ENST00000275493.2 75 GRCh37 Deletions within exon 19 of EGFR are most common in lung cancer. These deletions, in non-small cell lung cancer, have been shown to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib, afatinib, and erlotinib. There is also data to suggest that this event is a good prognostic marker in lung adenocarcinoma. Examples of exon 19 deletions include: p.746_A750delELREA, p.747_753delinsS, p.747_752delLREATS, and p.747_751delLREAT. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/273 https://civicdb.org/links/variants/133 https://civicdb.org/links/genes/19 false EGFR 1956 G719S Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports D Sensitivity/Response Gefinitib has been shown to be effective in treating cell lines with G719S missense mutations. 15118125 PubMed Paez et al., 2004, Science 4 accepted 274 134 19 7 55241707 55241707 G A ENST00000275493.2 75 GRCh37 While not as recurrent as the L858R mutation, EGFR G719S has also been shown to be an activating mutation. In lung cancer cell lines, it also confers sensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/274 https://civicdb.org/links/variants/134 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Gefitinib,Erlotinib Substitutes Predictive Supports B Sensitivity/Response In NSCLC patients treated with EGFR tyrosine kinase inhibitors, the presence of L858R mutation is prognostic for better progression free survival. 24457318 PubMed Fukihara et al., 2014, Oncology 4 accepted 275 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2016-02-18 18:39:43 UTC https://civicdb.org/links/evidence_items/275 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports D Sensitivity/Response Gefinitib has been shown to be effective in treating cell lines with L858R missense mutations. 15118125 PubMed Paez et al., 2004, Science 4 accepted 276 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/276 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Erlotinib,Pemetrexed Combination Predictive Supports C Sensitivity/Response In an NSCLC patient initially with L858R mutation, pemetrexed and cisplatin combination treatment was followed by erlotinib treatment. A slow progression developed which was found to be positive for L858R as well as T790M mutation which confers resistance to tyrosine kinase inhibitors. Due to slow tumor growth erlotinib was continued despite T790M, with re-addition of premetrexed, and this reduced tumor size and resulted in stable disease. 24636847 PubMed Li et al., 2014, Lung Cancer 3 accepted 277 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2017-05-31 02:19:22 UTC https://civicdb.org/links/evidence_items/277 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Staurosporine Predictive Supports E Sensitivity/Response In NSCLC containing a T790M mutation, staurosporine may be inhibitive of EGFR, especially when an L858R mutation is also present. 24658966 PubMed Ai et al., 2014, Amino Acids 1 accepted 278 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2015-06-21 16:49:49 UTC https://civicdb.org/links/evidence_items/278 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false ERBB2 2064 D769H Breast Cancer 1612 Lapatinib,Neratinib Substitutes Predictive Supports D Sensitivity/Response In MCF10A cell lines, the D769H mutation was shown to be sensitive to neratinib. 23220880 PubMed Bose et al., 2013, Cancer Discov 4 accepted 279 35 20 17 37880261 37880261 G C ENST00000269571.5 75 GRCh37 ERBB2 D769H was one of the first ERBB2 variants to be functionally classified (Bose et al. 2013). This mutation was shown to be an activating mutation in an in vitro assay. In the same paper, this mutation (along with other ERBB2 activating mutations) in MCF10A breast cancer cell lines were shown to be sensitive to the kinase inhibitor neratinib. More recent evidence may show that HER2 activating mutations confer sensitivity to a host of tyrosine kinase inhibitors, which is the topic of current clinical trials and research. Somatic 2017-10-21 23:12:01 UTC https://civicdb.org/links/evidence_items/279 https://civicdb.org/links/variants/35 https://civicdb.org/links/genes/20 false ERBB2 2064 D769Y Breast Cancer 1612 Neratinib Predictive Supports D Sensitivity/Response In MCF10A cell lines, the D769Y mutation was shown to be sensitive to neratinib. 23220880 PubMed Bose et al., 2013, Cancer Discov 4 accepted 280 36 20 17 37880261 37880261 G T ENST00000269571.5 75 GRCh37 ERBB2 D769Y was one of the first ERBB2 variants to be functionally classified (Bose et al., 2013). This mutation was shown to be an activating mutation in an in vitro assay. In the same paper, this mutation (along with other ERBB2 activating mutations) in MCF10A breast cancer cell lines have been shown to be sensitive to the kinase inhibitor neratinib. More recent evidence may show that HER2 acitivating mutations confer sensitivity to a host of tyrosine kinase inhibitors, which is the topic of current clinical trials and research. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/280 https://civicdb.org/links/variants/36 https://civicdb.org/links/genes/20 false ERBB2 2064 L755_T759del Breast Cancer 1612 Neratinib Predictive Supports D Sensitivity/Response In MCF10A cell lines retrovirally transduced with wildtype or mutant ERBB2, cells expressing the in-frame deletion of amino acids 755-759 were shown to be sensitive to neratinib. 23220880 PubMed Bose et al., 2013, Cancer Discov 5 accepted 281 37 20 17 37880219 37880233 TTGAGGGAAAACACA ENST00000269571.5 75 GRCh37 ERBB2 in-frame deletion of 755-759 was one of the first ERBB2 variants to be functionally classified (Bose et al. 2013). This mutation was shown to be an activating mutation in an in vitro assay. In the same paper, this mutation (along with other ERBB2 activating mutations) in MCF10A breast cancer cell lines have been shown to be sensitive to the kinase inhibitor neratinib. More recent evidence may show that HER2 acitivating mutations confer sensitivity to a host of tyrosine kinase inhibitors, which is the topic of current clinical trials and research. Somatic 2021-12-31 22:22:10 UTC https://civicdb.org/links/evidence_items/281 https://civicdb.org/links/variants/37 https://civicdb.org/links/genes/20 false ERBB2 2064 G309A Breast Cancer 1612 Neratinib Predictive Supports D Sensitivity/Response In MCF10A cell lines, the G309A mutation was shown to be sensitive to neratinib. 23220880 PubMed Bose et al., 2013, Cancer Discov 5 accepted 282 38 20 17 37868205 37868205 G C ENST00000269571.5 75 GRCh37 ERBB2 G309A was one of the first ERBB2 variants to be functionally classified (Bose et al. 2013). This mutation was shown to be an activating mutation in an in vitro assay. In the same paper, this mutation (along with other ERBB2 activating mutations) in MCF10A breast cancer cell lines have been shown to be sensitive to the kinase inhibitor neratinib. More recent evidence may show that HER2 acitivating mutations confer sensitivity to a host of tyrosine kinase inhibitors, which is the topic of current clinical trials and research. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/282 https://civicdb.org/links/variants/38 https://civicdb.org/links/genes/20 false ERBB2 2064 L755S Breast Cancer 1612 Neratinib Predictive Supports D Sensitivity/Response The L755S mutation showed mild response to neratinib in MCF10A cell lines retrovirally transduced with wildtype or mutant ERBB2. 23220880 PubMed Bose et al., 2013, Cancer Discov 5 accepted 283 39 20 17 37880220 37880220 T C ENST00000269571.5 75 GRCh37 ERBB2 L755S was one of the first ERBB2 variants to be functionally classified (Bose et al. 2013). This mutation was not shown to be an activating mutation, unlike many of the other variants queried. This mutation was also shown to confer resistance to the tyrosine kinase inhibitor lapatinib in MCF10A cell lines. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/283 https://civicdb.org/links/variants/39 https://civicdb.org/links/genes/20 false ERBB2 2064 L755W Breast Cancer 1612 Neratinib Predictive Supports D Sensitivity/Response MCF10A cells transduced with ERBB2 harboring an L755W mutation were sensitive to the irreversible kinase inhibitor neratinib in an matrigel colony forming assay. 23220880 PubMed Bose et al., 2013, Cancer Discov 5 accepted 284 40 20 17 37880220 37880220 T G ENST00000269571.5 75 GRCh37 ERBB2 L755W was one of the first ERBB2 variants to be functionally classified (Bose et al., 2013). This mutation was shown to be an activating mutation in an in vitro assay. In the same paper, this mutation (along with other ERBB2 activating mutations) in MCF10A breast cancer cell lines have been shown to be sensitive to the kinase inhibitor neratinib. More recent evidence may show that HER2 acitivating mutations confer sensitivity to a host of tyrosine kinase inhibitors, which is the topic of current clinical trials and research. Somatic 2021-12-31 21:28:56 UTC https://civicdb.org/links/evidence_items/284 https://civicdb.org/links/variants/40 https://civicdb.org/links/genes/20 true ERBB2 2064 P780INS Breast Cancer 1612 Neratinib Predictive Supports D Sensitivity/Response In MCF10A cell lines, the in-frame insertion of a single amino acid at position 780 was shown to be sensitive to neratinib. 23220880 PubMed Bose et al., 2013, Cancer Discov 5 accepted 285 41 20 17 37881011 37881012 GGCTCCCCA ENST00000269571.5 75 GRCh37 ERBB2 P780 insertion was one of the first ERBB2 variants to be functionally classified (Bose et al. 2013). This mutation was shown to be an activating mutation in an in vitro assay. In the same paper, this mutation (along with other ERBB2 activating mutations) in MCF10A breast cancer cell lines have been shown to be sensitive to the kinase inhibitor neratinib. More recent evidence may show that HER2 activating mutations confer sensitivity to a host of tyrosine kinase inhibitors, which is the topic of current clinical trials and research. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/285 https://civicdb.org/links/variants/41 https://civicdb.org/links/genes/20 false ERBB2 2064 R678Q Breast Cancer 1612 Lapatinib,Neratinib Substitutes Predictive Supports D Sensitivity/Response MCF10A cells transduced with ERBB2 harboring an R678Q mutation were sensitive to lapatinib and the irreversible kinase inhibitor neratinib in an matrigel colony forming assay. 23220880 PubMed Bose et al., 2013, Cancer Discov 5 accepted 286 42 20 17 37879658 37879658 G A ENST00000269571.5 75 GRCh37 ERBB2 R678Q was shown to have NO functional effect in tissue culture assay (Bose et al 2013). This conclusion was confirmed by a second, independent lab. Somatic 2017-05-31 15:40:02 UTC https://civicdb.org/links/evidence_items/286 https://civicdb.org/links/variants/42 https://civicdb.org/links/genes/20 false ERBB2 2064 R896C Breast Cancer 1612 Neratinib Predictive Supports D Sensitivity/Response In MCF10A cell lines, the R896C mutation was shown to be sensitive to neratinib. 23220880 PubMed Bose et al., 2013, Cancer Discov 5 accepted 287 43 20 17 37881616 37881616 C T ENST00000269571.5 75 GRCh37 ERBB2 R896C was one of the first ERBB2 variants to be functionally classified (Bose et al. 2013). This mutation was shown to be an activating mutation in an in vitro assay. In the same paper, this mutation (along with other ERBB2 activating mutations) in MCF10A breast cancer cell lines have been shown to be sensitive to the kinase inhibitor neratinib. More recent evidence may show that HER2 acitivating mutations confer sensitivity to a host of tyrosine kinase inhibitors, which is the topic of current clinical trials and research. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/287 https://civicdb.org/links/variants/43 https://civicdb.org/links/genes/20 false ERBB2 2064 V777L Breast Cancer 1612 Neratinib Predictive Supports D Sensitivity/Response In MCF10A cell lines, the V777L mutation was shown to be sensitive to neratinib. 23220880 PubMed Bose et al., 2013, Cancer Discov 5 accepted 288 44 20 17 37881000 37881000 G T ENST00000269571.5 75 GRCh37 ERBB2 V777L was one of the first ERBB2 variants to be functionally classified (Bose et al. 2013). This mutation was shown to be an activating mutation in an in vitro assay. In the same paper, this mutation (along with other ERBB2 activating mutations) in MCF10A breast cancer cell lines have been shown to be sensitive to the kinase inhibitor neratinib. More recent evidence may show that HER2 acitivating mutations confer sensitivity to a host of tyrosine kinase inhibitors, which is the topic of current clinical trials and research. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/288 https://civicdb.org/links/variants/44 https://civicdb.org/links/genes/20 false ERBB2 2064 V842I Breast Cancer 1612 Neratinib Predictive Supports D Sensitivity/Response In MCF10A cell lines, the V842I mutation was shown to be sensitive to neratinib. 23220880 PubMed Bose et al., 2013, Cancer Discov 5 accepted 289 45 20 17 37881332 37881332 G A ENST00000269571.5 75 GRCh37 ERBB2 V842I was one of the first ERBB2 variants to be functionally classified (Bose et al. 2013). This mutation was shown to be an activating mutation in an in vitro assay. In the same paper, this mutation (along with other ERBB2 activating mutations) in MCF10A breast cancer cell lines have been shown to be sensitive to the kinase inhibitor neratinib. More recent evidence may show that HER2 acitivating mutations confer sensitivity to a host of tyrosine kinase inhibitors, which is the topic of current clinical trials and research. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/289 https://civicdb.org/links/variants/45 https://civicdb.org/links/genes/20 false ESR1 2099 L536Q Breast Cancer 1612 Fulvestrant,Tamoxifen Substitutes Predictive Supports D Sensitivity/Response Using an estrogen response element (ERE)-luciferase reporter system co-transfected with one of five ESR1 mutants, the L536Q ligand binding domain mutation was shown to result in constitutive activity (response in the absence of beta-estradiol ligand) and continued responsiveness (inhibition of downstream target activation) to anti-estrogen therapies (tamoxifen or fulvestrant) in HEK293T cell lines. 24185510 PubMed Robinson et al., 2013, Nat. Genet. 5 accepted 290 46 21 6 152419920 152419921 TC AG ENST00000440973.1 75 GRCh37 ESR1 biology has become a central focus in breast cancer therapy. In ER+ tumors, mutations in the ESR1 ligand binding domain have been shown to confer resistance to hormone therapy. This evidence has led to an increased use of targeted sequencing of the estrogen receptor in breast and ovarian cancer. Y536Q is one of these ligand binding domain mutations, and is commonly implicated in this hormone resistance. Preliminary data suggests ER-degrading agents, such as fulvestrant, may be beneficial in treating ESR1 mutant, hormone resistant breast cancers. Somatic 2017-05-31 01:23:57 UTC https://civicdb.org/links/evidence_items/290 https://civicdb.org/links/variants/46 https://civicdb.org/links/genes/21 false ESR1 2099 D538G Breast Cancer 1612 Tamoxifen,Fulvestrant Substitutes Predictive Supports D Sensitivity/Response Using an estrogen response element (ERE)-luciferase reporter system co-transfected with one of five ESR1 mutants, the N538G ligand binding domain mutation was shown to result in constitutive activity (response in the absence of beta-estradiol ligand) and continued responsiveness (inhibition of downstream target activation) to anti-estrogen therapies (tamoxifen or fulvestrant) in HEK293T cell lines. 24185510 PubMed Robinson et al., 2013, Nat. Genet. 5 accepted 291 47 21 6 152419926 152419926 A G ENST00000206249.3 75 GRCh37 ESR1 biology has become a central focus in breast cancer therapy. In ER+ tumors, mutations in the ESR1 ligand binding domain have been shown to confer resistance to hormone therapy. This evidence has led to an increased use of targeted sequencing of the estrogen receptor in breast and ovarian cancer. D538G is one of these ligand binding domain mutations, and is commonly implicated in this hormone resistance. Preliminary data suggests ER-degrading agents, such as fulvestrant, may be beneficial in treating ESR1 mutant, hormone resistant breast cancers. Somatic 2017-05-31 01:24:19 UTC https://civicdb.org/links/evidence_items/291 https://civicdb.org/links/variants/47 https://civicdb.org/links/genes/21 false ESR1 2099 Y537C Breast Cancer 1612 Tamoxifen,Fulvestrant Substitutes Predictive Supports D Sensitivity/Response Using an estrogen response element (ERE)-luciferase reporter system co-transfected with one of five ESR1 mutants, the Y537C ligand binding domain mutation was shown to result in constitutive activity (response in the absence of beta-estradiol ligand) and continued responsiveness (inhibition of downstream target activation) to anti-estrogen therapies (tamoxifen or fulvestrant) in HEK293T cell lines. 24185510 PubMed Robinson et al., 2013, Nat. Genet. 5 accepted 292 48 21 6 152419923 152419923 A G ENST00000206249.3 75 GRCh37 ESR1 biology has become a central focus in breast cancer therapy. In ER+ tumors, mutations in the ESR1 ligand binding domain have been shown to confer resistance to hormone therapy. This evidence has led to an increased use of targeted sequencing of the estrogen receptor in breast and ovarian cancer. Y537C is one of these ligand binding domain mutations, and is commonly implicated in this hormone resistance. Preliminary data suggests ER-degrading agents, such as fulvestrant, may be beneficial in treating ESR1 mutant, hormone resistant breast cancers. Somatic 2017-05-31 01:24:51 UTC https://civicdb.org/links/evidence_items/292 https://civicdb.org/links/variants/48 https://civicdb.org/links/genes/21 false ESR1 2099 Y537N Breast Cancer 1612 Tamoxifen,Fulvestrant Substitutes Predictive Supports D Sensitivity/Response Using an estrogen response element (ERE)-luciferase reporter system co-transfected with one of five ESR1 mutants, the Y537N ligand binding domain mutation was shown to result in constitutive activity (response in the absence of beta-estradiol ligand) and continued responsiveness (inhibition of downstream target activation) to anti-estrogen therapies (tamoxifen or fulvestrant) in HEK293T cell lines. 24185510 PubMed Robinson et al., 2013, Nat. Genet. 5 accepted 293 49 21 6 152419922 152419922 T A ENST00000206249.3 75 GRCh37 ESR1 biology has become a central focus in breast cancer therapy. In ER+ tumors, mutations in the ESR1 ligand binding domain have been shown to confer resistance to hormone therapy. This evidence has led to an increased use of targeted sequencing of the estrogen receptor in breast and ovarian cancer. Y537N is one of these ligand binding domain mutations, and is commonly implicated in this hormone resistance. Preliminary data suggests ER-degrading agents, such as fulvestrant, may be beneficial in treating ESR1 mutant, hormone resistant breast cancers. Somatic 2017-05-31 01:25:14 UTC https://civicdb.org/links/evidence_items/293 https://civicdb.org/links/variants/49 https://civicdb.org/links/genes/21 false ESR1 2099 Y537S Breast Cancer 1612 Fulvestrant,Tamoxifen Substitutes Predictive Supports D Sensitivity/Response Using an estrogen response element (ERE)-luciferase reporter system co-transfected with one of five ESR1 mutants, the Y537S ligand binding domain mutation was shown to result in constitutive activity (response in the absence of beta-estradiol ligand) and continued responsiveness (inhibition of downstream target activation) to anti-estrogen therapies (tamoxifen or fulvestrant) in HEK293T cell lines. 24185510 PubMed Robinson et al., 2013, Nat. Genet. 5 accepted 294 50 21 6 152419923 152419923 A C ENST00000206249.3 75 GRCh37 ESR1 biology has become a central focus in breast cancer therapy. In ER+ tumors, mutations in the ESR1 ligand binding domain have been shown to confer resistance to hormone therapy. This evidence has led to an increased use of targeted sequencing of the estrogen receptor in breast and ovarian cancer. Y537S is one of these ligand binding domain mutations, and is commonly implicated in this hormone resistance. Preliminary data suggests ER-degrading agents, such as fulvestrant, may be beneficial in treating ESR1 mutant, hormone resistant breast cancers. Somatic 2017-05-31 01:18:53 UTC https://civicdb.org/links/evidence_items/294 https://civicdb.org/links/variants/50 https://civicdb.org/links/genes/21 false FGFR2 2263 FGFR2::MGEA5 Cholangiocarcinoma 4947 Ponatinib Predictive Supports C Sensitivity/Response In a single patient with this fusion in intrahepatic cholangiocarcinoma. Ponatinib treatment resulted in necrosis and shrinkage of the primary and metastatic sites and overall stable disease. However, this response did not meet criteria for RECIST partial response. 24550739 PubMed Borad et al., 2014, PLoS Genet. 2 accepted 295 52 22 10 123243212 123357917 ENST00000457416.2 10 103544209 103552700 ENST00000361464.3 75 GRCh37 In a clinical sequencing program for advanced stage cancers, Wu et al (2013, Cancer Discovery) has idenified a number of FGFR fusions in patients with many different cancer types. These fusions were also found to retain oligomerization capability, and result in enhanced cell proliferation. Cell lines harboring these fusions were shown to respond to pazopanib. Additionally, tumor size reduction was achieved by both ponatinib and pazopanib treatments administered separately in a single patient with intrahepatic cholangiocarcinoma and this fusion. The authors use these cases to highlight the need for enhanced clinical sequencing efforts. Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/295 https://civicdb.org/links/variants/52 https://civicdb.org/links/genes/22 false FGFR2 2263 FGFR2::TACC3 Cholangiocarcinoma 4947 Pazopanib,Ponatinib Sequential Predictive Supports C Sensitivity/Response In a 43 year old female patient with this fusion in intrahepatic cholangiocarcinoma. Both pazopanib and ponatinib separately resulted in minor tumor shrinkage. This fusion is also shown to be recurrent in multiple other cancer types. 24550739 PubMed Borad et al., 2014, PLoS Genet. 3 accepted 296 54 22 4 123243212 123357598 ENST00000358487.5 4 1723266 1741505 ENST00000313288.4 75 GRCh37 In a clinical sequencing program for advanced stage cancers, Wu et al has identified a number of FGFR fusions in patients with many different cancer types. These fusions were also found to retain oligomerization capability, and result in enhanced cell proliferation. These fusions were shown to respond to pazopanib. The authors use these cases to highlight the need for enhanced clinical sequencing efforts. Somatic 2017-05-31 00:16:50 UTC https://civicdb.org/links/evidence_items/296 https://civicdb.org/links/variants/54 https://civicdb.org/links/genes/22 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Lestaurtinib Predictive Supports B Sensitivity/Response CEP701 was effective in reducing blast counts of 5/14 heavily pre-treated AML patients with FLT3 mutations. 14726387 PubMed Smith et al., 2004, Blood 4 accepted 297 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/297 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Sorafenib Predictive Supports B Sensitivity/Response Sorafenib is effective in patients with FLT3 internal tandem repeats, but not in wild type or D835 mutation. 18230792 PubMed Zhang et al., 2008, J. Natl. Cancer Inst. 4 accepted 298 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2015-06-21 16:49:50 UTC https://civicdb.org/links/evidence_items/298 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Tyrphostin AG 1296 Predictive Supports D Sensitivity/Response AG1296 is effective in triggering apoptosis in Ba/F3 and primary AML cells with FLT3 internal tandem repeat. 12357354 PubMed Tse et al., 2002, Leukemia 4 accepted 299 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/299 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false GATA2 2624 EXPRESSION Lung Adenocarcinoma 3910 Fasudil,Bortezomib Combination Predictive Supports D Sensitivity/Response Targeting overactive GATA2-mediated pathways with inhibitors bortezomib and fasudil led to dramatic tumor regression. 22541434 PubMed Kumar et al., 2012, Cell 4 accepted 301 57 25 3 128198270 128212028 ENST00000341105.2 75 GRCh37 GATA2 misregulation has been observed in a number of hematologic malignancies, as well as non-small cell lung cancer. Treatment of over-active GATA2 pathways using the proteasome inhibitor bortezomib has shown dramatic tumor regression in lung cancer. Somatic 2016-11-03 19:01:10 UTC https://civicdb.org/links/evidence_items/301 https://civicdb.org/links/variants/57 https://civicdb.org/links/genes/25 false KIT 3815 Internal Duplication Malignant Anus Melanoma 14145 Imatinib Predictive Supports C Sensitivity/Response In a case study, a patient with anal melanoma harboring a 7 codon duplication in the juxtamambrane region (exon 11) of KIT showed marked response 4 months after imatinib treatment. 18421059 PubMed Hodi et al., 2008, J. Clin. Oncol. 3 accepted 302 67 29 4 55593582 55593708 ENST00000288135.5 75 GRCh37 c-KIT internal duplications have been observed in exon 11, within the juxtamembrane domain. In a case study of an anal melanoma patient harboring this event, imatinib confered marked response. Also, cells harboring exon 11 mutations have shown sensitivity to the tyrosine kinase inhibitor imatinib, offering a better prognosis to patients treated with the drug in the first year. Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/302 https://civicdb.org/links/variants/67 https://civicdb.org/links/genes/29 false KIT 3815 L576P Lung Non-small Cell Carcinoma 3908 Dasatinib,Nilotinib,Imatinib Substitutes Predictive Supports D Sensitivity/Response Ba/F3 cells harboring the KIT L576P mutation are sensitive to nilotinib, imatinib and lower concentrations of dasatinib. 17372901 PubMed Antonescu et al., 2007, Int. J. Cancer 3 accepted 303 72 29 4 55593661 55593661 T C ENST00000288135.5 75 GRCh37 KIT L576P is an exon 11 mutation that lies within the juxtamembrane domain. It is one of the most recurrent KIT mutations in melanoma, and both in vitro and in vivo studies have shown sensitivity to imatinib. Somatic 2019-02-25 19:15:40 UTC https://civicdb.org/links/evidence_items/303 https://civicdb.org/links/variants/72 https://civicdb.org/links/genes/29 false KIT 3815 V654A Gastrointestinal Stromal Tumor 9253 Sunitinib Predictive Supports B Sensitivity/Response In GIST tumor cells and patients harboring KIT V654A mutation, SU11248 is effective for those that are refractory to imatinib. 16638875 PubMed Prenen et al., 2006, Clin. Cancer Res. 3 accepted 304 73 29 4 55594258 55594258 T C ENST00000288135.5 75 GRCh37 KIT V654A is an exon 13 mutation that lies within the tyrosine kinase 1 domain of the protein. It has been shown to be an activating mutation by in vitro studies. This mutation is associated with imatinib resistance in melanoma patients. However, second generation TKI's such as sunitinib and midostaurin (PKC 412) have seen success in acheiving tumor response. Somatic 2015-08-05 18:28:35 UTC https://civicdb.org/links/evidence_items/304 https://civicdb.org/links/variants/73 https://civicdb.org/links/genes/29 false KRAS 3845 G12D Lung Non-small Cell Carcinoma 3908 Selumetinib,Dactolisib Combination Predictive Supports D Sensitivity/Response The use of NVP-BEZ235 in conjunction with ARRY-142886, but not as monotherapy, in a lung cancer model with KRAS G12D mutation led to marked tumor regression. 19029981 PubMed Engelman et al., 2008, Nat. Med. 4 accepted 305 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2017-05-30 23:57:42 UTC https://civicdb.org/links/evidence_items/305 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false KRAS 3845 G13D Colorectal Cancer 9256 Cetuximab Predictive Supports B Sensitivity/Response KRAS G13D mutation is associated with better response to Cetuximab with longer progression-free and overall survival in colorectal patients compared to other KRAS. 20978259 PubMed De Roock et al., 2010, JAMA 4 accepted 306 81 30 12 25398281 25398281 C T ENST00000256078.4 75 GRCh37 While the KRAS G13 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort. This mutation, along with the mutations affecting the neighboring G12 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, results are conflicting with retrospective analyses suggesting a better response to EGFR-Inhibition. A recent prospective phase-II study (12 patients, Schirripa et. al. 2015) could not reproduce this finding and another prospective phase II trial is currently ongoing. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/306 https://civicdb.org/links/variants/81 https://civicdb.org/links/genes/30 false MGMT 4255 Promoter Methylation Glioblastoma 3068 Temozolomide Predictive Supports A Sensitivity/Response In a randomized clinical trial, patients with MGMT promoter methylation benefitted from temozolomide. This benefit was also methylation status dependent, as those without methylation did not see increased survival. 15758010 PubMed Hegi et al., 2005, N. Engl. J. Med. 5 accepted 307 85 34 10 131264495 131265656 ENST00000306010.7 75 GRCh37 MGMT promoter methylation has been observed to impact tumor progression in glioblastoma multiforme. In patients exhibiting promoter methylation, the akylating agent carmustine has shown efficacy. In patients lacking methylation, combining carmustine with the MGMT inhibitor O(6)-benzylguanine may be effective, but more experiments are required. Clinical trials have also shown selective sensitivity of promoter methylation-positive patients to temozolomide, making a case for wider methylation screening in GBM patients. Somatic 2020-06-16 19:25:33 UTC https://civicdb.org/links/evidence_items/307 https://civicdb.org/links/variants/85 https://civicdb.org/links/genes/34 false MGMT 4255 Promoter Methylation Glioblastoma 3068 Carmustine Predictive Supports B Sensitivity/Response MGMT promoter methylation has been shown to confer sensitivity to alkylating agents, such as carmustine, in glioblastoma cells. 11070098 PubMed Esteller et al., 2000, N. Engl. J. Med. 4 accepted 308 85 34 10 131264495 131265656 ENST00000306010.7 75 GRCh37 MGMT promoter methylation has been observed to impact tumor progression in glioblastoma multiforme. In patients exhibiting promoter methylation, the akylating agent carmustine has shown efficacy. In patients lacking methylation, combining carmustine with the MGMT inhibitor O(6)-benzylguanine may be effective, but more experiments are required. Clinical trials have also shown selective sensitivity of promoter methylation-positive patients to temozolomide, making a case for wider methylation screening in GBM patients. Somatic 2015-06-21 16:49:50 UTC https://civicdb.org/links/evidence_items/308 https://civicdb.org/links/variants/85 https://civicdb.org/links/genes/34 false MGMT 4255 Promoter Methylation Glioblastoma 3068 O6-Benzylguanine Predictive Supports E Sensitivity/Response In patients lacking MGMT promoter methylation, the use of an MGMT inhibitor, such as O(6)-benzylguanine, in combination with alkylating agents (Carmustine) may be useful in treating patients with initial resistance to alkylating agents. 11070098 PubMed Esteller et al., 2000, N. Engl. J. Med. 4 accepted 309 85 34 10 131264495 131265656 ENST00000306010.7 75 GRCh37 MGMT promoter methylation has been observed to impact tumor progression in glioblastoma multiforme. In patients exhibiting promoter methylation, the akylating agent carmustine has shown efficacy. In patients lacking methylation, combining carmustine with the MGMT inhibitor O(6)-benzylguanine may be effective, but more experiments are required. Clinical trials have also shown selective sensitivity of promoter methylation-positive patients to temozolomide, making a case for wider methylation screening in GBM patients. Somatic 2015-06-21 16:49:51 UTC https://civicdb.org/links/evidence_items/309 https://civicdb.org/links/variants/85 https://civicdb.org/links/genes/34 false PIK3CA 5290 E542K Breast Cancer 1612 PI3K-alpha Inhibitor MEN1611 Predictive Supports D Sensitivity/Response Breast cancer cell lines with E542K/E545K mutations showed increased sensitivity to CH5132799 than cells with wild-type PIK3CA gene. 21558396 PubMed Tanaka et al., 2011, Clin. Cancer Res. 4 accepted 310 103 37 3 178936082 178936082 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K variants are the second most recurrent PIK3CA mutations in breast cancer and are highly recurrent mutations in many other cancer types. Colorectal cancer patients with the PIK3CA E545K variant, and possibly other variants in the E545 region, may indicate poor prognosis relative to patients with other PIK3CA variants or wild-type PIK3CA. The literature also suggests that E545/E542 variants may confer resistance to EGFR inhibitors (e.g., cetuximab). An FDA approved treatment regimen including a targeted PIK3CA inhibitor is available for specific subtypes of breast cancer. While PIK3CA variants are highly prevalent in many other cancer types, targeted therapies for PIK3CA variants are still in early clinical trial phases in other cancer types. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/310 https://civicdb.org/links/variants/103 https://civicdb.org/links/genes/37 false PIK3CA 5290 E542K Breast Cancer 1612 Sirolimus Predictive Supports D Sensitivity/Response Rapamycin inhibits transformation induced by mutation in PIK3CA. 15647370 PubMed Kang et al., 2005, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 311 103 37 3 178936082 178936082 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K variants are the second most recurrent PIK3CA mutations in breast cancer and are highly recurrent mutations in many other cancer types. Colorectal cancer patients with the PIK3CA E545K variant, and possibly other variants in the E545 region, may indicate poor prognosis relative to patients with other PIK3CA variants or wild-type PIK3CA. The literature also suggests that E545/E542 variants may confer resistance to EGFR inhibitors (e.g., cetuximab). An FDA approved treatment regimen including a targeted PIK3CA inhibitor is available for specific subtypes of breast cancer. While PIK3CA variants are highly prevalent in many other cancer types, targeted therapies for PIK3CA variants are still in early clinical trial phases in other cancer types. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/311 https://civicdb.org/links/variants/103 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Breast Cancer 1612 PI3K-alpha Inhibitor MEN1611 Predictive Supports D Sensitivity/Response Breast cancer cell lines with H1047R mutation showed increased sensitivity to CH5132799 than cells with wild-type PIK3CA gene. 21558396 PubMed Tanaka et al., 2011, Clin. Cancer Res. 4 accepted 314 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/314 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false PML 5371 PML::RARA Acute Promyelocytic Leukemia 0060318 Tretinoin Predictive Supports B Sensitivity/Response Fusion protein degradation is accelerated upon ATRA treatment of acute promyelocytic cells at pharmalogical concentrations. 8674046 PubMed Yoshida et al., 1996, Cancer Res. 5 accepted 316 108 39 15 74287058 74325755 ENST00000268058.3 17 38504568 38513048 ENST00000254066.5 75 GRCh37 The PML-RARA fusion is seen as a diagnostic event in acute promyelocytic leukemia (APL). Both in vitro and in vivo studies have shown sensitivity to ATRA in APL patients harboring the PML-RARa fusion. Recent interest has been shown in combining ATRA and arsenic trioxide for treating these patients, and early results seem promising. Somatic 2016-02-25 18:44:19 UTC https://civicdb.org/links/evidence_items/316 https://civicdb.org/links/variants/108 https://civicdb.org/links/genes/39 false PTEN 5728 R233* Breast Cancer 1612 MTOR Inhibitor Predictive Supports D Sensitivity/Response Cells with PTEN deficiency have been shown to exhibit slowed growth in reponse to PI3K-mTOR inhibitors. 20085938 PubMed Courtney et al., 2010, J. Clin. Oncol. 4 accepted 317 110 41 10 89717672 89717672 C T ENST00000371953.3 75 GRCh37 PTEN R233* has been shown to be a loss of function mutation, and PTEN loss has been the subject of considerable research in breast cancer. PTEN loss may sensitize cells to PI3K-mTOR inhibition. While still being debated, there is data to support that PTEN loss is both associated with poorer prognosis, and no change in prognosis. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/317 https://civicdb.org/links/variants/110 https://civicdb.org/links/genes/41 false TP53 7157 R175H Breast Cancer 1612 Doxorubicin Predictive Supports D Sensitivity/Response Breast tumors in a mouse model with R172H mutation (homologous to human R175H) are more responsive to doxorubicin than breast tumors with wild type TP53. 22698404 PubMed Jackson et al., 2012, Cancer Cell 3 accepted 319 116 45 17 7578406 7578406 C T ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R175H variant seems not only to result in loss of tumor-suppression, but also acts as a gain-of-function mutation that promotes tumorigenesis in mouse models. Cell lines harboring this mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been shown that the R175H mutation is correlated with worse overall survival than wild-type TP53, but is not as detrimental as the R248W variant. This variant is rare in population databases (ACMG code: PM2; 0.000003980 total exome AF gnomAD v2.1.1). Somatic 2018-05-23 18:10:53 UTC https://civicdb.org/links/evidence_items/319 https://civicdb.org/links/variants/116 https://civicdb.org/links/genes/45 false TSC1 7248 Frameshift Truncation Invasive Bladder Transitional Cell Carcinoma 6477 Everolimus Predictive Supports B Sensitivity/Response A patient with metastatic bladder cancer that responded well to the mTOR inhibitor everolimus was shown to harbor a TSC1 frameshift truncation mutation (c.1907_1908del, p.Glu636fs) and a nonsense NF2 mutation. 2/3 additional patients with TSC1 mutations also had mild responses to everolimus. 22923433 PubMed Iyer et al., 2012, Science NCT00805129 3 accepted 320 124 46 9 135766735 135820008 ENST00000298552.3 75 GRCh37 In a small cohort study of bladder cancer, patients with TSC1 mutations showed better responses to and increased treatment duration tolerance with the mTOR inhibitor everolimus. Additionally, patient-derived bladder cancer cell lines with TSC1 or TSC2 mutations are much more sensitive to everolimus treatment than TSC1/TSC2 wildtype cells. Somatic 2015-12-24 22:51:47 UTC https://civicdb.org/links/evidence_items/320 https://civicdb.org/links/variants/124 https://civicdb.org/links/genes/46 false FLT3 2322 TKD MUTATION Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A AML patients with D835 mutation of FLT3 did not have worse overall survival than patients with wild type FLT3. 11290608 PubMed Yamamoto et al., 2001, Blood 3 accepted 322 56 24 13 28592642 28592642 C A ENST00000241453.7 75 GRCh37 FLT3 tyrosine kinase domain mutations (FLT3-TKD) are much less common than FLT3-ITD (internal tandem duplication) mutations and may not confer the same prognostic impact. Although the majority of mutations are point mutations effecting D835 (most frequently D835Y), a small proportion involve an in-frame deletion of I836. These mutations are within the activation loop of the second tyrosine kinase domain of FLT3 and thought to result in constitutive activation of the receptor. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/322 https://civicdb.org/links/variants/56 https://civicdb.org/links/genes/24 false IDH1 3417 R132 Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A The complete remission and overall survival rates in patients with IDH1 R132 mutation is not significantly different from those who do not have this mutation. 20368538 PubMed Wagner et al., 2010, J. Clin. Oncol. 2 accepted 323 58 26 2 209113111 209113113 ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes, IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/323 https://civicdb.org/links/variants/58 https://civicdb.org/links/genes/26 false IDH1 3417 R132C Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A IDH1 R132 mutation in patients with AML is not associated with any prognostic value compared to patients with wild-type IDH1. 20538800 PubMed Abbas et al., 2010, Blood 2 accepted 324 59 26 2 209113113 209113113 G A ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes and acute myeloid leukemia (AML), IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2015-06-21 16:49:51 UTC https://civicdb.org/links/evidence_items/324 https://civicdb.org/links/variants/59 https://civicdb.org/links/genes/26 false IDH2 3418 R140 Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A In this meta-analysis of adult non-promyelocytic AML (11 studies), patients with IDH2 R140 or R172 mutations had event free survival and overall survival similar to those with wild-type IDH2. 22616558 PubMed Zhou et al., 2012, Leuk. Lymphoma 2 accepted 327 62 27 15 90631934 90631934 ENST00000330062.3 75 GRCh37 IDH2 mutations have been observed in a number of hematologic malignancies. In acute myeloid leukemia, the R140 mutants show mixed results affecting overall survival as compared to their wild-type counterparts. In myelodysplastic syndromes, however, no prognostic link was discovered between IDH2 mutation status and overall survival. Somatic 2016-06-27 23:43:11 UTC https://civicdb.org/links/evidence_items/327 https://civicdb.org/links/variants/62 https://civicdb.org/links/genes/27 false IDH2 3418 Mutation Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A In patients with IDH2 R140 and R172 mutation, the presence of mutation does not impact overall survival or disease free survival. 20421455 PubMed Thol et al., 2010, Blood NCT00209833 3 accepted 328 570 27 15 90626277 90645736 ENST00000330062.3 75 GRCh37 Somatic 2016-06-29 18:21:39 UTC https://civicdb.org/links/evidence_items/328 https://civicdb.org/links/variants/570 https://civicdb.org/links/genes/27 false IDH2 3418 R140 Myelodysplastic Syndrome 0050908 Prognostic Does Not Support B N/A In patients with myelodysplastic syndrome, the presence of IDH2 R140Q (N=3) or IDH1 R132 (N=2) mutations did not confer prognostic value (overall survival) compared to wild-type IDH1/2 patients (N=61; P=0.794). 21997850 PubMed Lin et al., 2012, Ann. Hematol. 2 accepted 329 62 27 15 90631934 90631934 ENST00000330062.3 75 GRCh37 IDH2 mutations have been observed in a number of hematologic malignancies. In acute myeloid leukemia, the R140 mutants show mixed results affecting overall survival as compared to their wild-type counterparts. In myelodysplastic syndromes, however, no prognostic link was discovered between IDH2 mutation status and overall survival. Somatic 2016-07-17 21:31:39 UTC https://civicdb.org/links/evidence_items/329 https://civicdb.org/links/variants/62 https://civicdb.org/links/genes/27 false IDH2 3418 R140 Myelodysplastic Syndrome 0050908 Prognostic Does Not Support B N/A R140Q mutation in IDH2 does not have prognostic value in patients with MDS. 22033490 PubMed Patnaik et al., 2012, Leukemia 3 accepted 330 62 27 15 90631934 90631934 ENST00000330062.3 75 GRCh37 IDH2 mutations have been observed in a number of hematologic malignancies. In acute myeloid leukemia, the R140 mutants show mixed results affecting overall survival as compared to their wild-type counterparts. In myelodysplastic syndromes, however, no prognostic link was discovered between IDH2 mutation status and overall survival. Somatic 2015-06-21 16:49:51 UTC https://civicdb.org/links/evidence_items/330 https://civicdb.org/links/variants/62 https://civicdb.org/links/genes/27 false IDH2 3418 R172K Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A AML patients with IDH2 mutations such as R172K have event free survival and overall survival similar to those with wild-type IDH2. 22616558 PubMed Zhou et al., 2012, Leuk. Lymphoma 2 accepted 331 63 27 15 90631838 90631838 C T ENST00000330062.3 75 GRCh37 IDH2 mutations have been observed in a number of hematologic malignancies. In acute myeloid leukemia, the R172K mutation has been linked with poorer prognosis and worse overall survival than IDH2 wild-type patients. However, in myelodisplastic syndromes, studies did not find a prognostic association between this variant and patient outcomes. Somatic 2015-06-21 16:49:51 UTC https://civicdb.org/links/evidence_items/331 https://civicdb.org/links/variants/63 https://civicdb.org/links/genes/27 false IDH2 3418 R172K Myelodysplastic Syndrome 0050908 Prognostic Does Not Support B N/A In patients suffering from MDS, the presence of IDH2 mutations such as R172K do not confer prognostic value (overall survival). 21997850 PubMed Lin et al., 2012, Ann. Hematol. 2 accepted 332 63 27 15 90631838 90631838 C T ENST00000330062.3 75 GRCh37 IDH2 mutations have been observed in a number of hematologic malignancies. In acute myeloid leukemia, the R172K mutation has been linked with poorer prognosis and worse overall survival than IDH2 wild-type patients. However, in myelodisplastic syndromes, studies did not find a prognostic association between this variant and patient outcomes. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/332 https://civicdb.org/links/variants/63 https://civicdb.org/links/genes/27 false KIT 3815 Exon 11 Mutation Gastrointestinal Stromal Tumor 9253 Prognostic Does Not Support B N/A KIT mutations were identified in morphologically benign, incidentally discovered GISTs at a rate similar to that seen in advanced, metastatic GIST patients indicating is not a prognostic marker for GIST. 12000708 PubMed Corless et al., 2002, Am. J. Pathol. 3 accepted 333 66 29 4 55593582 55593708 ENST00000288135.5 75 GRCh37 c-KIT mutations in exon 11 lie within the juxtamembrane domain, and are very recurrent in gastrointestinal stromal tumors, often bearing a poorer prognosis than other KIT mutations. Cells harboring exon 11 mutations have shown sensitivity to the tyrosine kinase inhibitor imatinib, offering a better prognosis to patients treated with the drug in the first year. Small cohorts of melanoma patients harboring exon 11 KIT mutations have shown response to imatinib and sunitinib. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/333 https://civicdb.org/links/variants/66 https://civicdb.org/links/genes/29 false KIT 3815 Exon 11 Mutation Lung Cancer 1324 Prognostic Does Not Support B N/A KIT mutations detected in 5/60 patients showed no prognostic significance in patients with small cell lung cancer. 15217946 PubMed Boldrini et al., 2004, Clin. Cancer Res. 2 accepted 334 66 29 4 55593582 55593708 ENST00000288135.5 75 GRCh37 c-KIT mutations in exon 11 lie within the juxtamembrane domain, and are very recurrent in gastrointestinal stromal tumors, often bearing a poorer prognosis than other KIT mutations. Cells harboring exon 11 mutations have shown sensitivity to the tyrosine kinase inhibitor imatinib, offering a better prognosis to patients treated with the drug in the first year. Small cohorts of melanoma patients harboring exon 11 KIT mutations have shown response to imatinib and sunitinib. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/334 https://civicdb.org/links/variants/66 https://civicdb.org/links/genes/29 false KRAS 3845 G12 Colorectal Cancer 9256 Prognostic Does Not Support B N/A In patients with stage III colorectal cancer undergoing chemotherapy, KRAS G12 mutation did not impact overall or disease free survival. 19934290 PubMed Ogino et al., 2009, Clin. Cancer Res. 4 accepted 336 76 30 12 25398284 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2015-08-05 18:28:35 UTC https://civicdb.org/links/evidence_items/336 https://civicdb.org/links/variants/76 https://civicdb.org/links/genes/30 false KRAS 3845 G12 Lung Non-small Cell Carcinoma 3908 Prognostic Does Not Support B N/A There is no strong association between KRAS mutation status and overall or progression free survival in patients with NSCLC. 11208838 PubMed Schiller et al., 2001, J. Clin. Oncol. 3 accepted 337 76 30 12 25398284 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/337 https://civicdb.org/links/variants/76 https://civicdb.org/links/genes/30 false U2AF1 7307 Q157P/R Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A In patients with AML, those who harbor Q157P/R mutation of U2AF1 do not show a statistically significant difference in complete remission rate compared to those who harbor wild type U2AF1. 23029227 PubMed Qian et al., 2012, PLoS ONE 2 accepted 338 127 48 21 44514777 44514777 T G ENST00000291552.4 75 GRCh37 U2AF1 Q157P/R has been shown to be a recurrent mutation in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and lung adenocarcinomas. This mutation is less common than the S34F mutation, occurs in the second zinc finger domain of U2AF1 and has been demonstrated to alter splicing. The impact of U2AF1 mutations on overall survival in MDS has been debated, however, patients with U2AF1 mutations were shown to be at an increased risk of transformation to secondary AML. The presence of this mutation was not associated with a specific prognostic outcome in AML when compared to U2AF1 wildtype patients. Somatic 2016-02-17 17:16:37 UTC https://civicdb.org/links/evidence_items/338 https://civicdb.org/links/variants/127 https://civicdb.org/links/genes/48 false U2AF1 7307 Q157P/R Myelodysplastic Syndrome 0050908 Prognostic Does Not Support B N/A In patients with MDS, those who harbor Q157P/R mutation of U2AF do not show statistical significance in complete remission rate compared to those who harbor wild type U2AF. 23029227 PubMed Qian et al., 2012, PLoS ONE 2 accepted 339 127 48 21 44514777 44514777 T G ENST00000291552.4 75 GRCh37 U2AF1 Q157P/R has been shown to be a recurrent mutation in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and lung adenocarcinomas. This mutation is less common than the S34F mutation, occurs in the second zinc finger domain of U2AF1 and has been demonstrated to alter splicing. The impact of U2AF1 mutations on overall survival in MDS has been debated, however, patients with U2AF1 mutations were shown to be at an increased risk of transformation to secondary AML. The presence of this mutation was not associated with a specific prognostic outcome in AML when compared to U2AF1 wildtype patients. Somatic 2016-02-13 05:36:38 UTC https://civicdb.org/links/evidence_items/339 https://civicdb.org/links/variants/127 https://civicdb.org/links/genes/48 false U2AF1 7307 S34Y/F Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A In patients with AML, complete remission rates are not different between patients who harbor the U2AF1 S34Y/F mutation and those with wild type U2AF1. 23029227 PubMed Qian et al., 2012, PLoS ONE 2 accepted 340 128 48 21 44524456 44524456 G A ENST00000291552.4 75 GRCh37 U2AF1 S34Y/F has been shown to be a recurrent mutation in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and lung adenocarcinomas. This mutation is the most commonly identified variant in MDS, occurs in the first zinc finger domain of U2AF1 and has been demonstrated to alter splicing. The impact of U2AF1 mutations on overall survival in MDS has been debated, however, patients with U2AF1 mutations were shown to be at an increased risk of transformation to secondary AML. The presence of this mutation was not associated with a specific prognostic outcome in AML when compared to U2AF1 wildtype patients. Somatic 2016-02-13 05:38:59 UTC https://civicdb.org/links/evidence_items/340 https://civicdb.org/links/variants/128 https://civicdb.org/links/genes/48 false CCND1 595 Expression Lung Non-small Cell Carcinoma 3908 Prognostic Does Not Support B Poor Outcome Three studies have found no significant survival impact for CCND1 in lung cancer. 17070615 PubMed Gautschi et al., 2007, Lung Cancer 3 accepted 342 19 8 11 69455855 69469242 ENST00000227507.2 75 GRCh37 CCND1 expression, and its prognositc impact, is still in dispute. Three experiments in non-small cell lung cancer have shown it to have no impact on survival, but three additional studies have shown it results in poorer prognosis. There is also some ambiguity in how the boundaries between expression and overexpression are defined. Somatic 2015-06-21 16:49:52 UTC https://civicdb.org/links/evidence_items/342 https://civicdb.org/links/variants/19 https://civicdb.org/links/genes/8 false PTEN 5728 R233* Glioblastoma 3068 Prognostic Does Not Support B Poor Outcome PTEN nonsense mutations, including R233*, have been shown to be inactivating and loss-of-function, but do not have prognostic value in glioblastoma multiforme patients. 22479427 PubMed Carico et al., 2012, PLoS ONE 3 accepted 343 110 41 10 89717672 89717672 C T ENST00000371953.3 75 GRCh37 PTEN R233* has been shown to be a loss of function mutation, and PTEN loss has been the subject of considerable research in breast cancer. PTEN loss may sensitize cells to PI3K-mTOR inhibition. While still being debated, there is data to support that PTEN loss is both associated with poorer prognosis, and no change in prognosis. Somatic 2015-06-21 16:49:52 UTC https://civicdb.org/links/evidence_items/343 https://civicdb.org/links/variants/110 https://civicdb.org/links/genes/41 false ABL1 25 BCR::ABL Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports A Sensitivity/Response BCR-ABL inhibitors such as imatinib have lead to significantly improved prognosis, response rate, overall survival, and patient outcome in CML patients compared to previous therapeutic regimens. 20537386 PubMed An et al., 2010, Leuk. Res. 5 accepted 344 1 4 22 23522397 23632600 ENST00000305877.8 9 133729451 133763063 ENST00000318560.5 75 GRCh37 The BCR-ABL fusion protein, commonly referred to as the Philadelphia chromosome, is one of the most studied fusion genes in cancer. It has widely been considered the initiating event in chronic myelogenous leukemia (CML). However, despite its ability to initiate disease in mice, its status as an initiating mutation is in dispute. In what is commonly used as the poster-child for targeted therapeutics, the development and use of imatinib in the clinic has led to profound improvements in the prognosis of the disease. However, imatinib resistance is still seen in patients with mutations in the ABL kinase domain of the fusion, most notably the T315I variant. In patients resistant to imatinib, either acquired or otherwise, second generation BCR-ABL TKI's (dasatinib and nilotinib) have seen some success in delivering a tumor response. Third generation ABL1 inhibitor ponatinib is the only FDA approved drug with activity against T315I . However due to risk of life-threatening blood clots and severe narrowing of blood vessels ponatinib is ONLY approved for T315I-positive CML or T315I-positive Ph+ ALL or in cases of CML, Ph+ ALL with resistance or intolerance to other approved ABL1 inhibitors. Somatic 2016-10-04 08:14:34 UTC https://civicdb.org/links/evidence_items/344 https://civicdb.org/links/variants/1 https://civicdb.org/links/genes/4 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Better Outcome Median survival of patients with EGFR L858R mutation is better than those with wild type EGFR. 24662454 PubMed Douillard et al., 2014, J Thorac Oncol 3 accepted 347 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2015-06-21 16:49:52 UTC https://civicdb.org/links/evidence_items/347 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false IDH1 3417 R132 Malignant Astrocytoma 3069 Prognostic Supports B Better Outcome In patients with astrocytoma, the presence of IDH1 R132 mutation is prognostic for better survival compared to patients who harbor wild type mutation. 19933982 PubMed Dubbink et al., 2009, Neurology 3 accepted 348 58 26 2 209113111 209113113 ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes, IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2015-06-21 16:49:52 UTC https://civicdb.org/links/evidence_items/348 https://civicdb.org/links/variants/58 https://civicdb.org/links/genes/26 false IDH1 3417 R132 Glioblastoma 3068 Prognostic Supports B Better Outcome In patients with glioblastoma, those harboring IDH1 R132 mutation has higher overall survival compared to those who do not have IDH1 mutation. 20127344 PubMed Bleeker et al., 2010, Acta Neuropathol. 3 accepted 349 58 26 2 209113111 209113113 ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes, IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/349 https://civicdb.org/links/variants/58 https://civicdb.org/links/genes/26 false IDH2 3418 R140 Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome In AML, patients with IDH2 R140 mutation have improved overall survival compared to those with wild-type IDH2. 21596855 PubMed Green et al., 2011, Blood 3 accepted 350 62 27 15 90631934 90631934 ENST00000330062.3 75 GRCh37 IDH2 mutations have been observed in a number of hematologic malignancies. In acute myeloid leukemia, the R140 mutants show mixed results affecting overall survival as compared to their wild-type counterparts. In myelodysplastic syndromes, however, no prognostic link was discovered between IDH2 mutation status and overall survival. Somatic 2016-06-28 00:05:40 UTC https://civicdb.org/links/evidence_items/350 https://civicdb.org/links/variants/62 https://civicdb.org/links/genes/27 false SF3B1 23451 Mutation Myelodysplastic Syndrome 0050908 Prognostic Supports B Better Outcome Patients with SF3B1 mutations had a statistically significant longer overall survival as well as event free-survival. Both before and after adjustment for age, karyotype and sex. 21995386 PubMed Papaemmanuil et al., 2011, N. Engl. J. Med. 3 accepted 352 215 44 2 198254508 198299815 ENST00000335508.6 75 GRCh37 Somatic 2016-11-04 23:17:21 UTC https://civicdb.org/links/evidence_items/352 https://civicdb.org/links/variants/215 https://civicdb.org/links/genes/44 false CCND1 595 Amplification Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome Inceased copy number of CCND1 is associated with poorer overall survival. 17070615 PubMed Gautschi et al., 2007, Lung Cancer 3 accepted 354 18 8 11 69455855 69469242 ENST00000227507.2 75 GRCh37 CCND1 amplification has been implicated in poorer prognosis in non-small cell lung cancer. Somatic 2015-06-21 16:49:52 UTC https://civicdb.org/links/evidence_items/354 https://civicdb.org/links/variants/18 https://civicdb.org/links/genes/8 false CCND1 595 Expression Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome Three studies have associated CCND1 expression with poorer survival. 17070615 PubMed Gautschi et al., 2007, Lung Cancer 3 accepted 355 19 8 11 69455855 69469242 ENST00000227507.2 75 GRCh37 CCND1 expression, and its prognositc impact, is still in dispute. Three experiments in non-small cell lung cancer have shown it to have no impact on survival, but three additional studies have shown it results in poorer prognosis. There is also some ambiguity in how the boundaries between expression and overexpression are defined. Somatic 2015-06-21 16:49:52 UTC https://civicdb.org/links/evidence_items/355 https://civicdb.org/links/variants/19 https://civicdb.org/links/genes/8 false CCND1 595 Overexpression Breast Cancer 1612 Prognostic Supports B Poor Outcome In ER-positive breast cancer patients, Cyclin D1 overexpression is associated with shorter overall survival and increased metastasis. 15961768 PubMed Arnold et al., 2005, J. Clin. Oncol. 4 accepted 356 20 8 11 69455855 69469242 ENST00000227507.2 75 GRCh37 Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK's) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, and range from genomic amplification to promoter methylation changes. While Cyclin D2 has only been found to be significantly misregulated in glioma, Cyclin D1 in particular seems to be a pan-cancer actor. Cyclin D misregulation has been shown to lead to poorer outcomes in a number of studies, and currently there are no FDA-approved targeted therapies. N/A 2020-10-22 01:52:57 UTC https://civicdb.org/links/evidence_items/356 https://civicdb.org/links/variants/20 https://civicdb.org/links/genes/8 false CCND1 595 Overexpression Head And Neck Squamous Cell Carcinoma 5520 Prognostic Supports B Poor Outcome Cyclin D1 overexpression is associated with shorter overall survival and increased metastasis in head and neck squamous cell carcinoma. 16309541 PubMed Thomas et al., 2005, Int J Exp Pathol 4 accepted 357 20 8 11 69455855 69469242 ENST00000227507.2 75 GRCh37 Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK's) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, and range from genomic amplification to promoter methylation changes. While Cyclin D2 has only been found to be significantly misregulated in glioma, Cyclin D1 in particular seems to be a pan-cancer actor. Cyclin D misregulation has been shown to lead to poorer outcomes in a number of studies, and currently there are no FDA-approved targeted therapies. N/A 2020-10-22 01:52:47 UTC https://civicdb.org/links/evidence_items/357 https://civicdb.org/links/variants/20 https://civicdb.org/links/genes/8 false CCND1 595 Overexpression Mantle Cell Lymphoma 0050746 Prognostic Supports B Poor Outcome Cyclin D1 overexpression is associated with shorter overall survival and increased metastasis in mantle cell lymphoma. 17891190 PubMed Jares et al., 2007, Nat. Rev. Cancer 4 accepted 358 20 8 11 69455855 69469242 ENST00000227507.2 75 GRCh37 Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK's) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, and range from genomic amplification to promoter methylation changes. While Cyclin D2 has only been found to be significantly misregulated in glioma, Cyclin D1 in particular seems to be a pan-cancer actor. Cyclin D misregulation has been shown to lead to poorer outcomes in a number of studies, and currently there are no FDA-approved targeted therapies. N/A 2020-10-22 01:52:40 UTC https://civicdb.org/links/evidence_items/358 https://civicdb.org/links/variants/20 https://civicdb.org/links/genes/8 false CCND2 894 OVEREXPRESSION Stomach Cancer 10534 Prognostic Supports D Poor Outcome Cyclin D2 overexpression is associated with poor prognosis in gastric cancers. 10547574 PubMed Takano et al., 1999, J. Pathol. 4 accepted 359 21 9 12 4382938 4414516 ENST00000261254.3 75 GRCh37 Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK's) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, and range from genomic amplification to promoter methylation changes. While Cyclin D2 has only been found to be significantly misregulated in glioma, Cyclin D1 in particular seems to be a pan-cancer actor. Cyclin D misregulation has been shown to lead to poorer outcomes in a number of studies, and currently there are no FDA-approved targeted therapies. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/359 https://civicdb.org/links/variants/21 https://civicdb.org/links/genes/9 false CCND2 894 OVEREXPRESSION Stomach Cancer 10534 Prognostic Supports D Poor Outcome Cyclin D2 overexpression is associated with the increased depth of cancer invasion in gastric cancers. 10547574 PubMed Takano et al., 1999, J. Pathol. 4 accepted 360 21 9 12 4382938 4414516 ENST00000261254.3 75 GRCh37 Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK's) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, and range from genomic amplification to promoter methylation changes. While Cyclin D2 has only been found to be significantly misregulated in glioma, Cyclin D1 in particular seems to be a pan-cancer actor. Cyclin D misregulation has been shown to lead to poorer outcomes in a number of studies, and currently there are no FDA-approved targeted therapies. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/360 https://civicdb.org/links/variants/21 https://civicdb.org/links/genes/9 false CCND2 894 OVEREXPRESSION Stomach Cancer 10534 Prognostic Supports D Poor Outcome Cyclin D2 overexpression is associated with the presence pf lymph node metastasis in gastric cancers. 10547574 PubMed Takano et al., 1999, J. Pathol. 4 accepted 361 21 9 12 4382938 4414516 ENST00000261254.3 75 GRCh37 Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK's) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, and range from genomic amplification to promoter methylation changes. While Cyclin D2 has only been found to be significantly misregulated in glioma, Cyclin D1 in particular seems to be a pan-cancer actor. Cyclin D misregulation has been shown to lead to poorer outcomes in a number of studies, and currently there are no FDA-approved targeted therapies. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/361 https://civicdb.org/links/variants/21 https://civicdb.org/links/genes/9 false CCND2 894 OVEREXPRESSION Stomach Cancer 10534 Prognostic Supports D Poor Outcome Cyclin D2 overexpression is associated with vascular invasion by cancer cells in gastric cancers. 10547574 PubMed Takano et al., 1999, J. Pathol. 4 accepted 362 21 9 12 4382938 4414516 ENST00000261254.3 75 GRCh37 Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK's) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, and range from genomic amplification to promoter methylation changes. While Cyclin D2 has only been found to be significantly misregulated in glioma, Cyclin D1 in particular seems to be a pan-cancer actor. Cyclin D misregulation has been shown to lead to poorer outcomes in a number of studies, and currently there are no FDA-approved targeted therapies. Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/362 https://civicdb.org/links/variants/21 https://civicdb.org/links/genes/9 false CCNE1 898 Overexpression Breast Cancer 1612 Prognostic Supports B Poor Outcome Patients with high expression of total cyclin E and low-molecular weight cyclin E is strongly associated with poor prognosis in breast cancer, and the hazard ratio for these patients in 13.3 times higher than those with normal cyclin E levels. 12432043 PubMed Keyomarsi et al., 2002, N. Engl. J. Med. 4 accepted 363 24 11 19 30302805 30315215 ENST00000262643.3 75 GRCh37 Cyclin E, while currenly not as widely implicated as its counterpart, cyclin D, has been implicated in various carcinomas, including breast, gastric, stomach and colorectal. High levels of cyclin E, either by gene amplification or overexpression, are correlated with later stage disease and have been shown to lead to poorer prognosis in gastic carcinoma. It has also been shown, in lung cancer specifically, that neoplastic cells with higher levels of the cyclin E/CDK2 complex are more radiosensitive than their lowly expressed counterparts. N/A 2020-10-24 06:41:27 UTC https://civicdb.org/links/evidence_items/363 https://civicdb.org/links/variants/24 https://civicdb.org/links/genes/11 false CCNE1 898 Overexpression Gastric Adenosquamous Carcinoma 5635 Prognostic Supports B Poor Outcome Elevated levels of CCNE1 mRNA has been shown to be correlated with advanced stage gastric carcinoma. 10224221 PubMed Donnellan et al., 1999, FASEB J. 4 accepted 364 24 11 19 30302805 30315215 ENST00000262643.3 75 GRCh37 Cyclin E, while currenly not as widely implicated as its counterpart, cyclin D, has been implicated in various carcinomas, including breast, gastric, stomach and colorectal. High levels of cyclin E, either by gene amplification or overexpression, are correlated with later stage disease and have been shown to lead to poorer prognosis in gastic carcinoma. It has also been shown, in lung cancer specifically, that neoplastic cells with higher levels of the cyclin E/CDK2 complex are more radiosensitive than their lowly expressed counterparts. N/A 2020-10-24 06:41:47 UTC https://civicdb.org/links/evidence_items/364 https://civicdb.org/links/variants/24 https://civicdb.org/links/genes/11 false CCNE1 898 Overexpression Gastric Adenosquamous Carcinoma 5635 Prognostic Supports B Poor Outcome Elevated levels of CCNE1 mRNA has been shown to be correlated with increased depth of tumor invasion in gastic carcinoma. 10224221 PubMed Donnellan et al., 1999, FASEB J. 4 accepted 365 24 11 19 30302805 30315215 ENST00000262643.3 75 GRCh37 Cyclin E, while currenly not as widely implicated as its counterpart, cyclin D, has been implicated in various carcinomas, including breast, gastric, stomach and colorectal. High levels of cyclin E, either by gene amplification or overexpression, are correlated with later stage disease and have been shown to lead to poorer prognosis in gastic carcinoma. It has also been shown, in lung cancer specifically, that neoplastic cells with higher levels of the cyclin E/CDK2 complex are more radiosensitive than their lowly expressed counterparts. N/A 2020-10-24 06:41:56 UTC https://civicdb.org/links/evidence_items/365 https://civicdb.org/links/variants/24 https://civicdb.org/links/genes/11 false CDKN2A 1029 Promoter Hypermethylation Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome In NSCLC patients younger than 60 years at age of diagnosis, p16 (CDKN2A) promoter hypermethylation is associated with shorter time to recurrence and shorter overall survival. 23111194 PubMed Bradly et al., 2012, Diagn. Mol. Pathol. 3 accepted 367 27 14 9 21974827 21994591 ENST00000498124.1 75 GRCh37 CDKN2A loss has been shown to be a significant event in a number of cancer types. One mechanism by which this can occur is by hypermethylation of the CDKN2A promoter region. While no targeted therapeutic has been engaged in clinical trials, the prognostic impact has been studied by a number of meta-analyses. The prognostic impact of promoter hypermethylation has been relatively ambiguous. Many studies have shown significant p-values suggesting poorer prognostic outcomes for patients with hypermethylation in colorectal, liver, and younger lung cancer patients. This being said, there is still research to be done before this becomes a widely-accepted prognostic indicator. Somatic 2016-02-24 00:13:09 UTC https://civicdb.org/links/evidence_items/367 https://civicdb.org/links/variants/27 https://civicdb.org/links/genes/14 false CDKN2A 1029 Promoter Hypermethylation Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome In NSCLC patients younger than 60 years at age of diagnosis, p16 (CDKN2A) promoter hypermethylation is associated with shorter time to recurrence. 23111194 PubMed Bradly et al., 2012, Diagn. Mol. Pathol. 3 accepted 368 27 14 9 21974827 21994591 ENST00000498124.1 75 GRCh37 CDKN2A loss has been shown to be a significant event in a number of cancer types. One mechanism by which this can occur is by hypermethylation of the CDKN2A promoter region. While no targeted therapeutic has been engaged in clinical trials, the prognostic impact has been studied by a number of meta-analyses. The prognostic impact of promoter hypermethylation has been relatively ambiguous. Many studies have shown significant p-values suggesting poorer prognostic outcomes for patients with hypermethylation in colorectal, liver, and younger lung cancer patients. This being said, there is still research to be done before this becomes a widely-accepted prognostic indicator. Somatic 2019-02-22 15:20:54 UTC https://civicdb.org/links/evidence_items/368 https://civicdb.org/links/variants/27 https://civicdb.org/links/genes/14 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome In NSCLC patients with T790M and another activating mutations, their progression free survival is shorter compared to those who do not possess T790M mutation. 24623981 PubMed Ding et al., 2014, Onco Targets Ther 4 accepted 369 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2015-06-21 16:49:52 UTC https://civicdb.org/links/evidence_items/369 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome Patients with NSCLC harboring EGFR T790M mutation have statistically worse overall survival compared to patients with L858R or other exon 19 activating mutations. 24729716 PubMed Li et al., 2014, Onco Targets Ther 4 accepted 370 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2015-06-21 16:49:53 UTC https://civicdb.org/links/evidence_items/370 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome AML patients with internal tandem repeat of FLT3 has worse overall survival than patients with wild type FLT3. 11290608 PubMed Yamamoto et al., 2001, Blood 3 accepted 371 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/371 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Simultaneous tandem repeat of FLT3 with loss of wild type FLT3 leads to poor survival and inferior disease free survival in patients with AML. 11585760 PubMed Whitman et al., 2001, Cancer Res. 4 accepted 372 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2015-06-21 16:49:53 UTC https://civicdb.org/links/evidence_items/372 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false FLT3 2322 TKD MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In AML patients, FLT3-TKD mutation was associated with poorer disease free survival compared to patients with wild type FLT3. 17940205 PubMed Whitman et al., 2008, Blood 4 accepted 373 56 24 13 28592642 28592642 C A ENST00000241453.7 75 GRCh37 FLT3 tyrosine kinase domain mutations (FLT3-TKD) are much less common than FLT3-ITD (internal tandem duplication) mutations and may not confer the same prognostic impact. Although the majority of mutations are point mutations effecting D835 (most frequently D835Y), a small proportion involve an in-frame deletion of I836. These mutations are within the activation loop of the second tyrosine kinase domain of FLT3 and thought to result in constitutive activation of the receptor. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/373 https://civicdb.org/links/variants/56 https://civicdb.org/links/genes/24 false IDH1 3417 R132 Myelodysplastic Syndrome 0050908 Prognostic Supports B Poor Outcome IDH1 R132 mutation in patients suffering from myelodysplastic syndromes is associated with worse overall survival. 20494930 PubMed Thol et al., 2010, Haematologica 4 accepted 374 58 26 2 209113111 209113113 ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes, IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/374 https://civicdb.org/links/variants/58 https://civicdb.org/links/genes/26 false IDH2 3418 R172K Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In AML, patients with an IDH2 R172K mutation have worse overall survival compared to those with wild-type IDH2. 21596855 PubMed Green et al., 2011, Blood 3 accepted 375 63 27 15 90631838 90631838 C T ENST00000330062.3 75 GRCh37 IDH2 mutations have been observed in a number of hematologic malignancies. In acute myeloid leukemia, the R172K mutation has been linked with poorer prognosis and worse overall survival than IDH2 wild-type patients. However, in myelodisplastic syndromes, studies did not find a prognostic association between this variant and patient outcomes. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/375 https://civicdb.org/links/variants/63 https://civicdb.org/links/genes/27 false KIT 3815 Exon 11 Mutation Gastrointestinal Stromal Tumor 9253 Prognostic Supports B Poor Outcome KIT mutation is associated with worse overall and cause-specific prognosis in patients with GIST compared to patients with wildtype KIT. 10485475 PubMed Taniguchi et al., 1999, Cancer Res. 3 accepted 376 66 29 4 55593582 55593708 ENST00000288135.5 75 GRCh37 c-KIT mutations in exon 11 lie within the juxtamembrane domain, and are very recurrent in gastrointestinal stromal tumors, often bearing a poorer prognosis than other KIT mutations. Cells harboring exon 11 mutations have shown sensitivity to the tyrosine kinase inhibitor imatinib, offering a better prognosis to patients treated with the drug in the first year. Small cohorts of melanoma patients harboring exon 11 KIT mutations have shown response to imatinib and sunitinib. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/376 https://civicdb.org/links/variants/66 https://civicdb.org/links/genes/29 false KRAS 3845 G12 Multiple Myeloma 9538 Prognostic Supports B Poor Outcome The presence of KRAS mutations in MM patients is prognostic for shorter overall and progression free survival. 18528420 PubMed Chng et al., 2008, Leukemia 3 accepted 377 76 30 12 25398284 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/377 https://civicdb.org/links/variants/76 https://civicdb.org/links/genes/30 false KRAS 3845 G12 Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome A meta-analysis showed KRAS mutation is associated with worse outcome in patients with NSCLC. 15597105 PubMed Mascaux et al., 2005, Br. J. Cancer 3 accepted 378 76 30 12 25398284 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/378 https://civicdb.org/links/variants/76 https://civicdb.org/links/genes/30 false NOTCH1 4851 D1642H Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome NOTCH1 gain-of-function mutations, including D1642H (called D1643H in publication), have shown to be correlated with poor prognosis in lung cancer. This is in a TP53 wild-type context. 20007775 PubMed Westhoff et al., 2009, Proc. Natl. Acad. Sci. U.S.A. 4 accepted 380 135 50 9 139399219 139399219 C G ENST00000277541.6 75 GRCh37 Activating mutations in NOTCH1, including D1642H, have been shown to be poor prognostic markers in lung cancer. Somatic 2016-03-31 23:13:04 UTC https://civicdb.org/links/evidence_items/380 https://civicdb.org/links/variants/135 https://civicdb.org/links/genes/50 false NOTCH1 4851 R2327W Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome NOTCH1 gain-of-function mutations, including R2327W (called R2328W in publication), have shown to be correlated to poor prognosis in lung cancer. This is in a TP53 wild-type context. 20007775 PubMed Westhoff et al., 2009, Proc. Natl. Acad. Sci. U.S.A. 4 accepted 381 136 50 9 139391212 139391212 G A ENST00000277541.6 75 GRCh37 Activating mutations in NOTCH1, including R2327W, have been shown to be poor prognostic markers in lung cancer. Somatic 2016-04-06 16:51:54 UTC https://civicdb.org/links/evidence_items/381 https://civicdb.org/links/variants/136 https://civicdb.org/links/genes/50 false NOTCH1 4851 S2275FS Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome NOTCH1 gain-of-function mutations, including S2275fs, have shown to be correlated to poor prognosis in lung cancer. This is in a TP53 wild-type context. 20007775 PubMed Westhoff et al., 2009, Proc. Natl. Acad. Sci. U.S.A. 4 accepted 382 138 50 9 139391369 139391370 A ENST00000277541.6 75 GRCh37 Activating mutations in NOTCH1, including a frameshift insertion at S2275, have been shown to be poor prognostic markers in lung cancer. Somatic 2015-06-21 16:49:53 UTC https://civicdb.org/links/evidence_items/382 https://civicdb.org/links/variants/138 https://civicdb.org/links/genes/50 false NOTCH1 4851 V2444FS Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome NOTCH1 gain-of-function mutations, including V2444fs, have shown to be correlated to poor prognosis in lung cancer. This is in a TP53 wild-type context. 20007775 PubMed Westhoff et al., 2009, Proc. Natl. Acad. Sci. U.S.A. 4 accepted 383 137 50 9 139390861 139390861 G TGT ENST00000277541.6 75 GRCh37 Activating mutations in NOTCH1, including a frameshift insertion at V2444, have been shown to be poor prognostic markers in lung cancer. Somatic 2015-06-21 16:49:53 UTC https://civicdb.org/links/evidence_items/383 https://civicdb.org/links/variants/137 https://civicdb.org/links/genes/50 false PIK3CA 5290 Exon 10 Mutation Colorectal Cancer 9256 Prognostic Does Not Support B Poor Outcome This study analyzed tumor and patient characteristics from 1,170 colorectal cancer patients derived from the prospective cohort studies: Nurses' Health Study and Health Professionals Follow Up Study. PIK3CA mutations were found in 16% (189/1170) of patients via pyrosequencing of FFPE samples. Of patients with PIK3CA mutated tumors, 58% (109/189) had mutations in exon 10 (listed as exon 9 in the publication, as it was common at the time of its publication to exclude non-coding exon 1). The presence of an exon 10 mutation was not significantly associated with differences in colorectal cancer-specific or overall survival when compared to patients with wt PIK3CA (multivariate, stage-stratified HR = 1.15 vs 1). Authors note that they had limited data on cancer treatment data, but assume that treatment regimens did not differ substantially based on PIK3CA mutation status given that patients were diagnosed prior to clinical availability of PIK3CA genotype data. They further note that treatment decisions were typically based on cancer stage, for which their analyses adjusted. 22357840 PubMed Liao et al., 2012, Clin. Cancer Res. 2 accepted 384 106 37 3 178935998 178936122 ENST00000263967.3 75 GRCh37 PIK3CA Exon 10 Mutations (e.g. E545K/E542K; often referred to as Exon 9 mutations if counting only coding exons) are the second most recurrent PIK3CA mutations in breast cancer, and highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that exon 10 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2020-05-28 17:58:42 UTC https://civicdb.org/links/evidence_items/384 https://civicdb.org/links/variants/106 https://civicdb.org/links/genes/37 false PIK3CA 5290 E545K Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Supports C Resistance In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS PIK3CA and PTEN were tested for mutation, and 1 patient (patient 95, see supplemental table 1) had PIK3CA E545K in the primary tumor without co-occurring mutations in the other tested genes. This response was consistent with observations made of the larger cohort, where patients with tumors harboring any PIK3CA mutation had significantly shorter progression free survival and decreased incidence of objective response than patients with wtPIK3CA tumors. However, there was one patient (Patient 55, Table S1) who had E545K as the only noted variant, but experienced partial response. 19223544 PubMed Sartore-Bianchi et al., 2009, Cancer Res. 3 accepted 387 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2018-10-23 22:28:12 UTC https://civicdb.org/links/evidence_items/387 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Supports C Resistance In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS PIK3CA and PTEN were tested for mutation; PIK3CA H1047R was the only variant noted in the primary tumors of four patients (Patient Ids: 7, 42, 52, 64; Table S1) and the metastatic tumor of one patient (11; Table S1), who experienced disease progression following treatment. It was also noted in the primary tumors of 3 patients (25, 48, 88; Table S1) who experienced stable disease following treatment.This response was consistent with observations made of the larger cohort, where patients with tumors harboring any PIK3CA mutation had significantly shorter progression free survival and decreased incidence of objective response than patients with wtPIK3CA tumors. However, one patient (38, Table S1) had PIK3CA H1047R as the only noted variant, but experienced partial response. 19223544 PubMed Sartore-Bianchi et al., 2009, Cancer Res. 2 accepted 388 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2018-11-02 21:41:52 UTC https://civicdb.org/links/evidence_items/388 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false TP53 7157 R175H Breast Cancer 1612 Prognostic Supports B Poor Outcome Breast cancer patients who harbor R175H mutation have worse overall survival than those with wild type TP53, but have better prognosis than those with R248W mutation. 16489069 PubMed Olivier et al., 2006, Clin. Cancer Res. 3 accepted 389 116 45 17 7578406 7578406 C T ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R175H variant seems not only to result in loss of tumor-suppression, but also acts as a gain-of-function mutation that promotes tumorigenesis in mouse models. Cell lines harboring this mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been shown that the R175H mutation is correlated with worse overall survival than wild-type TP53, but is not as detrimental as the R248W variant. This variant is rare in population databases (ACMG code: PM2; 0.000003980 total exome AF gnomAD v2.1.1). Somatic 2015-06-21 16:49:53 UTC https://civicdb.org/links/evidence_items/389 https://civicdb.org/links/variants/116 https://civicdb.org/links/genes/45 false TP53 7157 R248Q Breast Cancer 1612 Prognostic Supports B Poor Outcome Breast cancer patients who harbor a R248Q mutation (N=18) have worse overall survival than those with wild type TP53 (N=1460), but have better prognosis than those with a R248W mutation (N=8). 16489069 PubMed Olivier et al., 2006, Clin. Cancer Res. 3 accepted 390 117 45 17 7577538 7577538 C T ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R248 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, R248 mutations have been shown to confer worse overall survival. The R248Q mutation has also shown an increased invasive behavior in cell lines. This is specific to the 248Q variant. Somatic 2017-01-23 15:45:43 UTC https://civicdb.org/links/evidence_items/390 https://civicdb.org/links/variants/117 https://civicdb.org/links/genes/45 false TP53 7157 R248Q Breast Cancer 1612 Prognostic Supports B Poor Outcome In breast cancer patients harboring TP53 mutation, mutations in DNA contact regions such as R248 (N=10, 6 at R248) are prognostic for a worse relapse-free survival compared to other non-silent mutations in TP53 (N=43). 9569050 PubMed Berns et al., 1998, Br. J. Cancer 3 accepted 391 117 45 17 7577538 7577538 C T ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R248 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, R248 mutations have been shown to confer worse overall survival. The R248Q mutation has also shown an increased invasive behavior in cell lines. This is specific to the 248Q variant. Somatic 2021-01-29 00:22:24 UTC https://civicdb.org/links/evidence_items/391 https://civicdb.org/links/variants/117 https://civicdb.org/links/genes/45 false TP53 7157 R248W Breast Cancer 1612 Prognostic Supports B Poor Outcome In breast cancer patients harboring R248W mutation, the prognosis is worse than any other hotspot TP53 mutation, as well as worse than patients with wild type TP53. 16489069 PubMed Olivier et al., 2006, Clin. Cancer Res. 3 accepted 392 118 45 17 7577539 7577539 G A ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R248 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, R248 mutations have been shown to confer worse overall survival. Somatic 2015-06-21 16:49:53 UTC https://civicdb.org/links/evidence_items/392 https://civicdb.org/links/variants/118 https://civicdb.org/links/genes/45 false TP53 7157 R249 Breast Cancer 1612 Prognostic Supports B Poor Outcome In breast cancer patients harboring TP53 mutation, mutations in conserved regions such as R249 are prognostic for a worse overall survival compared to those harboring wild-type TP53. 9569050 PubMed Berns et al., 1998, Br. J. Cancer 3 accepted 393 119 45 17 7577535 7577535 C G ENST00000269305.4 75 GRCh37 This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been suggested that the R249 mutants have been correlated with worse overall survival in breast cancer patients when compared to wild-type. Somatic 2015-06-21 16:49:53 UTC https://civicdb.org/links/evidence_items/393 https://civicdb.org/links/variants/119 https://civicdb.org/links/genes/45 false TP53 7157 R273C Breast Cancer 1612 Prognostic Supports B Poor Outcome Breast cancer patients who harbor R273C mutation have worse overall survival than those with wild type TP53, but have better prognosis than those with R248W mutation. 16489069 PubMed Olivier et al., 2006, Clin. Cancer Res. 3 accepted 395 121 45 17 7577121 7577121 G A ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R273 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been suggested that the R273 mutants have been correlated with worse overall survival in breast cancer patients when compared to wild-type. Somatic 2015-06-21 16:49:53 UTC https://civicdb.org/links/evidence_items/395 https://civicdb.org/links/variants/121 https://civicdb.org/links/genes/45 false TP53 7157 R273C Breast Cancer 1612 Prognostic Supports B Poor Outcome In breast cancer patients harboring TP53 mutation, mutations in DNA contact regions such as R273 are prognostic for a worse relapse-free survival compared to other non-silent mutations in TP53. 9569050 PubMed Berns et al., 1998, Br. J. Cancer 3 accepted 396 121 45 17 7577121 7577121 G A ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R273 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been suggested that the R273 mutants have been correlated with worse overall survival in breast cancer patients when compared to wild-type. Somatic 2015-06-21 16:49:53 UTC https://civicdb.org/links/evidence_items/396 https://civicdb.org/links/variants/121 https://civicdb.org/links/genes/45 false TP53 7157 R273H Breast Cancer 1612 Prognostic Supports B Poor Outcome Breast cancer patients who harbor R273H mutation have worse overall survival than those with wild type TP53, but have better prognosis than those with R248W mutation. 16489069 PubMed Olivier et al., 2006, Clin. Cancer Res. 3 accepted 397 122 45 17 7577120 7577120 C T ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R273 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been suggested that the R273 mutants have been correlated with worse overall survival in breast cancer patients when compared to wild-type. Somatic 2015-06-21 16:49:53 UTC https://civicdb.org/links/evidence_items/397 https://civicdb.org/links/variants/122 https://civicdb.org/links/genes/45 false TP53 7157 R273H Breast Cancer 1612 Prognostic Supports B Poor Outcome In breast cancer patients harboring TP53 mutation, mutations in DNA contact regions such as R273 are prognostic for a worse relapse-free survival compared to other non-silent mutations in TP53. 9569050 PubMed Berns et al., 1998, Br. J. Cancer 3 accepted 398 122 45 17 7577120 7577120 C T ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R273 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been suggested that the R273 mutants have been correlated with worse overall survival in breast cancer patients when compared to wild-type. Somatic 2015-06-21 16:49:53 UTC https://civicdb.org/links/evidence_items/398 https://civicdb.org/links/variants/122 https://civicdb.org/links/genes/45 false TP53 7157 R249 Breast Cancer 1612 Doxorubicin Predictive Supports B Sensitivity/Response Breast tumors with R175H or R249 mutations are more responsive to doxorubicin than breast tumors with wild type TP53. 9569050 PubMed Berns et al., 1998, Br. J. Cancer 3 accepted 399 119 45 17 7577535 7577535 C G ENST00000269305.4 75 GRCh37 This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been suggested that the R249 mutants have been correlated with worse overall survival in breast cancer patients when compared to wild-type. Somatic 2015-11-26 21:20:55 UTC https://civicdb.org/links/evidence_items/399 https://civicdb.org/links/variants/119 https://civicdb.org/links/genes/45 false U2AF1 7307 Q157P/R Myelodysplastic Syndrome 0050908 Prognostic Supports B Poor Outcome After adjusting for age and cancer stage, presence of U2AF mutation such as Q157P/R is prognostic for poorer survival outcomes in patients with MDS. 23861105 PubMed Wu et al., 2013, Am. J. Hematol. 3 accepted 400 127 48 21 44514777 44514777 T G ENST00000291552.4 75 GRCh37 U2AF1 Q157P/R has been shown to be a recurrent mutation in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and lung adenocarcinomas. This mutation is less common than the S34F mutation, occurs in the second zinc finger domain of U2AF1 and has been demonstrated to alter splicing. The impact of U2AF1 mutations on overall survival in MDS has been debated, however, patients with U2AF1 mutations were shown to be at an increased risk of transformation to secondary AML. The presence of this mutation was not associated with a specific prognostic outcome in AML when compared to U2AF1 wildtype patients. Somatic 2016-02-13 05:34:21 UTC https://civicdb.org/links/evidence_items/400 https://civicdb.org/links/variants/127 https://civicdb.org/links/genes/48 false U2AF1 7307 S34Y/F Myelodysplastic Syndrome 0050908 Prognostic Supports B Poor Outcome After adjusting for age and cancer stage, the presence of U2AF mutations such as S34Y/F are prognostic for poorer survival outcomes in patients with MDS. 23861105 PubMed Wu et al., 2013, Am. J. Hematol. 3 accepted 401 128 48 21 44524456 44524456 G A ENST00000291552.4 75 GRCh37 U2AF1 S34Y/F has been shown to be a recurrent mutation in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and lung adenocarcinomas. This mutation is the most commonly identified variant in MDS, occurs in the first zinc finger domain of U2AF1 and has been demonstrated to alter splicing. The impact of U2AF1 mutations on overall survival in MDS has been debated, however, patients with U2AF1 mutations were shown to be at an increased risk of transformation to secondary AML. The presence of this mutation was not associated with a specific prognostic outcome in AML when compared to U2AF1 wildtype patients. Somatic 2016-02-13 05:38:46 UTC https://civicdb.org/links/evidence_items/401 https://civicdb.org/links/variants/128 https://civicdb.org/links/genes/48 false CSF1R 1436 MEF2D::CSF1R Acute Lymphoblastic Leukemia 9952 Imatinib,GW-2580 Substitutes Predictive Supports D Sensitivity/Response Cell lines with MEF2D-CSF1R fusion show sensitivity to the tyrosine kinase inhibitors Imatinib and GW-2580. 24186003 PubMed Lilljebjörn et al., 2014, Leukemia 3 accepted 403 30 33 1 156446804 156470620 ENST00000348159.4 5 149433787 149441412 ENST00000286301.3 75 GRCh37 MEF2D-CSF1R is a fusion that has been observed in acute lymphocytic leukemia. In cell lines harboring this event, treatment with imatinib has shown notable sensitivity. Somatic 2017-05-31 15:35:49 UTC https://civicdb.org/links/evidence_items/403 https://civicdb.org/links/variants/30 https://civicdb.org/links/genes/33 false PRKACA 5566 DNAJB1::PRKACA Fibrolamellar Carcinoma 5015 Diagnostic Supports B Positive A head-to-tail in-frame fusion between exon1 of DNAJB1 and exon2 of PRKACA resulting from a ~400kb deletion was observed in 100% (15/15) fibrolamellar hepatocellular carcinomas examined. The fusion was confirmed at both RNA and DNA level in all primary and metastatic tumor samples but not in adjacent normal tissue. Immunoprecipitation and Western blot analyses confirmed that the chimeric protein is expressed in tumor tissue, and a cell culture assay indicated that it retains kinase activity. 24578576 PubMed Honeyman et al., 2014, Science 4 accepted 405 31 17 19 14628951 14629232 ENST00000254322.2 19 14202500 14218221 ENST00000308677.4 75 GRCh37 This fusion has been found to be very recurrent in the rare form of adolescent liver cancer, fibrolamellar hepatocellular carcinoma. In one study, this fusion was observed in 15/15 FL-HCC cases examined and functional studies found that the fusion retained kinase activity. The presence of this fusion may be used as a diagnostic marker for this rare tumor type. Somatic 2015-09-28 19:35:58 UTC https://civicdb.org/links/evidence_items/405 https://civicdb.org/links/variants/31 https://civicdb.org/links/genes/17 false BCL2 596 IGH::BCL2 Diffuse Large B-cell Lymphoma 0050745 Diagnostic Supports B Positive The t(14;18) transloaction of BCL2 is shown to be associated with germinal-center B-cell–like diffuse large-B-cell lymphomas. 12075054 PubMed Rosenwald et al., 2002, N. Engl. J. Med. 4 accepted 407 151 59 14 106032614 107288051 18 60794268 60987019 ENST00000333681.4 75 GRCh37 The typically reciprocal t(14;18)(q32;q21) translocation involves rearrangement between the immunoglobulin heavy chain locus on chromosome 14 and the 3' UTR of BCL2 on chromosome 18, leading to the overexpression of BCL2. This rearrangment is observed in >80% of patients with follicular lymphoma. Somatic 2015-06-21 16:49:54 UTC https://civicdb.org/links/evidence_items/407 https://civicdb.org/links/variants/151 https://civicdb.org/links/genes/59 false FOXP1 27086 AMPLIFICATION Diffuse Large B-cell Lymphoma 0050745 Diagnostic Supports B Positive Amplification of FOXP1 is shown to be associated with ABC DLBCL. 18765795 PubMed Lenz et al., 2008, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 408 153 56 3 71003844 71633140 ENST00000318789.4 75 GRCh37 Amplication in FOXP1 has been shown to be associated with the ABC subtype of DLBCL. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/408 https://civicdb.org/links/variants/153 https://civicdb.org/links/genes/56 false REL 5966 AMPLIFICATION Diffuse Large B-cell Lymphoma 0050745 Diagnostic Supports B Positive Amplification of REL is shown to be associated with germinal-center B-cell–like diffuse large-B-cell lymphomas. 12075054 PubMed Rosenwald et al., 2002, N. Engl. J. Med. 4 accepted 409 154 57 2 61108709 61149800 ENST00000295025.8 75 GRCh37 Somatic 2015-06-21 16:49:54 UTC https://civicdb.org/links/evidence_items/409 https://civicdb.org/links/variants/154 https://civicdb.org/links/genes/57 false RUNX1 861 Mutation Acute Myeloid Leukemia 9119 Cytarabine Predictive Supports B Resistance In non-APL patients with AML (age 18-60), those who had mutations in RUNX1 had significantly shorter relapse-free survival following conventional post-remission treatment (repetitive cycles of high-dose cytarabine) than those treated with an allogeneic hematopoietic stem-cell transplantation (N=32) at first remission (4-year RFS; 0% vs 52%; P<0.0001). 21343560 PubMed Gaidzik et al., 2011, J. Clin. Oncol. NCT00146120,NCT00151242 4 accepted 411 155 43 21 36160098 36421641 ENST00000300305.3 75 GRCh37 RUNX1 mutations are associated with poor prognosis in patients with acute myeloid leukemia or adult T-cell acute lymphocytic leukemia. In younger (<60 years old) AML patients, allogeneic stem cell transplant at complete remission led to much better relapse-free survival than repetitive cycles of high-dose cytarabine. Somatic 2016-11-03 21:50:47 UTC https://civicdb.org/links/evidence_items/411 https://civicdb.org/links/variants/155 https://civicdb.org/links/genes/43 false IGF2 3481 Overexpression Prostate Cancer 10283 Linsitinib Predictive Does Not Support D Sensitivity/Response Increased IGF2 expression was shown to mediate chemotherapy resistance in several prostate cancer cell lines. The IGF1R/INSR inhibitor OSI-906 did not have a significant effect on chemotherapy resistant castration-resistant prostate cancer cell lines, as measured by colony formation assay. Similarly, in vivo experiments showed no difference between OSI-906 and control treatment in terms of tumor growth and survival. 25670080 PubMed Vidal et al., 2015, Cancer Cell 3 accepted 412 156 60 11 2150348 2170833 ENST00000300632.5 75 GRCh37 Somatic 2022-03-11 17:20:35 UTC https://civicdb.org/links/evidence_items/412 https://civicdb.org/links/variants/156 https://civicdb.org/links/genes/60 false EGFR 1956 Exon 19 Deletion Lung Non-small Cell Carcinoma 3908 Gefitinib,Erlotinib Substitutes Predictive Supports B Sensitivity/Response NSCLC patients with exon 19 deletions in EGFR had longer overall survival than patients with an L858R mutation when treated with gefitinib or erlotinib (38 versus 17 months; P = 0.04). 16818686 PubMed Jackman et al., 2006, Clin. Cancer Res. 4 accepted 413 133 19 7 55242415 55242513 ENST00000275493.2 75 GRCh37 Deletions within exon 19 of EGFR are most common in lung cancer. These deletions, in non-small cell lung cancer, have been shown to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib, afatinib, and erlotinib. There is also data to suggest that this event is a good prognostic marker in lung adenocarcinoma. Examples of exon 19 deletions include: p.746_A750delELREA, p.747_753delinsS, p.747_752delLREATS, and p.747_751delLREAT. Somatic 2017-07-06 19:58:55 UTC https://civicdb.org/links/evidence_items/413 https://civicdb.org/links/variants/133 https://civicdb.org/links/genes/19 false IGF2 3481 Overexpression Prostate Cancer 10283 Cabazitaxel,Linsitinib,Docetaxel Substitutes Predictive Supports D Sensitivity/Response OSI-906, an IGF1R/INSR inhibitor, sensitizes cell lines to docetaxel and cabazitaxel, resulting in better overall survival in mouse xenografts of patient derived chemotherapy resistant castration-resistant prostate cancer cell lines. 25670080 PubMed Vidal et al., 2015, Cancer Cell 3 accepted 414 156 60 11 2150348 2170833 ENST00000300632.5 75 GRCh37 Somatic 2017-05-31 15:45:34 UTC https://civicdb.org/links/evidence_items/414 https://civicdb.org/links/variants/156 https://civicdb.org/links/genes/60 false TET2 54790 Mutation Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A In a cohort of 783 young adult patients with acute myeloid leukemia, those with TET2 mutations did not have significantly different rates of complete recovery, refractory disease, or hypoplastic death. 22430270 PubMed Gaidzik et al., 2012, J. Clin. Oncol. 4 accepted 415 157 55 4 106067450 106200973 ENST00000513237.1 75 GRCh37 TET2 mutations are commonly found in acute myeloid leukemia occurring in 9-23% of cases with many occurring in the elderly. Generally these mutations are loss-of-function which have been shown in mouse models to impair hematopoietic stem cell differentiation and cause aberrant hematopoiesis. These mutations have been found to be mutually exclusive with MLL and IDH1/2 mutations and have been associated with shortened event-free-survival and disease-free-survival when co-occurring with NPM1+/FLT3- genotypes. Overall Survival has been found to be shorter when occurring with NPM1+/FLT3+ genotypes. Studies involving "CN AML" and "de novo AML" however have been unable to elucidate a clinical impact. Somatic 2019-02-22 15:13:23 UTC https://civicdb.org/links/evidence_items/415 https://civicdb.org/links/variants/157 https://civicdb.org/links/genes/55 false AURKA 6790 EXPRESSION Ovarian Carcinoma 4001 Prognostic Supports B Better Outcome In patients with ovarian carcinomas, those with Aurora kinase A expression (as measured by immunohistochemistry) had increased progression-free and overall survival compared to those without expression. 19157502 PubMed Mendiola et al., 2009, Hum. Pathol. 3 accepted 416 158 61 20 54944446 54967393 ENST00000395913.3 75 GRCh37 Somatic 2015-06-21 16:49:54 UTC https://civicdb.org/links/evidence_items/416 https://civicdb.org/links/variants/158 https://civicdb.org/links/genes/61 false TET2 54790 Mutation Myelodysplastic Syndrome 0050908 Prognostic Supports B Better Outcome In patients with myelodysplastic syndromes, those with TET2 mutations have been shown to have better overall survival than patients without TET2 mutations. 19666869 PubMed Kosmider et al., 2009, Blood 4 accepted 417 157 55 4 106067450 106200973 ENST00000513237.1 75 GRCh37 TET2 mutations are commonly found in acute myeloid leukemia occurring in 9-23% of cases with many occurring in the elderly. Generally these mutations are loss-of-function which have been shown in mouse models to impair hematopoietic stem cell differentiation and cause aberrant hematopoiesis. These mutations have been found to be mutually exclusive with MLL and IDH1/2 mutations and have been associated with shortened event-free-survival and disease-free-survival when co-occurring with NPM1+/FLT3- genotypes. Overall Survival has been found to be shorter when occurring with NPM1+/FLT3+ genotypes. Studies involving "CN AML" and "de novo AML" however have been unable to elucidate a clinical impact. Somatic 2015-06-21 16:49:54 UTC https://civicdb.org/links/evidence_items/417 https://civicdb.org/links/variants/157 https://civicdb.org/links/genes/55 false VHL 7428 Mutation Clear Cell Renal Cell Carcinoma 4467 Prognostic Supports B Better Outcome In patients with renal clear cell carcinoma, patients with VHL mutations had longer cancer-specific survival. 18464292 PubMed Patard et al., 2008, Int. J. Cancer 4 accepted 418 160 58 3 10182692 10193904 ENST00000256474.2 75 GRCh37 Somatic 2015-06-21 16:49:54 UTC https://civicdb.org/links/evidence_items/418 https://civicdb.org/links/variants/160 https://civicdb.org/links/genes/58 false TET2 54790 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome In patients with cytogenetically normal acute myeloid leukemia, those in the intermediate-I risk group with TET2 mutations had higher rates of complete remission. 22430270 PubMed Gaidzik et al., 2012, J. Clin. Oncol. 4 accepted 419 157 55 4 106067450 106200973 ENST00000513237.1 75 GRCh37 TET2 mutations are commonly found in acute myeloid leukemia occurring in 9-23% of cases with many occurring in the elderly. Generally these mutations are loss-of-function which have been shown in mouse models to impair hematopoietic stem cell differentiation and cause aberrant hematopoiesis. These mutations have been found to be mutually exclusive with MLL and IDH1/2 mutations and have been associated with shortened event-free-survival and disease-free-survival when co-occurring with NPM1+/FLT3- genotypes. Overall Survival has been found to be shorter when occurring with NPM1+/FLT3+ genotypes. Studies involving "CN AML" and "de novo AML" however have been unable to elucidate a clinical impact. Somatic 2019-02-22 15:13:27 UTC https://civicdb.org/links/evidence_items/419 https://civicdb.org/links/variants/157 https://civicdb.org/links/genes/55 false PBRM1 55193 Mutation Clear Cell Renal Cell Carcinoma 4467 Prognostic Supports B N/A In renal clear cell carcinoma, patients with PBRM1 mutations did not have a significantly different cancer specific survival. 23620406 PubMed Hakimi et al., 2013, Clin. Cancer Res. 3 accepted 420 161 62 3 52581857 52719852 ENST00000394830.3 75 GRCh37 Somatic 2015-06-21 16:49:54 UTC https://civicdb.org/links/evidence_items/420 https://civicdb.org/links/variants/161 https://civicdb.org/links/genes/62 false TET2 54790 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B N/A In patients with cytogenetically normal acute myeloid leukemia, those in the intermediate-I risk group with TET2 mutations did not have significantly different rates of event-free survival, complete remission, disease-free survival, or overall survival. 21343549 PubMed Metzeler et al., 2011, J. Clin. Oncol. 4 accepted 421 157 55 4 106067450 106200973 ENST00000513237.1 75 GRCh37 TET2 mutations are commonly found in acute myeloid leukemia occurring in 9-23% of cases with many occurring in the elderly. Generally these mutations are loss-of-function which have been shown in mouse models to impair hematopoietic stem cell differentiation and cause aberrant hematopoiesis. These mutations have been found to be mutually exclusive with MLL and IDH1/2 mutations and have been associated with shortened event-free-survival and disease-free-survival when co-occurring with NPM1+/FLT3- genotypes. Overall Survival has been found to be shorter when occurring with NPM1+/FLT3+ genotypes. Studies involving "CN AML" and "de novo AML" however have been unable to elucidate a clinical impact. Somatic 2015-06-21 16:49:54 UTC https://civicdb.org/links/evidence_items/421 https://civicdb.org/links/variants/157 https://civicdb.org/links/genes/55 false VHL 7428 Mutation Clear Cell Renal Cell Carcinoma 4467 Prognostic Supports B N/A In renal clear cell carcinoma, patients with VHL mutations did not have a significant impact on cancer specific survival. 23620406 PubMed Hakimi et al., 2013, Clin. Cancer Res. 3 accepted 422 160 58 3 10182692 10193904 ENST00000256474.2 75 GRCh37 Somatic 2015-06-21 16:49:54 UTC https://civicdb.org/links/evidence_items/422 https://civicdb.org/links/variants/160 https://civicdb.org/links/genes/58 false BCL2 596 Overexpression Diffuse Large B-cell Lymphoma 0050745 Prognostic Supports B Poor Outcome In patients with Diffuse Large B-Cell Lymphoma, those with increased levels of BCL2 were shown to have decreased overall, disease-free, and relapse-free survival. 9207459 PubMed Gascoyne et al., 1997, Blood 4 accepted 423 152 59 18 60790579 60987361 ENST00000398117.1 75 GRCh37 N/A 2020-10-22 01:51:50 UTC https://civicdb.org/links/evidence_items/423 https://civicdb.org/links/variants/152 https://civicdb.org/links/genes/59 false EZH2 2146 Mutation Myelodysplastic Syndrome 0050908 Prognostic Supports B Poor Outcome In myelodysplastic syndrome, patients with point mutations in EZH2 have worse overall survival that their wild-type counterparts. 20601954 PubMed Nikoloski et al., 2010, Nat. Genet. 3 accepted 425 163 63 7 148504477 148581370 ENST00000320356.2 75 GRCh37 Somatic 2015-08-05 18:28:35 UTC https://civicdb.org/links/evidence_items/425 https://civicdb.org/links/variants/163 https://civicdb.org/links/genes/63 false TET2 54790 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In patients classified as intermediate-risk via cytogenetics, TET2 mutations have been shown to be correlated with poor prognosis. 21828143 PubMed Chou et al., 2011, Blood 4 accepted 426 157 55 4 106067450 106200973 ENST00000513237.1 75 GRCh37 TET2 mutations are commonly found in acute myeloid leukemia occurring in 9-23% of cases with many occurring in the elderly. Generally these mutations are loss-of-function which have been shown in mouse models to impair hematopoietic stem cell differentiation and cause aberrant hematopoiesis. These mutations have been found to be mutually exclusive with MLL and IDH1/2 mutations and have been associated with shortened event-free-survival and disease-free-survival when co-occurring with NPM1+/FLT3- genotypes. Overall Survival has been found to be shorter when occurring with NPM1+/FLT3+ genotypes. Studies involving "CN AML" and "de novo AML" however have been unable to elucidate a clinical impact. Somatic 2015-06-21 16:49:54 UTC https://civicdb.org/links/evidence_items/426 https://civicdb.org/links/variants/157 https://civicdb.org/links/genes/55 false TET2 54790 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In patients with cytogenetically normal acute myeloid leukemia, those in the ELN favorable-risk group with TET2 mutations had shorter event-free survival, lower rates of complete remission, and shorter disease-free survival. 21343549 PubMed Metzeler et al., 2011, J. Clin. Oncol. 4 accepted 427 157 55 4 106067450 106200973 ENST00000513237.1 75 GRCh37 TET2 mutations are commonly found in acute myeloid leukemia occurring in 9-23% of cases with many occurring in the elderly. Generally these mutations are loss-of-function which have been shown in mouse models to impair hematopoietic stem cell differentiation and cause aberrant hematopoiesis. These mutations have been found to be mutually exclusive with MLL and IDH1/2 mutations and have been associated with shortened event-free-survival and disease-free-survival when co-occurring with NPM1+/FLT3- genotypes. Overall Survival has been found to be shorter when occurring with NPM1+/FLT3+ genotypes. Studies involving "CN AML" and "de novo AML" however have been unable to elucidate a clinical impact. Somatic 2015-06-21 16:49:54 UTC https://civicdb.org/links/evidence_items/427 https://civicdb.org/links/variants/157 https://civicdb.org/links/genes/55 false VHL 7428 Loss-of-function Clear Cell Renal Cell Carcinoma 4467 Prognostic Supports B Poor Outcome In patients with renal clear cell carcinoma, patients with loss of function VHL mutations had shorter tumor-specific survival. 11793370 PubMed Schraml et al., 2002, J. Pathol. 3 accepted 428 159 58 3 10182692 10193904 ENST00000256474.2 75 GRCh37 Somatic 2015-06-21 16:49:54 UTC https://civicdb.org/links/evidence_items/428 https://civicdb.org/links/variants/159 https://civicdb.org/links/genes/58 false RUNX1 861 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In 878 non-APL patients with AML, those who had mutations in RUNX1 (N=53) had higher rates of refractory disease than those without (30% versus 19%; P = 0.047). 21343560 PubMed Gaidzik et al., 2011, J. Clin. Oncol. NCT00146120,NCT00151242 4 accepted 429 155 43 21 36160098 36421641 ENST00000300305.3 75 GRCh37 RUNX1 mutations are associated with poor prognosis in patients with acute myeloid leukemia or adult T-cell acute lymphocytic leukemia. In younger (<60 years old) AML patients, allogeneic stem cell transplant at complete remission led to much better relapse-free survival than repetitive cycles of high-dose cytarabine. Somatic 2016-06-22 19:25:07 UTC https://civicdb.org/links/evidence_items/429 https://civicdb.org/links/variants/155 https://civicdb.org/links/genes/43 false RUNX1 861 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In 878 non-APL patients with AML (18-60 years), those who had mutations in RUNX1 (N=53) had shorter event-free survival (8% vs 30%, P<0.0001) and relapse-free survival (26% vs 44%, P=0.022) relative to wild-type. EFS was also shorter for the cytogenetically normal (CN) subgroup with RUNX1 mutations (N=34; 10% vs 34%; P<0.0001) compared to wild-type (N=499), but only trending for relapse-free survival (29% vs 43%; P=0.21). For multivariate analysis, RUNX1 was a significant marker of inferior EFS in the entire cohort (P=0.011) and the intermediate-risk (P=0.005) subgroup but not the CN subgroup. 21343560 PubMed Gaidzik et al., 2011, J. Clin. Oncol. NCT00146120,NCT00151242 4 accepted 430 155 43 21 36160098 36421641 ENST00000300305.3 75 GRCh37 RUNX1 mutations are associated with poor prognosis in patients with acute myeloid leukemia or adult T-cell acute lymphocytic leukemia. In younger (<60 years old) AML patients, allogeneic stem cell transplant at complete remission led to much better relapse-free survival than repetitive cycles of high-dose cytarabine. Somatic 2016-06-28 23:23:17 UTC https://civicdb.org/links/evidence_items/430 https://civicdb.org/links/variants/155 https://civicdb.org/links/genes/43 false FLI1 2313 EWSR1::FLI1 e7-e6 Ewing Sarcoma 3369 Prognostic Supports B Better Outcome In patients with Ewing's sarcoma, those with type 1 EWS-FLI1 fusions had longer overall survival than those with other types of EWS-FLI1 fusions. 9552022 PubMed de Alava et al., 1998, J. Clin. Oncol. 4 accepted 431 164 53 22 29664007 29683123 ENST00000397938.2 11 128675261 128683162 ENST00000527786.2 75 GRCh37 Although multiple fusion transcripts have been described, type 1 consists of EWSR1 exon 7 fused to FLI1 exon 6, the most common arrangement in Ewings Sarcoma. Somatic 2020-08-12 05:34:03 UTC https://civicdb.org/links/evidence_items/431 https://civicdb.org/links/variants/164 https://civicdb.org/links/genes/53 false EZH2 2146 Y646 Diffuse Large B-cell Lymphoma 0050745 Diagnostic Supports B Positive Heterozygous mutations in EZH2 at Y641 were the second most frequent genetic event (after BCL2 t(14;18)) associated with a diagnosis of GCB-DLBCL in 35 / 320 patient samples. In contrast, mutations in EZH2 Y641 are not observed in centroblast samples from healthy controls. 20081860 PubMed Morin et al., 2010, Nat. Genet. 4 accepted 432 165 63 7 148508726 148508728 ENST00000320356.2 75 GRCh37 Mutations of Y646 are associated with a diagnosis of Germinal Center B type DLBCL and Follicular non-Hodgkin Lymphoma. In vitro experimental findings suggest that this may be due to reduced methyltransferase activity of EZH2 on protein H3K27 (Morin et al., 2010). Somatic 2015-07-24 22:40:54 UTC https://civicdb.org/links/evidence_items/432 https://civicdb.org/links/variants/165 https://civicdb.org/links/genes/63 false EZH2 2146 Y646 Follicular Lymphoma 0050873 Diagnostic Supports B Positive Heterozygous mutations in EZH2 at Y641 were the second most frequent genetic event (after BCL2 t(14;18)) associated with a diagnosis of Follicular non-Hodgkin Lymphoma in 18 / 251 patient samples. In contrast, mutations in EZH2 Y641 are not observed in centroblast samples from healthy controls. 20081860 PubMed Morin et al., 2010, Nat. Genet. 4 accepted 433 165 63 7 148508726 148508728 ENST00000320356.2 75 GRCh37 Mutations of Y646 are associated with a diagnosis of Germinal Center B type DLBCL and Follicular non-Hodgkin Lymphoma. In vitro experimental findings suggest that this may be due to reduced methyltransferase activity of EZH2 on protein H3K27 (Morin et al., 2010). Somatic 2015-07-24 22:41:08 UTC https://civicdb.org/links/evidence_items/433 https://civicdb.org/links/variants/165 https://civicdb.org/links/genes/63 false KMT2D 8085 Loss-of-function Follicular Lymphoma 0050873 Diagnostic Supports B Positive MLL2 was found to be the most frequently mutated gene in a sample of 31/35 follicular lymphoma patients and was not mutated in normal centroblast samples. Furthermore, MLL2 mutations were as frequently observed as t(14;18) Igh-BCL2 translocations, which are the most common clinically significant genetic event observed in follicular lymphoma. Mutations were predicted to be loss-of-function. 21796119 PubMed Morin et al., 2011, Nature 3 accepted 435 167 64 12 49412758 49449107 ENST00000301067.7 75 GRCh37 Somatic 2016-01-04 23:36:11 UTC https://civicdb.org/links/evidence_items/435 https://civicdb.org/links/variants/167 https://civicdb.org/links/genes/64 false BTK 695 C481S Chronic Lymphocytic Leukemia 1040 Ibrutinib Predictive Supports B Resistance Whole exome sequencing of 6 chronic lymphocytic leukemia patients with acquired resistance to ibrutinib determined 5/6 patients harbored a C481S mutation in BTK. 24869598 PubMed Woyach et al., 2014, N. Engl. J. Med. 4 accepted 436 168 65 X 100611165 100611165 A T ENST00000308731.7 75 GRCh37 Somatic 2015-07-24 22:41:51 UTC https://civicdb.org/links/evidence_items/436 https://civicdb.org/links/variants/168 https://civicdb.org/links/genes/65 false AKT1 207 Q79K Melanoma 1909 Vemurafenib Predictive Supports D Resistance The AKT1 Q79K mutation has been shown to confer resistance to BRAF inhibitors (vemurafenib) in melanoma cell line M229. 24265152 PubMed Shi et al., 2014, Cancer Discov 4 accepted 439 169 2 14 105243048 105243048 G T ENST00000407796.2 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/439 https://civicdb.org/links/variants/169 https://civicdb.org/links/genes/2 false ALK 238 EML4::ALK and Amplification Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports D Resistance Amplification of wild-type EML4-ALK in the non-small cell lung carcinoma cell line, H3122, caused resistance to crizotinib. 22277784 PubMed Katayama et al., 2012, Sci Transl Med 3 accepted 440 170 1 2 42396490 42528380 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/440 https://civicdb.org/links/variants/170 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion G1202R Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports D Resistance The G1202R mutation in the EML4-ALK fusion was found to confer resistance to crizotinib in Ba/F3 cells. 22277784 PubMed Katayama et al., 2012, Sci Transl Med 4 accepted 441 171 1 2 29443613 29443613 C T ENST00000389048.3 75 GRCh37 ALK fusion with G1202R mutation in the ALK kinase domain was first identified in a lung adenocarcinoma patient who had progressed after 10 months of responding to crizotinib. Further characterization of this variant verified crizotinib resistance and additionally demonstrated resistance to multiple next generation ALK inhibitors including ceritinib, alectinib and brigatinib. Experiments using the HSP90 inhibitor 17-AAG have indicated potential sensitivity of EML4-ALK G1202R to this drug, suggesting this variant may be an HSP90 client protein. Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/441 https://civicdb.org/links/variants/171 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK L1196M Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports D Resistance The L1196M mutation in the EML4-ALK fusion was found to confer resistance to crizotinib in Ba/F3 cells. 22277784 PubMed Katayama et al., 2012, Sci Transl Med 4 accepted 442 7 1 2 29443631 29443631 G T ENST00000389048.3 75 GRCh37 In patients with non-small cell lung cancer exhibiting EML4-ALK fusion, L1196M has been shown to confer resistance to crizotinib. This was also true in a patient with both EML4-ALK C1156Y & L1196M. Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/442 https://civicdb.org/links/variants/7 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK S1206Y Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports D Resistance The S1206Y mutation in the EML4-ALK fusion was found to confer resistance to crizotinib in Ba/F3 cells. 22277784 PubMed Katayama et al., 2012, Sci Transl Med 4 accepted 443 172 1 2 29443600 29443600 G T ENST00000389048.3 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/443 https://civicdb.org/links/variants/172 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK T1151INST Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Resistance A lung adenocarcinoma patient responded to crizotinib treatment for 12 months, after which the cancer relapsed and sequencing of the ALK tyrosine kinase domain revealed a 1151insT mutation. This mutation was not found in the pre-crizotinib biopsy. EML4-ALK T1151insT was expressed In Ba/F3 cells and an IC50 of 431.8 nM was obtained, which was 16 times higher than for EML4-ALK wild-type, indicating strong crizotinib resistance. EML4-ALK containing H3122 NSCLC cells were incubated in increasing levels of crizotinib inducing resistance. The resulting cell line H3122 CR2 had IC50 10x greater to crizotinib than parental H3122, and was found to contain 1151 insT mutation. In western blots, pALK levels in H3122 CR2 cells remained apparent under 1000 nM crizotinib, whereas pALK signal was ablated under these conditions in parental H3122 cells. 22277784 PubMed Katayama et al., 2012, Sci Transl Med 4 accepted 444 173 1 2 29445271 29445272 CGT ENST00000389048.3 75 GRCh37 The ALK fusion variant with insertion of T at amino acid 1151 was found in an ALK rearranged lung adenocarcinoma which had progressed after responding to crizotinib treatment. The mutation was absent in tumor sample taken before crizotinib treatment. Characterization of the variant using cell lines expressing EML4-ALK with 1151 T insert found the variant to be highly crizotinib resistant, and other work demonstrated resistance to next generation inhibitor alectinib, while resistance to tool compound TAE684 indicates potential resistance to the next generation ALK inhibitor ceritinib which is derived from TAE684. Other experiments suggest theraputic potential for HSP90 inhibitors, as EML4-ALK T1151 Tins sensitivity to 17-AAG has been observed. Somatic 2016-08-15 20:02:25 UTC https://civicdb.org/links/evidence_items/444 https://civicdb.org/links/variants/173 https://civicdb.org/links/genes/1 false APC 324 Mutation Colon Carcinoma 1520 JW55 Predictive Supports D Sensitivity/Response Canonical Wnt signaling in colon carcinoma cells with APC mutation was inhibited by JW55 treatment. 22440753 PubMed Waaler et al., 2012, Cancer Res. 3 accepted 445 174 66 5 112043218 112181936 ENST00000457016.1 75 GRCh37 Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/445 https://civicdb.org/links/variants/174 https://civicdb.org/links/genes/66 false APC 324 Mutation Colorectal Cancer 9256 G007-LK Predictive Supports D Sensitivity/Response G007-LK inhibits in vivo tumor growth in a subset of APC-mutant colorectal cancers xenograft models but may be limited by intestinal toxicity. 23539443 PubMed Lau et al., 2013, Cancer Res. 4 accepted 446 174 66 5 112043218 112181936 ENST00000457016.1 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/446 https://civicdb.org/links/variants/174 https://civicdb.org/links/genes/66 false AR 367 F877L Prostate Cancer 10283 Apalutamide,Enzalutamide Substitutes Predictive Supports D Resistance Mutations F876L in the ligand binding domain of the androgen receptor confered resistance to enzalutamide and ARN-509, causing these compounds to function as partial agonists in two prostate cancer cell lines. 23779130 PubMed Joseph et al., 2013, Cancer Discov 4 accepted 447 175 67 X 66943549 66943549 T C ENST00000374690.3 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/447 https://civicdb.org/links/variants/175 https://civicdb.org/links/genes/67 false AR 367 W742 Prostate Carcinoma 10286 Bicalutamide Predictive Supports D Resistance LNCaP-FGC cells with mutations at codon 741 (W741C, W741L) were able to use bicalutamide as an AR agonist, promoting cell growth and increased prostate-specific antigen secretion. 12517791 PubMed Hara et al., 2003, Cancer Res. 4 accepted 448 176 67 X 66937370 66937372 ENST00000374690.3 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/448 https://civicdb.org/links/variants/176 https://civicdb.org/links/genes/67 false ASXL1 171023 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In patients with acute myeloid leukemia, in a univariate analysis those with mutations in ASXL1 had worse overall survival than wild-type. 25412851 PubMed Ohgami et al., 2015, Mod. Pathol. 2 accepted 449 177 68 20 30946155 31027122 ENST00000375687.4 75 GRCh37 ASXL1 mutations are most frequently observed in the absence of FLT3-ITD and NPM1 mutations in acute myeloid leukemia (AML) patients and seem to be enriched in older patients (>60 years). These mutations are associated with poor prognosis with respect to both survival and compete remission rates. Somatic 2015-10-09 18:40:31 UTC https://civicdb.org/links/evidence_items/449 https://civicdb.org/links/variants/177 https://civicdb.org/links/genes/68 false ASXL1 171023 Mutation Acute Myeloid Leukemia 9119 Diagnostic Supports B Positive Among patients with AML, those with mutations in ASXL1 were more likely to have the AML with myelodysplasia-related changes (AML-MRC) subtype. 25412851 PubMed Ohgami et al., 2015, Mod. Pathol. 3 accepted 450 177 68 20 30946155 31027122 ENST00000375687.4 75 GRCh37 ASXL1 mutations are most frequently observed in the absence of FLT3-ITD and NPM1 mutations in acute myeloid leukemia (AML) patients and seem to be enriched in older patients (>60 years). These mutations are associated with poor prognosis with respect to both survival and compete remission rates. Somatic 2015-10-09 18:40:31 UTC https://civicdb.org/links/evidence_items/450 https://civicdb.org/links/variants/177 https://civicdb.org/links/genes/68 false ASXL1 171023 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In a meta-analysis of six studies totalling 3311 patients with non-M3 acute myeloid leukemia, those with mutations in ASXL1 had worse overall survival than wild-type patients (Hazard ratio 1.86, 95% CI 1.49-2.33). 25308295 PubMed Shivarov et al., 2015, Leuk. Lymphoma 4 accepted 451 177 68 20 30946155 31027122 ENST00000375687.4 75 GRCh37 ASXL1 mutations are most frequently observed in the absence of FLT3-ITD and NPM1 mutations in acute myeloid leukemia (AML) patients and seem to be enriched in older patients (>60 years). These mutations are associated with poor prognosis with respect to both survival and compete remission rates. Somatic 2016-06-22 19:18:54 UTC https://civicdb.org/links/evidence_items/451 https://civicdb.org/links/variants/177 https://civicdb.org/links/genes/68 false ATM 472 Mutation Glioblastoma 3068 Temozolomide Predictive Supports D Sensitivity/Response Glioblastoma cell lines were shown to have increased sensitivity to Temozolomide when siRNA-induced ATM knockdown was applied. 23960094 PubMed Eich et al., 2013, Mol. Cancer Ther. 3 accepted 452 178 69 11 108093559 108239826 ENST00000278616.4 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/452 https://civicdb.org/links/variants/178 https://civicdb.org/links/genes/69 false ATM 472 Mutation Melanoma 1909 Temozolomide Predictive Supports D Sensitivity/Response Melanoma cell lines were shown to have increased sensitivity to Temozolomide when siRNA-induced ATM knockdown was applied. 23960094 PubMed Eich et al., 2013, Mol. Cancer Ther. 3 accepted 453 178 69 11 108093559 108239826 ENST00000278616.4 75 GRCh37 Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/453 https://civicdb.org/links/variants/178 https://civicdb.org/links/genes/69 false ATM 472 Underexpression Cancer 162 NU7441,KU-0060648 Substitutes Predictive Supports D Sensitivity/Response ATM-deficient H1395 and HT144 cancer cell lines showed growth inhibition when treated with DNA PKcs inhibitors KU-0060648 and NU7441. These agents also increased the lifespan of mice transfused with ATM-deficient lymphoma cells when compared with etoposide or control. 23761041 PubMed Riabinska et al., 2013, Sci Transl Med 5 accepted 454 179 69 11 108093559 108239826 ENST00000278616.4 75 GRCh37 Somatic 2016-10-10 19:29:40 UTC https://civicdb.org/links/evidence_items/454 https://civicdb.org/links/variants/179 https://civicdb.org/links/genes/69 false ATM 472 Mutation Hematologic Cancer 2531 Olaparib Predictive Supports D Sensitivity/Response Olaparib was found to inhibit cancer cell growth in ATM mutant cell lines of several blood cancers including Lymphoblastoid Leukemia, Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, and in a murine xenograft model of Mantle Cell Lymphoma. 20739657 PubMed Weston et al., 2010, Blood 5 accepted 455 178 69 11 108093559 108239826 ENST00000278616.4 75 GRCh37 Somatic 2016-12-01 15:24:19 UTC https://civicdb.org/links/evidence_items/455 https://civicdb.org/links/variants/178 https://civicdb.org/links/genes/69 false AURKA 6790 Amplification Esophagus Adenocarcinoma 4914 Cisplatin,Alisertib Combination Predictive Supports E Sensitivity/Response Antitumour effect of alisertib treatment in esophageal adenocarcinomas can be intensified in combination with cisplatin. 22302096 PubMed Sehdev et al., 2012, Mol. Cancer Ther. 3 accepted 456 180 61 20 54944446 54967393 ENST00000395913.3 75 GRCh37 Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/456 https://civicdb.org/links/variants/180 https://civicdb.org/links/genes/61 false AURKA 6790 Overexpression Cervical Adenocarcinoma 3702 Paclitaxel Predictive Supports D Resistance In the cervial andenocarcinoma cell line HeLa, when AURK-A was overexpressed, the cells were resistant to the apoptotic effects of Taxol. 12559175 PubMed Anand et al., 2003, Cancer Cell 3 accepted 457 181 61 20 54944446 54967393 ENST00000395913.3 75 GRCh37 Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/457 https://civicdb.org/links/variants/181 https://civicdb.org/links/genes/61 false BAP1 8314 EXPRESSION Uveal Melanoma 6039 Prognostic Supports B Better Outcome In patients with uveal melanoma, those with BAP1 expression (determined by immunohistochemical staining) had better survival. 25147369 PubMed van Essen et al., 2014, Br J Ophthalmol 3 accepted 458 182 70 3 52435029 52444366 ENST00000460680.1 75 GRCh37 N/A 2020-11-24 20:28:05 UTC https://civicdb.org/links/evidence_items/458 https://civicdb.org/links/variants/182 https://civicdb.org/links/genes/70 false BAP1 8314 Mutation Clear Cell Renal Cell Carcinoma 4467 Prognostic Supports B Poor Outcome In patients with clear cell renal cell carcinoma, in a multivariate analysis those with mutations in BAP1 had worse overall survival than wild-type. 23797736 PubMed Sato et al., 2013, Nat. Genet. 5 accepted 459 183 70 3 52435029 52444366 ENST00000460680.1 75 GRCh37 BAP1 is a tumor suppressor gene, mutations in this gene have been observed in a number of cancers including melanoma, and renal cancers. These mutations generally lead to loss-of-function and mutations in the UHC domain of BAP1 have been shown to lead to structural instability and β-amyloid aggregation in models. Germline mutations are associated with an increased risk of tumorgenesis and can lead to the development of "atypical Spitz tumours (ASTs), cutaneous melanoma (CM), epithelioid malignant mesothelioma (MM) and clear cell RCC". Somatic 2015-10-09 18:40:31 UTC https://civicdb.org/links/evidence_items/459 https://civicdb.org/links/variants/183 https://civicdb.org/links/genes/70 false BAP1 8314 Mutation Renal Cell Carcinoma 4450 Prognostic Supports B Poor Outcome In patients with clear cell renal cell carcinoma, in a multivariate analysis those with mutations in BAP1 had worse overall survival than wild-type. 23797736 PubMed Sato et al., 2013, Nat. Genet. 5 accepted 460 183 70 3 52435029 52444366 ENST00000460680.1 75 GRCh37 BAP1 is a tumor suppressor gene, mutations in this gene have been observed in a number of cancers including melanoma, and renal cancers. These mutations generally lead to loss-of-function and mutations in the UHC domain of BAP1 have been shown to lead to structural instability and β-amyloid aggregation in models. Germline mutations are associated with an increased risk of tumorgenesis and can lead to the development of "atypical Spitz tumours (ASTs), cutaneous melanoma (CM), epithelioid malignant mesothelioma (MM) and clear cell RCC". Somatic 2017-07-15 23:38:50 UTC https://civicdb.org/links/evidence_items/460 https://civicdb.org/links/variants/183 https://civicdb.org/links/genes/70 false BAP1 8314 Mutation Clear Cell Renal Cell Carcinoma 4467 Prognostic Supports B Poor Outcome In patients with clear cell renal cell carcinoma, those with nonsilent mutations of BAP1 had worse overall survival than wild-type. 23792563 PubMed 2013, Nature 5 accepted 461 183 70 3 52435029 52444366 ENST00000460680.1 75 GRCh37 BAP1 is a tumor suppressor gene, mutations in this gene have been observed in a number of cancers including melanoma, and renal cancers. These mutations generally lead to loss-of-function and mutations in the UHC domain of BAP1 have been shown to lead to structural instability and β-amyloid aggregation in models. Germline mutations are associated with an increased risk of tumorgenesis and can lead to the development of "atypical Spitz tumours (ASTs), cutaneous melanoma (CM), epithelioid malignant mesothelioma (MM) and clear cell RCC". Somatic 2015-10-09 18:40:31 UTC https://civicdb.org/links/evidence_items/461 https://civicdb.org/links/variants/183 https://civicdb.org/links/genes/70 false BRAF 673 AKAP9::BRAF Thyroid Gland Papillary Carcinoma 3969 Diagnostic Supports B Positive The AKAP9-BRAF fusion gene was found in 3/28 tumor samples of radiation-associated papillary thyroid carcinoma, and no samples of non-radiation associated papillary thyroid carcinoma. This fusion was associated with elevated BRAF kinase activity, similar to the V600E variant. 15630448 PubMed Ciampi et al., 2005, J. Clin. Invest. 4 accepted 462 184 5 7 91570181 91625114 ENST00000356239.3 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2015-10-09 18:40:30 UTC https://civicdb.org/links/evidence_items/462 https://civicdb.org/links/variants/184 https://civicdb.org/links/genes/5 false BRAF 673 V600E Multiple Myeloma 9538 Prognostic Supports B Poor Outcome In patients with multiple myeloma, those with BRAF V600E had shorter overall survival than wild-type. 23612012 PubMed Andrulis et al., 2013, Cancer Discov 3 accepted 463 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-04-08 22:38:19 UTC https://civicdb.org/links/evidence_items/463 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRCA1 672 Mutation Epithelial Ovarian Cancer 2152 Prognostic Supports B Better Outcome In patients with invasive epithelial ovarian cancer, those with mutations in BRCA1 had better five-year overall survival. 22274685 PubMed Bolton et al., 2012, JAMA 3 accepted 464 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Rare Germline 2015-08-05 18:46:44 UTC https://civicdb.org/links/evidence_items/464 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false BRCA2 675 Mutation Epithelial Ovarian Cancer 2152 Prognostic Supports B Better Outcome In patients with invasive epithelial ovarian cancer, those with mutations in BRCA2 had better five-year overall survival. 22274685 PubMed Bolton et al., 2012, JAMA 3 accepted 465 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Rare Germline 2015-08-05 18:46:44 UTC https://civicdb.org/links/evidence_items/465 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false CCNE1 898 Amplification Ovarian Carcinoma 4001 Prognostic Supports B Poor Outcome In a retrospective study of 88 ovarian carcinomas, 18 had amplification of CCNE1. Those with amplification had worse overall and disease-free survival. 20336784 PubMed Nakayama et al., 2010, Cancer 4 accepted 466 187 11 19 30302805 30315215 ENST00000262643.3 75 GRCh37 Somatic 2015-08-05 19:02:18 UTC https://civicdb.org/links/evidence_items/466 https://civicdb.org/links/variants/187 https://civicdb.org/links/genes/11 false CEBPA 1050 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome In children with acute myeloid leukemia, those with mutations in CEBPA had better overall and event-free survival and decreased cummulative incidence of relapse. 19304957 PubMed Ho et al., 2009, Blood NCT00002798,NCT00070174 4 accepted 467 29 15 19 33790840 33793470 ENST00000498907.2 75 GRCh37 CEBPA mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) and a favorable prognosis. However, NPM1 and FLT3 mutations should also be assessed in CN-AML patients as concurrent mutations may have prognostic implications. Somatic 2015-11-22 00:11:45 UTC https://civicdb.org/links/evidence_items/467 https://civicdb.org/links/variants/29 https://civicdb.org/links/genes/15 false CEBPA 1050 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome In a set of 315 pediatric patients with acute myeloid leukemia, 47 had mutations in CEBPA. Those with mutations had better overall survival than wild-type patients. 25014773 PubMed Matsuo et al., 2014, Blood Cancer J 4 accepted 468 29 15 19 33790840 33793470 ENST00000498907.2 75 GRCh37 CEBPA mutations are associated with cytogenetically normal acute myeloid leukemia (CN-AML) and a favorable prognosis. However, NPM1 and FLT3 mutations should also be assessed in CN-AML patients as concurrent mutations may have prognostic implications. Somatic 2015-10-09 18:40:30 UTC https://civicdb.org/links/evidence_items/468 https://civicdb.org/links/variants/29 https://civicdb.org/links/genes/15 false DNMT3A 1788 Mutation T-cell Acute Lymphoblastic Leukemia 5603 Prognostic Supports B Poor Outcome In adult patients with early (n = 30), cortical (n = 30), mature (n = 3) or unknown (n = 8) T-cell acute lymphoblastic leukemia, those with mutations in DNMT3A (n=12) had shorter overall survival than wild-type patients (n=59; p=0.011). This was also true for the subset of patients with early T-ALL DNMT3A-mutated (n = 8) compared to wild-type patients (n = 22; p=0.005). 23341344 PubMed Grossmann et al., 2013, Genes Chromosomes Cancer 4 accepted 469 189 18 2 25455845 25565459 ENST00000264709.3 75 GRCh37 DNMT3A mutations occur in a variety of myeloid malignancies. These mutations are associated with adverse prognosis in acute myeloid leukemia (AML), particularly in the context of NPM1 and FLT3-ITD mutations, which often co-occur. Early results indicate AML patients with DNMT3A mutations may respond better to decitabine than those with wild-type. Shorter survival has been indicated in patients with T-cell acute lymphoblastic leukemia and myelodysplastic syndrome, however, larger cohorts are required to verify this finding. DNMT3A mutations have been suggested as a pre-leukemic lesion and found in older individuals with clonal hematopoiesis but no overt malignancy. Somatic 2016-03-26 22:10:05 UTC https://civicdb.org/links/evidence_items/469 https://civicdb.org/links/variants/189 https://civicdb.org/links/genes/18 false EGFR 1956 Amplification Barrett's Adenocarcinoma 7941 Prognostic Supports B Poor Outcome In patients with Barrett's adenocarcinoma, those with amplification of EGFR had shorter disease-specific survial. 20840671 PubMed Marx et al., 2010, Histopathology 3 accepted 470 190 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2015-08-05 18:46:45 UTC https://civicdb.org/links/evidence_items/470 https://civicdb.org/links/variants/190 https://civicdb.org/links/genes/19 false EGFR 1956 Amplification Cervical Squamous Cell Carcinoma 3744 Prognostic Supports B Poor Outcome In patients with cervical squamous cell carcinoma, those with gene amplification of EGFR had worse overall survival. 21730982 PubMed Iida et al., 2011, Br. J. Cancer 3 accepted 471 190 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2015-08-05 19:02:17 UTC https://civicdb.org/links/evidence_items/471 https://civicdb.org/links/variants/190 https://civicdb.org/links/genes/19 false EGFR 1956 Copy Number Variation Head And Neck Squamous Cell Carcinoma 5520 Prognostic Supports B Poor Outcome In 134 patients with head and neck squamous cancer 32 had copy number variations. Tumors with variation (either increase or decrease) in copy number of EGFR had worse overall, cancer-specific, and disease-free survival. 17538160 PubMed Temam et al., 2007, J. Clin. Oncol. 4 accepted 472 191 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/472 https://civicdb.org/links/variants/191 https://civicdb.org/links/genes/19 false EGFR 1956 Amplification Head And Neck Squamous Cell Carcinoma 5520 Prognostic Supports B Poor Outcome The group of 43 out of 75 tumor samples with increased copy number or amplification of EGFR as determined by FISH (FISH-positive) had worse progression-free and overall survival than FISH-negative tumors. 16943533 PubMed Chung et al., 2006, J. Clin. Oncol. 4 accepted 473 190 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2015-12-22 23:00:30 UTC https://civicdb.org/links/evidence_items/473 https://civicdb.org/links/variants/190 https://civicdb.org/links/genes/19 false EGFR 1956 Overexpression Brain Glioblastoma Multiforme 3073 Prognostic Supports B Poor Outcome In patients with glioblastoma multiforme, those with overespression of wild-type EGFR had shorter overall survival. 14583498 PubMed Shinojima et al., 2003, Cancer Res. 3 accepted 474 193 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 N/A 2020-10-20 06:02:51 UTC https://civicdb.org/links/evidence_items/474 https://civicdb.org/links/variants/193 https://civicdb.org/links/genes/19 false ERG 2078 EWSR1::ERG Ewing Sarcoma 3369 Diagnostic Supports B Positive t(21;22) rearrangements of EWSR1-ERG are associated with a diagnosis of Ewing sarcoma and are the second most common gene fusion reported in this disease. 23706910 PubMed Warren et al., 2013, Hum. Pathol. 5 accepted 475 194 71 22 29664007 29683123 ENST00000397938.2 21 39751949 39755845 ENST00000398907.1 75 GRCh37 EWSR1-ERG is found in 5% of patients with Ewing Sarcoma and considered to be diagnostic of this disease, a small tumor more often found in bone, but less frequently in soft tissue. To better identify EWSR1-ERG in patients, conventional cytogenetics methods were analyzed: FISH and RT-PCR. Ultimately concluding that more than one method is needed to accurately diagnose patients due to the strengths and weaknesses of each individual method. Somatic 2015-10-09 18:40:31 UTC https://civicdb.org/links/evidence_items/475 https://civicdb.org/links/variants/194 https://civicdb.org/links/genes/71 false ERG 2078 TMPRSS2::ERG Prostate Carcinoma 10286 Diagnostic Supports B Positive TMPRSS2/ERG gene fusion was observed in 23 of 29 (79%) of prostate carcinoma samples, and 90% of ERG expression positive prostate carcinoma samples. 16254181 PubMed Tomlins et al., 2005, Science 3 accepted 476 195 71 21 42879877 42879992 ENST00000398585.3 21 39751949 39817544 ENST00000398910.1 75 GRCh37 TMPRSS2 fusions are prevalent in Prostate Cancer. TMPRSS2 fusion with ETS family members such as ERG are among the most common. Fusion of TMPRSS2 with ERG may result in overexpression of ERG driven by the TMPRSS2 androgen-responsive promoter elements. Due to the high prevalence of this fusion, it may have diagnostic utility for prostate cancer, especially ERG expression positive prostate cancer. Somatic 2015-10-09 18:40:31 UTC https://civicdb.org/links/evidence_items/476 https://civicdb.org/links/variants/195 https://civicdb.org/links/genes/71 false FGFR3 2261 Y373C Bladder Carcinoma 4007 Diagnostic Supports B Positive Y375C mutation results in activation of FGFR3 and is associated with bladder carcinoma. Patients with low-grade tumors were more likely to have FGFR3 mutations than those with high-grade tumors. 20542753 PubMed Bodoor et al., 2010, Cancer Epidemiol 3 accepted 477 2404 23 4 1806099 1806099 A G ENST00000440486.2 75 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. Somatic 2022-06-23 18:41:20 UTC https://civicdb.org/links/evidence_items/477 https://civicdb.org/links/variants/2404 https://civicdb.org/links/genes/23 false EWSR1 2130 EWSR1::FLI1 Ewing Sarcoma 3369 Diagnostic Supports B Positive t(11;22) rearrangements of EWSR1-FLI1 are diagnostic of ewing sarcoma, and are observed in 90% of cytogenetic samples. 23706910 PubMed Warren et al., 2013, Hum. Pathol. 5 accepted 478 706 54 22 29664307 29688158 ENST00000414183.2 11 128638013 128683162 ENST00000527786.2 75 GRCh37 In approximately 90% of Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) a translocation t(11;22)(q24; q12) is identified, fusing the 5’ exons (containing the transactivatin domain, at least exon 1-7) of EWSR1, with the 3’ exons (from exon 9, coding the DNA binding domain) of FLI1. Somatic 2022-07-31 12:46:18 UTC https://civicdb.org/links/evidence_items/478 https://civicdb.org/links/variants/706 https://civicdb.org/links/genes/54 false FOXL2 668 C134W Ovarian Granulosa Cell Tumor 2999 Diagnostic Supports B Positive FOXL2 C134W mutation was found in 52 / 56 adult granulosa cell tumors, and is absent in other types of sex-cord stromal tumors, and juvenile granulosa tumors. 20693978 PubMed Jamieson et al., 2010, Mod. Pathol. 4 accepted 479 198 72 3 138665163 138665163 G C ENST00000330315.3 75 GRCh37 The variant C134W on the FOXL2 gene was revealed to have a high frequency (95-97%) in the adult form of granulosa cell tumors that comprises 5% of ovarian cancers. Due to the mutation's high frequency, future therapeutics might target for this single apparent mechanism. However, the consequence of this mutation remain unknown. Somatic 2016-03-16 22:09:27 UTC https://civicdb.org/links/evidence_items/479 https://civicdb.org/links/variants/198 https://civicdb.org/links/genes/72 false IDH1 3417 R132 Glioblastoma 3068 Prognostic Supports B Better Outcome In patients with a glioblastoma, those with mutations at R132 of IDH1 had better overall survival than wild-type patients. 19228619 PubMed Yan et al., 2009, N. Engl. J. Med. 5 accepted 480 58 26 2 209113111 209113113 ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes, IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2019-02-22 15:06:33 UTC https://civicdb.org/links/evidence_items/480 https://civicdb.org/links/variants/58 https://civicdb.org/links/genes/26 false IDH1 3417 R132 Malignant Astrocytoma 3069 Prognostic Supports B Better Outcome In patients with anaplastic astrocytoma, those with mutations at R132 of IDH1 had better overall survival than wild-type patients. 19228619 PubMed Yan et al., 2009, N. Engl. J. Med. 5 accepted 481 58 26 2 209113111 209113113 ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes, IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2019-02-22 15:06:51 UTC https://civicdb.org/links/evidence_items/481 https://civicdb.org/links/variants/58 https://civicdb.org/links/genes/26 false IDH2 3418 R172 Glioblastoma 3068 Prognostic Supports B Better Outcome In patients with a glioblastoma, those with mutations at R172 of IDH2 had better overall survival than wild-type patients. 19228619 PubMed Yan et al., 2009, N. Engl. J. Med. 5 accepted 482 199 27 15 90631837 90631839 ENST00000330062.3 75 GRCh37 IDH2 R172 is a gain-of-function mutation commonly observed in acute myeloid leukemia and is enriched in those patients which are cytogenetically normal. R172 is analogous to IDH1 R132 mutations and leads to neomorphic enzymatic activity. Specifically this mutation "catalyzes the conversion of alpha ketoglurarate to beta-hydrozyglutarate" leading to increased levels of beta-hydrozyglutarate. This in turn leads to hypermethylation of target genes and an inhibition of cellular differentiation. R172 mutations generally lead to worse overall survival and higher rates of relapse compared to the most common IDH2 mutations in AML (R140). Somatic 2019-02-22 15:06:54 UTC https://civicdb.org/links/evidence_items/482 https://civicdb.org/links/variants/199 https://civicdb.org/links/genes/27 false IDH2 3418 R172 Malignant Astrocytoma 3069 Prognostic Supports B Better Outcome In patients with anaplastic astrocytoma, those with mutations at R172 of IDH2 had better overall survival than wild-type patients. 19228619 PubMed Yan et al., 2009, N. Engl. J. Med. 5 accepted 483 199 27 15 90631837 90631839 ENST00000330062.3 75 GRCh37 IDH2 R172 is a gain-of-function mutation commonly observed in acute myeloid leukemia and is enriched in those patients which are cytogenetically normal. R172 is analogous to IDH1 R132 mutations and leads to neomorphic enzymatic activity. Specifically this mutation "catalyzes the conversion of alpha ketoglurarate to beta-hydrozyglutarate" leading to increased levels of beta-hydrozyglutarate. This in turn leads to hypermethylation of target genes and an inhibition of cellular differentiation. R172 mutations generally lead to worse overall survival and higher rates of relapse compared to the most common IDH2 mutations in AML (R140). Somatic 2019-02-22 15:06:58 UTC https://civicdb.org/links/evidence_items/483 https://civicdb.org/links/variants/199 https://civicdb.org/links/genes/27 false IKZF1 10320 Deletion B-lymphoblastic Leukemia/lymphoma 0080630 Prognostic Supports B Poor Outcome In children with bone marrow relapsed B-cell precursor acute lymphoblastic leukemia, those with deletions of IKZF1 had worse event-free and overall survival than patients without deletions. 22699455 PubMed Krentz et al., 2013, Leukemia 4 accepted 484 200 73 7 50344378 50472799 ENST00000331340.3 75 GRCh37 IKZF1 deletions have been reported in a variety of cancer types including pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL), Chronic Myeloid Leukemia, diffuse large B-cell lymphoma, myelodysplastic syndrome, T-cell ALL as well as solid tumors of the large intestine, lung, and liver. The clinical impact of these deletions is unknown for many cancer types however a poor outcome has been observed in leukemia based disease. This gene has been strongly implicated as a regulator for "normal hematopoiesis". In regards to BCP ALL, mouse models have shown that mutations in IKZF1 are not sufficient in and of themselves to cause disease. Haploinsuffeciency in combination with BCR-ABL1 however, will accelerate leukemiagenesis possibly indicating that at least in regards to BCP ALL these are secondary events that may be necessary for the development of leukaemic clones. Somatic 2020-11-20 16:21:28 UTC https://civicdb.org/links/evidence_items/484 https://civicdb.org/links/variants/200 https://civicdb.org/links/genes/73 false KIT 3815 M541L Chronic Myeloid Leukemia 8552 Diagnostic Does Not Support B Positive M541L mutation was not associated with CML in caucasian patients, and was common among healthy controls (8.1%), in contrast to a previous study in a Japanese CML patient population in which M541L was strongly associated with CML disease. 16307017 PubMed Krüger et al., 2006, Leukemia 4 accepted 485 201 29 4 55593464 55593464 A C ENST00000288135.5 75 GRCh37 Common Germline 2021-10-07 14:48:55 UTC https://civicdb.org/links/evidence_items/485 https://civicdb.org/links/variants/201 https://civicdb.org/links/genes/29 false KIT 3815 V560DEL Thymic Carcinoma 3284 Imatinib Predictive Supports C Sensitivity/Response In a patient with thymic carcinoma, the tumor expressing an activating mutation in exon 11 of KIT (V560del) was sensitive to imatinib. 15201427 PubMed Ströbel et al., 2004, N. Engl. J. Med. 5 accepted 486 202 29 4 55593612 55593614 GTT ENST00000288135.5 75 GRCh37 V560 Resides within the Juxtamembrane domain on exon 11 of KIT. In melanoma this region is one 4 hotspots and is the 3rd highest recurrently mutated region. Mouse models have shown that mutations in this hotspot lead to constitutive phosphorylation of KIT which will induce a stronger activation of the PI3K pathway however it is currently unknown if deletions follow the same model. Case studies in Gastrointestinal Stromal Tumors with V560DEL have reported a sensitivity when treated with imatinib and regorafenib. Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/486 https://civicdb.org/links/variants/202 https://civicdb.org/links/genes/29 false KRAS 3845 G12 Multiple Myeloma 9538 Prognostic Supports B Poor Outcome In a retrospective study of 439 patients with multiple myeloma enrolled in a clinical trial, 28 had mutations in KRAS (22/28 in G12/G13). Those with KRAS (but not NRAS) mutations had worse overall (median 19.9 vs 44.3 months, p=0.005) and progression free survival (median 14.7 vs 30.3 months, p<0.001) than those without mutations. 18528420 PubMed Chng et al., 2008, Leukemia 4 accepted 487 76 30 12 25398284 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2016-10-25 04:25:22 UTC https://civicdb.org/links/evidence_items/487 https://civicdb.org/links/variants/76 https://civicdb.org/links/genes/30 false KRAS 3845 G13 Multiple Myeloma 9538 Prognostic Supports B Poor Outcome In a retrospective study of 439 patients with multiple myeloma enrolled in a clinical trial, 28 had mutations in KRAS (22/28 in G12/G13). Those with KRAS (but not NRAS) mutations had worse overall (median 19.9 vs 44.3 months, p=0.005) and progression free survival (median 14.7 vs 30.3 months, p<0.001) than those without mutations. 18528420 PubMed Chng et al., 2008, Leukemia 4 accepted 488 80 30 12 25398281 25398282 ENST00000256078.4 75 GRCh37 While the KRAS G13 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G12 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2016-06-22 19:21:13 UTC https://civicdb.org/links/evidence_items/488 https://civicdb.org/links/variants/80 https://civicdb.org/links/genes/30 false KRAS 3845 Q61 Multiple Myeloma 9538 Prognostic Supports B Poor Outcome In a retrospective study of 439 patients with multiple myeloma enrolled in a clinical trial, 28 had mutaions in KRAS. Those with mutations had worse overall and progression free survival than those without mutations. 18528420 PubMed Chng et al., 2008, Leukemia 4 accepted 489 203 30 12 25380275 25380277 ENST00000256078.4 75 GRCh37 Somatic 2019-02-22 14:56:26 UTC https://civicdb.org/links/evidence_items/489 https://civicdb.org/links/variants/203 https://civicdb.org/links/genes/30 false MGMT 4255 Promoter Methylation Oligodendroglioma 3181 Prognostic Supports B Better Outcome In a study of 152 anaplastic oligodendroglial tumors, 121 samples had MGMT promoter methylation. Those with promoter methylation had better progression-free and overall survival. 19901104 PubMed van den Bent et al., 2009, J. Clin. Oncol. 4 accepted 490 85 34 10 131264495 131265656 ENST00000306010.7 75 GRCh37 MGMT promoter methylation has been observed to impact tumor progression in glioblastoma multiforme. In patients exhibiting promoter methylation, the akylating agent carmustine has shown efficacy. In patients lacking methylation, combining carmustine with the MGMT inhibitor O(6)-benzylguanine may be effective, but more experiments are required. Clinical trials have also shown selective sensitivity of promoter methylation-positive patients to temozolomide, making a case for wider methylation screening in GBM patients. Somatic 2015-08-05 18:46:53 UTC https://civicdb.org/links/evidence_items/490 https://civicdb.org/links/variants/85 https://civicdb.org/links/genes/34 false MGMT 4255 Promoter Methylation Glioblastoma 3068 Prognostic Supports B Better Outcome In patients with glioblastoma, those with methylated MGMT promoters have better overall survival than those with unmethylated promoters. 15758010 PubMed Hegi et al., 2005, N. Engl. J. Med. 5 accepted 491 85 34 10 131264495 131265656 ENST00000306010.7 75 GRCh37 MGMT promoter methylation has been observed to impact tumor progression in glioblastoma multiforme. In patients exhibiting promoter methylation, the akylating agent carmustine has shown efficacy. In patients lacking methylation, combining carmustine with the MGMT inhibitor O(6)-benzylguanine may be effective, but more experiments are required. Clinical trials have also shown selective sensitivity of promoter methylation-positive patients to temozolomide, making a case for wider methylation screening in GBM patients. Somatic 2019-02-22 15:14:42 UTC https://civicdb.org/links/evidence_items/491 https://civicdb.org/links/variants/85 https://civicdb.org/links/genes/34 false NCOA3 8202 AMPLIFICATION Breast Cancer 1612 Prognostic Supports B Poor Outcome In patients with breast cancer, those with amplification of NCOA3 had shorter disease-specific survival. 23322234 PubMed Burandt et al., 2013, Breast Cancer Res. Treat. 3 accepted 492 204 74 20 46130646 46285621 ENST00000372004.3 75 GRCh37 Somatic 2015-08-05 19:02:18 UTC https://civicdb.org/links/evidence_items/492 https://civicdb.org/links/variants/204 https://civicdb.org/links/genes/74 false NCOA3 8202 OVEREXPRESSION Breast Cancer 1612 Prognostic Supports B Poor Outcome High expression determined by immunohistochemistry of NCOA3 was found in 571 out of 1,836 breast cancer samples. Those with high expression had worse overall and disease-specific survival. 23322234 PubMed Burandt et al., 2013, Breast Cancer Res. Treat. 3 accepted 493 205 74 20 46130646 46285621 ENST00000372004.3 75 GRCh37 Somatic 2015-08-05 19:02:18 UTC https://civicdb.org/links/evidence_items/493 https://civicdb.org/links/variants/205 https://civicdb.org/links/genes/74 false NOTCH1 4851 Mutation Mantle Cell Lymphoma 0050746 Prognostic Supports B Poor Outcome 14 out of 121 patient samples contained mutations in NOTCH1. Those with mutations had worse overall survival than wild-type (median OS, 1.43 years vs. 3.86 years). 22210878 PubMed Kridel et al., 2012, Blood 3 accepted 494 206 50 9 139388896 139440314 ENST00000277541.6 75 GRCh37 Somatic 2017-04-21 18:58:16 UTC https://civicdb.org/links/evidence_items/494 https://civicdb.org/links/variants/206 https://civicdb.org/links/genes/50 false NOTCH1 4851 P2514FS Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome In a cohort of 120 patients with chronic lymphoytic leukemia, those with P2515 frameshift deletions in NOTCH1 at diagnosis had worse overall and treatment free survival. NOTCH1 mutations were also found to be an independent poor predictor of survival regardless of TP53 and IGHV status. 21670202 PubMed Fabbri et al., 2011, J. Exp. Med. 3 accepted 495 207 50 9 139390649 139390650 ENST00000277541.6 75 GRCh37 This mutation disrupts the C-terminal PEST domain that in normal conditions promotes degradation, resulting in accumulation of an active NOTCH1 isoform sustaining deregulated signaling. Somatic 2015-08-05 19:02:17 UTC https://civicdb.org/links/evidence_items/495 https://civicdb.org/links/variants/207 https://civicdb.org/links/genes/50 false NRAS 4893 Mutation Multiple Myeloma 9538 Prognostic Supports B N/A In patients with multiple myeloma, the presence of a mutation in NRAS was not significantly associated with progression-free or overall survival. 18528420 PubMed Chng et al., 2008, Leukemia 4 accepted 496 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2019-02-22 14:56:38 UTC https://civicdb.org/links/evidence_items/496 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false NRAS 4893 Q61 Thyroid Gland Follicular Carcinoma 3962 Prognostic Supports B N/A In patients with follicular thyroid carcinoma, those with mutations in NRAS at codon 61 did not have significantly different overall survival than patients with wild-type NRAS (p=0.36). 22650231 PubMed Fukahori et al., 2012, Thyroid 3 accepted 497 94 36 1 115256528 115256530 ENST00000369535.4 75 GRCh37 NRAS Q61 mutations have been found in multiple myeloma, gastrointestinal stromal tumors, melanoma, and others. Two melanoma patients, each harboring mutations at this locus (Q61L and Q61R), responded to treatment with the akylating agent temozolomide. However, in colorectal cancer patients, mutations at this locus have been shown to confer resistance to cetuximab. The prognostic impact of mutations at this locus is currently under study. Somatic 2015-08-05 18:46:56 UTC https://civicdb.org/links/evidence_items/497 https://civicdb.org/links/variants/94 https://civicdb.org/links/genes/36 false PAX8 7849 PAX8::PPARG Thyroid Gland Follicular Carcinoma 3962 Diagnostic Supports B Positive PAX8–PPARG gene fusions were found in 12/33 follicular thyroid carcinoma tumor samples, but were rarely found in thyroid Hürthle cell tumors. 12727991 PubMed Nikiforova et al., 2003, J. Clin. Endocrinol. Metab. 3 accepted 498 209 75 2 113992971 114036521 ENST00000429538.3 3 12329400 12475810 ENST00000397015.2 75 GRCh37 PAX8-PPAR gamma is a oncogene caused by a translocation between 2q13 and 3p25 resulting in an in-frame fusion between the two genes. It has been observed in Follicular Thyroid Cancer (FTC) and is one of two known fusion products involving PPAR gamma in FTC indicating this region may be a breakpoint hotspot. Studies have indicated that the fusion product increases cell viability and proliferation and decreases apoptosis. Somatic 2015-08-05 18:46:58 UTC https://civicdb.org/links/evidence_items/498 https://civicdb.org/links/variants/209 https://civicdb.org/links/genes/75 false PBRM1 55193 Mutation Renal Cell Carcinoma 4450 Prognostic Supports B Better Outcome In patients with sporatic clear cell renal cell carcinoma, those with mutations in PBRM1 had better overall survival than patients with BAP1 mutations. 23333114 PubMed Kapur et al., 2013, Lancet Oncol. 3 accepted 499 161 62 3 52581857 52719852 ENST00000394830.3 75 GRCh37 Somatic 2015-08-05 19:02:17 UTC https://civicdb.org/links/evidence_items/499 https://civicdb.org/links/variants/161 https://civicdb.org/links/genes/62 false PGR 5241 Expression Breast Cancer 1612 Prognostic Supports B Better Outcome In patients with breast cancer, those with expression of PgR (determined by immunohistochemical staining) had better relapse-free survival than those without expression. 16497822 PubMed Dowsett et al., 2006, Ann. Oncol. 3 accepted 500 210 76 11 100900355 101001255 ENST00000325455.5 75 GRCh37 N/A 2020-10-24 06:40:11 UTC https://civicdb.org/links/evidence_items/500 https://civicdb.org/links/variants/210 https://civicdb.org/links/genes/76 false PGR 5241 Expression Breast Cancer 1612 Tamoxifen Predictive Does Not Support B Sensitivity/Response In patients with ER-Positive breast cancer, expression of PgR does not effect the outcome of treatment with tamoxifen. 23280579 PubMed Patani et al., 2013, Int. J. Cancer 1 accepted 501 210 76 11 100900355 101001255 ENST00000325455.5 75 GRCh37 N/A 2020-12-17 19:10:10 UTC https://civicdb.org/links/evidence_items/501 https://civicdb.org/links/variants/210 https://civicdb.org/links/genes/76 false PGR 5241 Expression Breast Cancer 1612 Exemestane,Tamoxifen Substitutes Predictive Does Not Support B Sensitivity/Response Multivariate Cox regression analysis showed no disease free survival benefit for exemestane compared with tamoxifen in either PgR-low (n=984; HR, 0.85; 95% CI, 0.61 to 1.19) or PgR-high (n=3,341; HR, 0.83; 95% CI, 0.65 to 1.05) breast cancer patients (P=.88 for interaction). 21422407 PubMed Bartlett et al., 2011, J. Clin. Oncol. 4 accepted 502 210 76 11 100900355 101001255 ENST00000325455.5 75 GRCh37 N/A 2020-12-10 02:05:11 UTC https://civicdb.org/links/evidence_items/502 https://civicdb.org/links/variants/210 https://civicdb.org/links/genes/76 false PGR 5241 Expression Breast Cancer 1612 Prognostic Supports B Poor Outcome In patients with breast cancer, those with low expression of PgR had worse disease-free survival than those with high expression. 21422407 PubMed Bartlett et al., 2011, J. Clin. Oncol. 4 accepted 503 210 76 11 100900355 101001255 ENST00000325455.5 75 GRCh37 N/A 2020-10-24 06:37:08 UTC https://civicdb.org/links/evidence_items/503 https://civicdb.org/links/variants/210 https://civicdb.org/links/genes/76 false PIK3CA 5290 Amplification Gastric Adenocarcinoma 3717 Prognostic Supports B Poor Outcome In patients with gastric cancer, those with amplification of PIK3CA had shorter overall survival than those without amplification. 22292935 PubMed Shi et al., 2012, BMC Cancer 3 accepted 504 212 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 Somatic 2015-10-09 18:40:30 UTC https://civicdb.org/links/evidence_items/504 https://civicdb.org/links/variants/212 https://civicdb.org/links/genes/37 false PTEN 5728 Deletion Prostate Adenocarcinoma 2526 Prognostic Supports B Poor Outcome In a study of 107 prostate adenocarcinomas, those with either hemi- or homozygous deletions of PTEN (as determined by interphase FISH) have shorter biochemical recurence-free survival than those without deletions. 17700571 PubMed Yoshimoto et al., 2007, Br. J. Cancer 4 accepted 505 213 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2015-10-09 18:40:30 UTC https://civicdb.org/links/evidence_items/505 https://civicdb.org/links/variants/213 https://civicdb.org/links/genes/41 false PTEN 5728 Loss Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance In 27 patients with chemotherapy-naive or chemotherapy-refractory metastatic colorectal cancer who were treated with cetuximab and chemotherapy, PTEN loss was associated with non-response. 21163703 PubMed De Roock et al., 2011, Lancet Oncol. 3 accepted 506 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2015-10-09 18:40:30 UTC https://civicdb.org/links/evidence_items/506 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PTEN 5728 Loss Prostate Cancer 10283 Temsirolimus Predictive Supports D Sensitivity/Response In prostate cancer xenographs, PTEN null tumors had a significant decrease in cell size and proliferation when treated with Temsirolimus (CCI-779). 11504908 PubMed Neshat et al., 2001, Proc. Natl. Acad. Sci. U.S.A. 4 accepted 507 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/507 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false RUNX1 861 Mutation Acute Lymphoblastic Leukemia 9952 Prognostic Supports B Poor Outcome In univariate analysis, mutations in RUNX1 were significantly associated with shorter overall survival compared to wildtype RUNX1 in adult (18-87 years old) T-cell acute lymphoblastic leukemia (N=9 mutated, 62 wild type patients; P=0.014) and the early subtype (N=7 mutated, 23 wild type patients; P=0.027). RUNX1 mutations were associated with other poor-risk parameters, early subtype and older age. 23341344 PubMed Grossmann et al., 2013, Genes Chromosomes Cancer 3 accepted 508 155 43 21 36160098 36421641 ENST00000300305.3 75 GRCh37 RUNX1 mutations are associated with poor prognosis in patients with acute myeloid leukemia or adult T-cell acute lymphocytic leukemia. In younger (<60 years old) AML patients, allogeneic stem cell transplant at complete remission led to much better relapse-free survival than repetitive cycles of high-dose cytarabine. Somatic 2016-06-28 23:18:57 UTC https://civicdb.org/links/evidence_items/508 https://civicdb.org/links/variants/155 https://civicdb.org/links/genes/43 false RUNX1 861 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In a study of patients with cytogenically normal acute myeloid leukemia, RUNX1 mutations were more frequent in patients 60 years old or older. Patients with RUNX1 mutations had shorter disease-free (younger, P = 0.058; older, P < 0.001), event-free (both, P < 0.001), and overall survival (younger, P = 0.003; older, P < 0.001) as well as lower complete remission rates (younger, P = 0.005; older, P = 0.006). 22753902 PubMed Mendler et al., 2012, J. Clin. Oncol. 4 accepted 509 155 43 21 36160098 36421641 ENST00000300305.3 75 GRCh37 RUNX1 mutations are associated with poor prognosis in patients with acute myeloid leukemia or adult T-cell acute lymphocytic leukemia. In younger (<60 years old) AML patients, allogeneic stem cell transplant at complete remission led to much better relapse-free survival than repetitive cycles of high-dose cytarabine. Somatic 2016-06-22 19:21:38 UTC https://civicdb.org/links/evidence_items/509 https://civicdb.org/links/variants/155 https://civicdb.org/links/genes/43 false SF3B1 23451 Mutation Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome In patients with chronic lymphocytic leukemia, those with mutations in SF3B1 had shorter time to treatment, progression-free survival, and overall survival. A majority of the mutations are in the C-terminal domain with the most frequent location being K700E (50% of reported cases). 23568491 PubMed Wan et al., 2013, Blood 4 accepted 510 215 44 2 198254508 198299815 ENST00000335508.6 75 GRCh37 Somatic 2016-07-02 15:28:28 UTC https://civicdb.org/links/evidence_items/510 https://civicdb.org/links/variants/215 https://civicdb.org/links/genes/44 false SMAD4 4089 Mutation Pancreatic Adenocarcinoma 4074 Prognostic Supports B Poor Outcome In a study of 89 patients with adenocarcinoma of the pancreas who underwent a pancreaticoduodenectomy, those with mutations in SMAD4 had shorter overall survival than wild-type patients. 19584151 PubMed Blackford et al., 2009, Clin. Cancer Res. 3 accepted 511 216 77 18 48556583 48611409 ENST00000342988.3 75 GRCh37 Somatic 2015-10-09 18:40:30 UTC https://civicdb.org/links/evidence_items/511 https://civicdb.org/links/variants/216 https://civicdb.org/links/genes/77 false SMARCA4 6597 MUTATION Small-cell Carcinoma Of The Ovary Of Hypercalcemic Type 7651 Diagnostic Supports B Positive Nonsense mutations in SMARCA4 were associated with small cell carcinoma of the ovary, hypercalcemic type in 10/10 tumor samples, and were rarely found in other solid tumor types catalogued by TCGA. 24658004 PubMed Jelinic et al., 2014, Nat. Genet. 5 accepted 512 217 78 19 11071598 11172958 ENST00000358026.2 75 GRCh37 Somatic 2015-08-05 18:47:08 UTC https://civicdb.org/links/evidence_items/512 https://civicdb.org/links/variants/217 https://civicdb.org/links/genes/78 false SMARCA4 6597 INACTIVATING MUTATION Lung Adenocarcinoma 3910 Prognostic Supports B Poor Outcome In patients with lung adenocarcinoma, those with loss-of-function mutations in SMARCA4 had worse overall survival than those with only missense or no mutations. 24658004 PubMed Jelinic et al., 2014, Nat. Genet. 4 accepted 513 218 78 19 11071598 11172958 ENST00000358026.2 75 GRCh37 Somatic 2020-08-12 15:43:09 UTC https://civicdb.org/links/evidence_items/513 https://civicdb.org/links/variants/218 https://civicdb.org/links/genes/78 false TERT 7015 Amplification Acral Lentiginous Melanoma 6367 Prognostic Supports B Poor Outcome In patients with acral lentiginous melanoma, those with amplification of TERT had shorter overall survival. 25219713 PubMed Diaz et al., 2014, J. Am. Acad. Dermatol. 3 accepted 514 219 79 5 1253282 1295162 ENST00000310581.5 75 GRCh37 Somatic 2015-08-05 19:02:17 UTC https://civicdb.org/links/evidence_items/514 https://civicdb.org/links/variants/219 https://civicdb.org/links/genes/79 false TERT 7015 Promoter Mutation Skin Melanoma 8923 Prognostic Supports B Poor Outcome In patients with nonacral cutaneous melanoma, those with mutations in the TERT promoter had shorter overall survival than wild-type patients. 25217772 PubMed Griewank et al., 2014, J. Natl. Cancer Inst. 3 accepted 515 220 79 5 1295161 1295373 ENST00000310581.5 75 GRCh37 TERT promoter mutations are activating and commonly found at two hotspots within the TERT promoter region which occur 124 and 146 base pairs (hg19) upstream of the translation start site. These hotspots, termed C228T and C250T are observed in many cancer types and have a particularly high prevalence in glioblastoma (83%), melanoma (71%), bladder cancer (66%) and hepatocelluar carcinoma (HCC) (47%). The two mutations are usually heterozygous and mutually exclusive and result in an increased similarity to an ETS binding domain and may act as a binding site to an ETS transcription factor. These mutations are thought to be early events in tumorgenesis and aid in cellular immortality. Decreased overall survival in patients with these mutations have been observed in medulloblastoma, thyroid cancer, urogenital cancer, melanoma, and laryngeal tumors. The presence of these mutations has also been shown to be predictive of malignant/premalignant nodules in HCC and meningiomas. Somatic 2015-10-09 18:40:30 UTC https://civicdb.org/links/evidence_items/515 https://civicdb.org/links/variants/220 https://civicdb.org/links/genes/79 false TERT 7015 Promoter Mutation Glioblastoma 3068 Prognostic Supports B Poor Outcome In 187 patients with glioblastoma, those with TERT promoter mutations had worse cummulative survival than wild-type patients. The most common mutation was C228T (73% of mutants) followed by C250T (27% of mutants). However, most of the Prognostic value of TERT mutations is thought to be derived from their inverse coorelation with IDH1 mutations. 23955565 PubMed Nonoguchi et al., 2013, Acta Neuropathol. 4 accepted 516 220 79 5 1295161 1295373 ENST00000310581.5 75 GRCh37 TERT promoter mutations are activating and commonly found at two hotspots within the TERT promoter region which occur 124 and 146 base pairs (hg19) upstream of the translation start site. These hotspots, termed C228T and C250T are observed in many cancer types and have a particularly high prevalence in glioblastoma (83%), melanoma (71%), bladder cancer (66%) and hepatocelluar carcinoma (HCC) (47%). The two mutations are usually heterozygous and mutually exclusive and result in an increased similarity to an ETS binding domain and may act as a binding site to an ETS transcription factor. These mutations are thought to be early events in tumorgenesis and aid in cellular immortality. Decreased overall survival in patients with these mutations have been observed in medulloblastoma, thyroid cancer, urogenital cancer, melanoma, and laryngeal tumors. The presence of these mutations has also been shown to be predictive of malignant/premalignant nodules in HCC and meningiomas. Somatic 2015-08-05 19:02:17 UTC https://civicdb.org/links/evidence_items/516 https://civicdb.org/links/variants/220 https://civicdb.org/links/genes/79 false TP53 7157 Deleterious Mutation Head And Neck Squamous Cell Carcinoma 5520 Prognostic Supports B Poor Outcome In a study of 74 patients with head and neck squamous cell carcinoma, those with disruptive mutations in TP53 had shorter overall survival and a higher rate of locoregional recurrence than those without mutations or with nondisruptive mutations. 22090360 PubMed Skinner et al., 2012, Clin. Cancer Res. 3 accepted 517 221 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Deleterious mutations are mutations of TP53 with prior characterization demonstrating significant deleterious effect on TP53 protein function. Inactivating TP53 mutations prevent on target activity and efficacy of MDM2-TP53 interaction inhibitors. Somatic 2015-10-09 18:40:30 UTC https://civicdb.org/links/evidence_items/517 https://civicdb.org/links/variants/221 https://civicdb.org/links/genes/45 false TP53 7157 Mutation Head And Neck Squamous Cell Carcinoma 5520 Prognostic Does Not Support B Poor Outcome Unlike other studies, in this study of 110 patients with head and neck squamous cell carcinoma, there was no significant difference in the overall survival of patients with and without any TP53 mutations. 8901856 PubMed Koch et al., 1996, J. Natl. Cancer Inst. 3 accepted 518 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2015-10-09 18:40:30 UTC https://civicdb.org/links/evidence_items/518 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false TP53 7157 Mutation Esophagus Squamous Cell Carcinoma 3748 Prognostic Supports B Poor Outcome In a retrospective study of patients with esophageal carcinoma, those with mutations in TP53 had worse overall survival. 19941080 PubMed Yamasaki et al., 2010, Ann. Surg. Oncol. 4 accepted 519 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/519 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false TP53 7157 Mutation B-lymphoblastic Leukemia/lymphoma 0080630 Prognostic Supports B Poor Outcome In children with bone marrow relapsed B-cell precursor acute lymphoblastic leukemia, in multivariate analysis those with mutations in TP53 had worse event-free survival than patients without mutations. 22699455 PubMed Krentz et al., 2013, Leukemia 4 accepted 520 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2020-11-20 16:21:28 UTC https://civicdb.org/links/evidence_items/520 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false TP53 7157 Mutation Myelodysplastic Syndrome 0050908 Prognostic Supports B Poor Outcome In patients with myelodysplastic syndrome, in a multivariate analysis those with mutations in TP53 had shorter overall survival than wild-type patients. 24836762 PubMed Bally et al., 2014, Leuk. Res. 4 accepted 521 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2015-08-05 19:02:17 UTC https://civicdb.org/links/evidence_items/521 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false TP53 7157 Mutation Myeloid Neoplasm 0070004 Prognostic Supports B Poor Outcome In patients with myeloma, those with mutations in TP53 had worse overall survival than those without. 17215851 PubMed Chng et al., 2007, Leukemia 4 accepted 522 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2015-08-05 18:47:11 UTC https://civicdb.org/links/evidence_items/522 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false TP53 7157 Mutation Head And Neck Squamous Cell Carcinoma 5520 Prognostic Does Not Support B Poor Outcome Tumors from 114 patients with head and neck squamous cell carcinoma were analyzed for TP53 mutations, 21 of which were treated with surgery. Unlike those treated with radiotherapy, those treated with surgery did not show a significant difference in rates of loco-regional control between those with and without mutations in TP53. 11325447 PubMed Alsner et al., 2001, Radiother Oncol 4 accepted 523 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2015-10-09 18:40:30 UTC https://civicdb.org/links/evidence_items/523 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false TP53 7157 Mutation Head And Neck Squamous Cell Carcinoma 5520 Prognostic Supports B Poor Outcome Tumors from 114 patients with head and neck squamous cell carcinoma were analyzed for TP53 mutations. Of the 93 patients treated with radiotherapy, patients with mutations in TP53 had lower rates of loco-regional control and shorter disease-free, disease-specific, and overall survival. 11325447 PubMed Alsner et al., 2001, Radiother Oncol 4 accepted 524 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2015-10-09 18:40:30 UTC https://civicdb.org/links/evidence_items/524 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false TP53 7157 Truncating Mutation Head And Neck Squamous Cell Carcinoma 5520 Prognostic Supports B Poor Outcome In patients with head and neck squamous cell carcinoma, in a multivariate analysis those with truncating mutations in TP53 had worse progression-free and overall survival than wild-type patients. 21467160 PubMed Lindenbergh-van der Plas et al., 2011, Clin. Cancer Res. 4 accepted 525 223 45 17 7573998 7579714 ENST00000269305.4 75 GRCh37 Somatic 2015-10-09 18:40:30 UTC https://civicdb.org/links/evidence_items/525 https://civicdb.org/links/variants/223 https://civicdb.org/links/genes/45 false TP53 7157 Truncating Mutation Head And Neck Squamous Cell Carcinoma 5520 Prognostic Does Not Support B Poor Outcome In patients with head and neck squamous cell carcinoma, when comparing patients with any mutation in TP53 to wild-type, there was not a significant difference in overall survival in a multivariate analysis. 21467160 PubMed Lindenbergh-van der Plas et al., 2011, Clin. Cancer Res. 4 accepted 526 223 45 17 7573998 7579714 ENST00000269305.4 75 GRCh37 Somatic 2015-10-09 18:40:30 UTC https://civicdb.org/links/evidence_items/526 https://civicdb.org/links/variants/223 https://civicdb.org/links/genes/45 false TTF1 7270 AMPLIFICATION Lung Adenocarcinoma 3910 Prognostic Does Not Support B N/A 6 of 89 patients with lung adenocarcinoma had amplification of TTF1. There was no statistical difference in overall survival between patients with and without gene amplification. 19040416 PubMed Barletta et al., 2009, J. Cell. Mol. Med. 3 accepted 527 224 80 9 135251008 135282209 ENST00000334270.2 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/527 https://civicdb.org/links/variants/224 https://civicdb.org/links/genes/80 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Supports B Sensitivity/Response A randomized clinical trial of 469 patients with previously untreated, HER2-positive, metastatic breast cancer demonstrated improved time to disease progression, objective response rate, and duration of response for patients who received trastuzumab in addition to chemotherapy compared to chemotherapy alone. 11248153 PubMed Slamon et al., 2001, N. Engl. J. Med. 5 accepted 528 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-01-11 18:47:57 UTC https://civicdb.org/links/evidence_items/528 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Supports B Sensitivity/Response A randomized clinical trial of 186 patients with previously untreated, HER2-positive, metastatic breast cancer demonstrated improved overall survival, response rate, response duration, time to progression, and time to treatment failure for patients who received trastuzumab in addition to chemotherapy (docetaxel) compared to chemotherapy alone. 15911866 PubMed Marty et al., 2005, J. Clin. Oncol. 5 accepted 529 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-01-11 18:48:22 UTC https://civicdb.org/links/evidence_items/529 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false KRAS 3845 EXON 2 Mutations Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance Patients with colorectal cancer who harbor KRAS mutation have low response rate to cetuximab. 16618717 PubMed Lièvre et al., 2006, Cancer Res. 3 accepted 530 74 30 12 25398208 25398329 ENST00000256078.4 (v75) GRCh37 A study by Lièvre et al in 2006 showed that colorectal cancer patients with KRAS exon 1 mutations had low cetuximab response rates. Somatic 2015-11-21 23:56:45 UTC https://civicdb.org/links/evidence_items/530 https://civicdb.org/links/variants/74 https://civicdb.org/links/genes/30 false CHEK2 11200 Loss-of-function Cancer 162 Predisposing Supports B Uncertain Significance Heterozygous germline truncating (frameshift) and missense mutations confer highly penetrant predisposition to multiple cancer types including sarcoma, breast cancer, and brain tumors. Screening of individuals with Li-Fraumeni syndrome but lacking TP53 mutations identified 1/4 classical and 2/18 LFS variant presentation. This included 1 large family pedigree with strong co-segregation of the mutation with cancer development. 10617473 PubMed Bell et al., 1999, Science 5 accepted 531 230 8950 22 29083732 29137832 ENST00000328354.6 75 GRCh37 Rare Germline 2018-11-01 19:49:48 UTC https://civicdb.org/links/evidence_items/531 https://civicdb.org/links/variants/230 https://civicdb.org/links/genes/8950 false PRKACA 5566 DNAJB1::PRKACA Fibrolamellar Carcinoma 5015 Diagnostic Supports B Positive RT-PCR and FISH assays were developed for the detection of rearrangements of the PRKACA locus. A total of 106 primary liver tumors were studied by RT-PCR (26 fibrolamellar carcinomas, 25 conventional hepatocellular carcinomas, 25 cholangiocarcinomas, 25 hepatic adenomas, and 5 hepatoblastomas). FISH was tested in 19 fibrolamellar carcinomas and in 6 scirrhous hepatocellular carcinomas. Evidence of the DNAJB1-PRKACA fusion was found in all fibrolamellar cases but not in other tumor types for both methods indicating that detection of DNAJB1-PRKACA is a very sensitive and specific finding in support of the diagnosis of fibrolamellar carcinoma. 25698061 PubMed Graham et al., 2015, Mod. Pathol. 5 accepted 532 31 17 19 14628951 14629232 ENST00000254322.2 19 14202500 14218221 ENST00000308677.4 75 GRCh37 This fusion has been found to be very recurrent in the rare form of adolescent liver cancer, fibrolamellar hepatocellular carcinoma. In one study, this fusion was observed in 15/15 FL-HCC cases examined and functional studies found that the fusion retained kinase activity. The presence of this fusion may be used as a diagnostic marker for this rare tumor type. Somatic 2015-09-28 19:29:41 UTC https://civicdb.org/links/evidence_items/532 https://civicdb.org/links/variants/31 https://civicdb.org/links/genes/17 false KRAS 3845 G12/G13 Pancreatic Adenocarcinoma 4074 Gemcitabine,Trametinib Combination Predictive Supports B Resistance Adding trametinib to gemcitabine does not improve overall survival (OS), progression-free survival (PFS), overall response rate (ORR) or duration of response (DOR) in patients with untreated metastatic adenocarcinoma of the pancreas. 24915778 PubMed Infante et al., 2014, Eur. J. Cancer NCT01231581 4 accepted 622 77 30 12 25398280 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2015-10-09 13:28:38 UTC https://civicdb.org/links/evidence_items/622 https://civicdb.org/links/variants/77 https://civicdb.org/links/genes/30 false CDK12 51755 Loss-of-function Ovarian Serous Carcinoma 0050933 Olaparib Predictive Supports D Sensitivity/Response In models of high-grade serous ovarian cancer (HGS-OVCa), CDK12 attenuation was sufficient to confer sensitivity to PARP1/2 inhibition, suppression of DNA repair via homologous recombination, and reduced expression of BRCA1. 24240700 PubMed Bajrami et al., 2014, Cancer Res. 4 accepted 623 236 12112 17 37618292 37691399 ENST00000447079.4 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/623 https://civicdb.org/links/variants/236 https://civicdb.org/links/genes/12112 false IKZF1 10320 Deletion B-lymphoblastic Leukemia/lymphoma 0080630 Prognostic Supports B Poor Outcome IKZF1 deletions are associated with poor outcome in patients with childhood BCR-ABL–positive B-cell precursor acute lymphoblastic leukemia even when treated with imatinib. This phenomenon was observed in patients treated in the pre-TKI era as well as those treated with imatinib when compared to wild-type patients undergoing similar treatment. 24366361 PubMed van der Veer et al., 2014, Blood 3 accepted 624 200 73 7 50344378 50472799 ENST00000331340.3 75 GRCh37 IKZF1 deletions have been reported in a variety of cancer types including pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL), Chronic Myeloid Leukemia, diffuse large B-cell lymphoma, myelodysplastic syndrome, T-cell ALL as well as solid tumors of the large intestine, lung, and liver. The clinical impact of these deletions is unknown for many cancer types however a poor outcome has been observed in leukemia based disease. This gene has been strongly implicated as a regulator for "normal hematopoiesis". In regards to BCP ALL, mouse models have shown that mutations in IKZF1 are not sufficient in and of themselves to cause disease. Haploinsuffeciency in combination with BCR-ABL1 however, will accelerate leukemiagenesis possibly indicating that at least in regards to BCP ALL these are secondary events that may be necessary for the development of leukaemic clones. Somatic 2020-11-20 16:21:28 UTC https://civicdb.org/links/evidence_items/624 https://civicdb.org/links/variants/200 https://civicdb.org/links/genes/73 false IKZF1 10320 Deletion Acute Lymphoblastic Leukemia 9952 Prognostic Supports B Poor Outcome IKZF1 deletions in patients with BCR-ABL–positive adult acute lymphoblastic leukemia were associated with reduced disease-free survival compared to wild type patients. 19770381 PubMed Martinelli et al., 2009, J. Clin. Oncol. 3 accepted 625 200 73 7 50344378 50472799 ENST00000331340.3 75 GRCh37 IKZF1 deletions have been reported in a variety of cancer types including pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL), Chronic Myeloid Leukemia, diffuse large B-cell lymphoma, myelodysplastic syndrome, T-cell ALL as well as solid tumors of the large intestine, lung, and liver. The clinical impact of these deletions is unknown for many cancer types however a poor outcome has been observed in leukemia based disease. This gene has been strongly implicated as a regulator for "normal hematopoiesis". In regards to BCP ALL, mouse models have shown that mutations in IKZF1 are not sufficient in and of themselves to cause disease. Haploinsuffeciency in combination with BCR-ABL1 however, will accelerate leukemiagenesis possibly indicating that at least in regards to BCP ALL these are secondary events that may be necessary for the development of leukaemic clones. Somatic 2015-10-28 20:33:58 UTC https://civicdb.org/links/evidence_items/625 https://civicdb.org/links/variants/200 https://civicdb.org/links/genes/73 false IKZF1 10320 Deletion Acute Lymphoblastic Leukemia 9952 Prognostic Supports B Poor Outcome A targeted copy number screen of 131 precursor B-ALL cases revealed that IKZF1 deletions are significantly associated with poor relapse-free and overall survival rates. Furthermore non-high-risk patients with IKZF1 deletions exhibited a ~12-fold higher relative relapse rate than those without IKZF1 deletions. 20445578 PubMed Kuiper et al., 2010, Leukemia 3 accepted 626 200 73 7 50344378 50472799 ENST00000331340.3 75 GRCh37 IKZF1 deletions have been reported in a variety of cancer types including pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL), Chronic Myeloid Leukemia, diffuse large B-cell lymphoma, myelodysplastic syndrome, T-cell ALL as well as solid tumors of the large intestine, lung, and liver. The clinical impact of these deletions is unknown for many cancer types however a poor outcome has been observed in leukemia based disease. This gene has been strongly implicated as a regulator for "normal hematopoiesis". In regards to BCP ALL, mouse models have shown that mutations in IKZF1 are not sufficient in and of themselves to cause disease. Haploinsuffeciency in combination with BCR-ABL1 however, will accelerate leukemiagenesis possibly indicating that at least in regards to BCP ALL these are secondary events that may be necessary for the development of leukaemic clones. Somatic 2015-10-09 18:40:30 UTC https://civicdb.org/links/evidence_items/626 https://civicdb.org/links/variants/200 https://civicdb.org/links/genes/73 false IDH2 3418 R172 Peripheral T-cell Lymphoma 0050749 Prognostic Does Not Support B Better Outcome In patients with angioimmunoblastic T-cell lymphoma (a subtype of peripheral T-cell lymphoma), IDH2 R172 mutations (N=16) had no impact on overall survival when compared to patients with wildtype IDH2 (N=24). 26268241 PubMed Wang et al., 2015, Blood 3 accepted 627 199 27 15 90631837 90631839 ENST00000330062.3 75 GRCh37 IDH2 R172 is a gain-of-function mutation commonly observed in acute myeloid leukemia and is enriched in those patients which are cytogenetically normal. R172 is analogous to IDH1 R132 mutations and leads to neomorphic enzymatic activity. Specifically this mutation "catalyzes the conversion of alpha ketoglurarate to beta-hydrozyglutarate" leading to increased levels of beta-hydrozyglutarate. This in turn leads to hypermethylation of target genes and an inhibition of cellular differentiation. R172 mutations generally lead to worse overall survival and higher rates of relapse compared to the most common IDH2 mutations in AML (R140). Somatic 2016-01-05 07:57:30 UTC https://civicdb.org/links/evidence_items/627 https://civicdb.org/links/variants/199 https://civicdb.org/links/genes/27 false IDH2 3418 R172 Peripheral T-cell Lymphoma 0050749 Diagnostic Supports B Positive IDH2 R172 mutations were frequently observed in patients with the angioimmunoblastic T-cell lymphoma subtype of peripheral T-cell lymphomas but not observed in other subtypes. 22215888 PubMed Cairns et al., 2012, Blood 4 accepted 628 199 27 15 90631837 90631839 ENST00000330062.3 75 GRCh37 IDH2 R172 is a gain-of-function mutation commonly observed in acute myeloid leukemia and is enriched in those patients which are cytogenetically normal. R172 is analogous to IDH1 R132 mutations and leads to neomorphic enzymatic activity. Specifically this mutation "catalyzes the conversion of alpha ketoglurarate to beta-hydrozyglutarate" leading to increased levels of beta-hydrozyglutarate. This in turn leads to hypermethylation of target genes and an inhibition of cellular differentiation. R172 mutations generally lead to worse overall survival and higher rates of relapse compared to the most common IDH2 mutations in AML (R140). Somatic 2015-10-29 19:35:56 UTC https://civicdb.org/links/evidence_items/628 https://civicdb.org/links/variants/199 https://civicdb.org/links/genes/27 false IKZF1 10320 Deletion B-lymphoblastic Leukemia/lymphoma 0080630 Prognostic Supports B Poor Outcome In patients with Philadelphia Chromosome negative B-cell precursor acute lymphoblastic leukemia, focal deletion involving 3-5 exons of IKZF1 was associated with higher cumulative incidence of relapse (CIR) than wildtype IKZF1. 24740809 PubMed Beldjord et al., 2014, Blood NCT00222027,NCT00327678 4 accepted 629 200 73 7 50344378 50472799 ENST00000331340.3 75 GRCh37 IKZF1 deletions have been reported in a variety of cancer types including pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL), Chronic Myeloid Leukemia, diffuse large B-cell lymphoma, myelodysplastic syndrome, T-cell ALL as well as solid tumors of the large intestine, lung, and liver. The clinical impact of these deletions is unknown for many cancer types however a poor outcome has been observed in leukemia based disease. This gene has been strongly implicated as a regulator for "normal hematopoiesis". In regards to BCP ALL, mouse models have shown that mutations in IKZF1 are not sufficient in and of themselves to cause disease. Haploinsuffeciency in combination with BCR-ABL1 however, will accelerate leukemiagenesis possibly indicating that at least in regards to BCP ALL these are secondary events that may be necessary for the development of leukaemic clones. Somatic 2020-11-20 16:21:28 UTC https://civicdb.org/links/evidence_items/629 https://civicdb.org/links/variants/200 https://civicdb.org/links/genes/73 false NT5C2 22978 R367Q T-cell Acute Lymphoblastic Leukemia 5603 Thioguanine,Mercaptopurine Substitutes Predictive Supports D Resistance CCRF-CEM and to a lesser extent CUTLL1 T-ALL cell lines expressing the NT5C2 R367Q mutation had increased resistance to 6-mercaptopurine and 6-thioguanine treatment than cells expressing wildtype NT5C2. Consistent with this, isolated mutant proteins also showed increased enzyme activity compared to wildtype proteins. 23377281 PubMed Tzoneva et al., 2013, Nat. Med. 4 accepted 630 238 9189 10 104852955 104852955 C T ENST00000343289.5 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/630 https://civicdb.org/links/variants/238 https://civicdb.org/links/genes/9189 false NT5C2 22978 K359Q T-cell Acute Lymphoblastic Leukemia 5603 Mercaptopurine,Thioguanine Substitutes Predictive Supports D Resistance CCRF-CEM and to a lesser extent CUTLL1 T-ALL cell lines expressing the NT5C2 K359Q mutation had increased resistance to 6-mercaptopurine and 6-thioguanine treatment than cells expressing wildtype NT5C2. Consistent with this, isolated mutant proteins also showed increased enzyme activity compared to wildtype proteins. 23377281 PubMed Tzoneva et al., 2013, Nat. Med. 4 accepted 631 239 9189 10 104852980 104852980 T G ENST00000343289.5 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/631 https://civicdb.org/links/variants/239 https://civicdb.org/links/genes/9189 false NT5C2 22978 D407A T-cell Acute Lymphoblastic Leukemia 5603 Mercaptopurine,Thioguanine Substitutes Predictive Supports D Resistance CCRF-CEM and to a lesser extent CUTLL1 T-ALL cell lines expressing the NT5C2 D407A mutation had increased resistance to 6-mercaptopurine and 6-thioguanine treatment than cells expressing wildtype NT5C2. Consistent with this, isolated mutant proteins also showed increased enzyme activity compared to wildtype protein. 23377281 PubMed Tzoneva et al., 2013, Nat. Med. 4 accepted 632 240 9189 10 104850745 104850745 T G ENST00000343289.5 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/632 https://civicdb.org/links/variants/240 https://civicdb.org/links/genes/9189 false NT5C2 22978 R367Q T-cell Acute Lymphoblastic Leukemia 5603 Nelarabine,Arabinosylguanine Substitutes Predictive Does Not Support D Resistance CCRF-CEM and CUTLL1 T-ALL cell lines expressing NT5C2 mutant proteins (K359Q, R367Q or D407A) observed in relapsed T-ALL patients showed no difference in sensitivity to nelarabine or arabinosylguanine treatment when compared to cells expressing wildtype protein or vector alone. 23377281 PubMed Tzoneva et al., 2013, Nat. Med. 4 accepted 633 238 9189 10 104852955 104852955 C T ENST00000343289.5 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/633 https://civicdb.org/links/variants/238 https://civicdb.org/links/genes/9189 false NT5C2 22978 D407A T-cell Acute Lymphoblastic Leukemia 5603 Arabinosylguanine,Nelarabine Substitutes Predictive Does Not Support D Resistance CCRF-CEM and CUTLL1 T-ALL cell lines expressing NT5C2 mutant proteins (K359Q, R367Q or D407A) observed in relapsed T-ALL patients showed no difference in sensitivity to nelarabine or arabinosylguanine treatment when compared to cells expressing wildtype protein or vector alone. 23377281 PubMed Tzoneva et al., 2013, Nat. Med. 4 accepted 635 240 9189 10 104850745 104850745 T G ENST00000343289.5 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/635 https://civicdb.org/links/variants/240 https://civicdb.org/links/genes/9189 false NT5C2 22978 K359Q T-cell Acute Lymphoblastic Leukemia 5603 Nelarabine,Arabinosylguanine Substitutes Predictive Does Not Support D Resistance CCRF-CEM and CUTLL1 T-ALL cell lines expressing NT5C2 mutant proteins (K359Q, R367Q or D407A) observed in relapsed T-ALL patients showed no difference in sensitivity to nelarabine or arabinosylguanine treatment when compared to cells expressing wildtype protein or vector alone. 23377281 PubMed Tzoneva et al., 2013, Nat. Med. 4 accepted 636 239 9189 10 104852980 104852980 T G ENST00000343289.5 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/636 https://civicdb.org/links/variants/239 https://civicdb.org/links/genes/9189 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports B Resistance BCR-ABL F317L has been shown to confer resistance to dasatinib in patients with CML. 18818391 PubMed Jabbour et al., 2008, Blood 5 accepted 637 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2015-10-21 20:26:06 UTC https://civicdb.org/links/evidence_items/637 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Ponatinib Predictive Supports D Sensitivity/Response Molecular dynamics simulations and calculated solvated interaction energies indicate BCR-ABL F317L mutations are Ponatinib sensitive. 24236021 PubMed Tanneeru et al., 2013, PLoS ONE 3 accepted 638 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2016-12-01 15:25:46 UTC https://civicdb.org/links/evidence_items/638 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Ponatinib Predictive Supports B Sensitivity/Response Ponatinib has shown to be effective in patients with BCR-ABL kinase domain mutations like F317L. 25349473 PubMed Miller et al., 2014, Biologics 5 accepted 639 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2022-07-30 20:02:15 UTC https://civicdb.org/links/evidence_items/639 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 true TP53 7157 Mutation B-lymphoblastic Leukemia/lymphoma 0080630 Prognostic Supports B Poor Outcome In relapsed B-ALL patients, TP53 mutations were associated with morphologic nonresponse to therapy (>5% blasts in the bone marrow after 9 weeks of treatment) as well as reduced event free and overall survival when compared to TP53 wildtype patients. 21747090 PubMed Hof et al., 2011, J. Clin. Oncol. 4 accepted 640 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2020-11-20 16:21:28 UTC https://civicdb.org/links/evidence_items/640 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false TP53 7157 DNA Binding Domain Mutation Oral Squamous Cell Carcinoma 0050866 Prognostic Supports B Poor Outcome Oral squamous cell carcinoma patients with TP53 mutations in the DNA binding domain (L2, L3 and the LSH motif) have significantly reduced cumulative survival when compared to patients with TP53 mutations outside of this DNA binding domain. These mutations were also significantly associated with locoregional failure, cervical lymph node metastasis and distant metastasis, likely contributing to this finding. 12509970 PubMed Yamazaki et al., 2003, Oral Oncol. 4 accepted 641 242 45 17 7577149 7578443 ENST00000269305.4 75 GRCh37 Somatic 2015-10-28 20:36:29 UTC https://civicdb.org/links/evidence_items/641 https://civicdb.org/links/variants/242 https://civicdb.org/links/genes/45 false EGFR 1956 T790M Lung Cancer 1324 Gefitinib,Multikinase Inhibitor AEE788 Sequential Predictive Supports D Resistance Lung cancers can accumulate activating mutations in oncogenes such as EGFR. The common L858R EGFR mutation has been shown previously to be sensitive to small molecular tyrosine kinase inhibitors (ie. erlotinib). In response, tumors may accumulate an additional 'gatekeeper' mutation in EGFR, T790M. Authors show that T790M retain low affinity for gefitinib and that introduction of T790M in the presence of L858R mutant increases the ATP affinity of L858R and activates wild-type EGFR, thus showing that increased ATP affinity is the primary mode of resistance in tumors with T790M, though irreversible ATP inhibitors (ie. HKI-272) are able to overcome this resistance via covalent bonding. 18227510 PubMed Yun et al., 2008, Proc. Natl. Acad. Sci. U.S.A. 5 accepted 642 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/642 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false PTEN 5728 Loss Prostate Cancer 10283 Prognostic Supports B Poor Outcome PTEN Loss (by FISH) is associated with poorer prognosis in patients with prostate cancer. 17700571 PubMed Yoshimoto et al., 2007, Br. J. Cancer 4 accepted 643 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2015-11-01 00:30:25 UTC https://civicdb.org/links/evidence_items/643 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PTEN 5728 Loss Bladder Carcinoma 4007 Everolimus Predictive Supports B Resistance PTEN loss is associated with reduced response to mTOR inhibitors in patients with bladder cancer. 23989949 PubMed Seront et al., 2013, Br. J. Cancer 4 accepted 644 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2015-11-01 00:47:11 UTC https://civicdb.org/links/evidence_items/644 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PTEN 5728 Loss Breast Cancer 1612 Trastuzumab Predictive Supports B Resistance PTEN loss is associated with loss of sensitivity to the HER2-antibody trastuzumab in breast cancer in smaller trials, a phase III trial (NCCTG N9831) did not show an effect of PTEN on disease-free survival. 24387334 PubMed Dillon et al., 2014, Curr Drug Targets 1 accepted 645 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-02-19 22:49:06 UTC https://civicdb.org/links/evidence_items/645 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Rociletinib Predictive Supports B Sensitivity/Response In a phase1-2 study, patients with the T790M mutation were more sensitive to rocelitinib in comparison to patients with T790M-negative NSCLC. 25923550 PubMed Sequist et al., 2015, N. Engl. J. Med. NCT01526928 4 accepted 646 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2015-11-09 20:33:58 UTC https://civicdb.org/links/evidence_items/646 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false ATM 472 S2289* Prostate Cancer 10283 Olaparib Predictive Supports C Sensitivity/Response Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. Overall, 4/6 patients (3/5 with no other identified aberrations in DNA repair genes) with several germline and somatic aberrations of ATM had a response. Responders included a single patient with a somatic frameshift mutation (ATM V2288fs*1) predicted to result in truncation prior to the PI3K catalytic domain and other domains for p53 recognition and response to DNA damage. No other alterations in ATM were observed; however, this patient also had frameshift mutations in MLH3, MRE11 and NBN. 26510020 PubMed Mateo et al., 2015, N. Engl. J. Med. NCT01682772 3 accepted 647 243 69 11 108196840 108196841 TC ENST00000278616.4 75 GRCh37 A frameshift mutation at the DNA level predicted to cause truncation before the C-terminal phosphoinositide 3-kinase (PI3K) catalytic domain at amino acid 2289. Somatic 2016-04-08 15:13:01 UTC https://civicdb.org/links/evidence_items/647 https://civicdb.org/links/variants/243 https://civicdb.org/links/genes/69 false ATM 472 N2875H Prostate Cancer 10283 Olaparib Predictive Supports C Sensitivity/Response Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. Overall, 4/6 patients (3/5 with no other identified aberrations in DNA repair genes) with several germline and somatic aberrations of ATM had a response. Responders included a single patient with a somatic missense mutation (ATM N2875H) and no other alterations in ATM or other DNA repair genes. 26510020 PubMed Mateo et al., 2015, N. Engl. J. Med. NCT01682772 3 accepted 648 244 69 11 108218044 108218044 A C ENST00000278616.4 75 GRCh37 A missense mutation within the C-terminal phosphoinositide 3-kinase (PI3K) catalytic domain Somatic 2016-04-08 15:17:02 UTC https://civicdb.org/links/evidence_items/648 https://civicdb.org/links/variants/244 https://civicdb.org/links/genes/69 false NF2 4771 Y177fs Peritoneal Mesothelioma 1788 Carboplatin,Cisplatin Substitutes Predictive Supports C Resistance A frameshift mutation in NF2 at position Y177 was found in a patient who responded poorly to therapy and died within 8 months of diagnosis. Initially treated with 3 cycles of systemic chemotherapy with cisplatin and pemetrexed with modest response, 2 months after cytoreductive surgery the patient had no response to platinum doublet chemotherapy. 25798586 PubMed Sheffield et al., 2015, PLoS ONE 3 accepted 649 245 3870 22 30051593 30051594 T ENST00000338641.4 75 GRCh37 Somatic 2021-05-10 22:38:11 UTC https://civicdb.org/links/evidence_items/649 https://civicdb.org/links/variants/245 https://civicdb.org/links/genes/3870 false BRCA2 675 Loss-of-function Prostate Cancer 10283 Olaparib Predictive Supports B Sensitivity/Response In a phase 2 trial of patients with metastatic, castration-resistant prostate cancer, treated with olaparib tablets at a dose of 400 mg twice a day, all 7 patients harbouring BRCA2 loss of function alleles (biallelic somatic loss or germline mutations in combination with somatic copy loss or copy neutral LOH) demonstrated a clinical response. 26510020 PubMed Mateo et al., 2015, N. Engl. J. Med. NCT01682772 4 accepted 650 132 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 BRCA2 loss of function mutations have been shown to increase risk of breast and ovarian cancer in those carrying the allele in their germline. Treating BRCA mutant patients with PARP inhibitors such as Olaparib has led to significant response. Somatic 2015-11-20 22:33:06 UTC https://civicdb.org/links/evidence_items/650 https://civicdb.org/links/variants/132 https://civicdb.org/links/genes/7 false PDGFRA 5156 D842V Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports D Resistance When 293T cells stably transduced with PDGFRA A842V were treated with imatinib, tyrosine phosphorylation was maintained at 1 and 10umol/L concentrations that inhibited phosphorylation of wildtype PDGFRA, consistent with resistance to this inhibitor. 12949711 PubMed Hirota et al., 2003, Gastroenterology 3 accepted 651 99 38 4 55152093 55152093 A T ENST00000257290.5 75 GRCh37 PDGFRA D842 mutations are characterized broadly as imatinib resistance mutations. This is most well characterized in gastrointestinal stromal tumors, but other cell lines containing these mutations have been shown to be resistant as well. Exogenous expression of the A842V mutation resulted in constitutive tyrosine phosphorylation of PDGFRA in the absence of ligand in 293T cells and cytokine-independent proliferation of the IL-3-dependent Ba/F3 cell line, both evidence that this is an activating mutation. In imatinib resistant cell lines, a number of other therapeutics have demonstrated efficacy. These include; crenolanib, sirolimus, and midostaurin (PKC412). Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/651 https://civicdb.org/links/variants/99 https://civicdb.org/links/genes/38 false PDGFRA 5156 V561A Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports D Sensitivity/Response 293T cells stably transduced with PDGFRA V561A showed constitutive tyrosine phosphorylation in the absense of ligand; however, when treated with imatinib, this phosphorylation was inhibited similarly to that of wildtype PDGFRA, consistent with sensitivity to this inhibitor. 12949711 PubMed Hirota et al., 2003, Gastroenterology 3 accepted 652 247 38 4 55141036 55141036 T C ENST00000257290.5 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/652 https://civicdb.org/links/variants/247 https://civicdb.org/links/genes/38 false KIT 3815 Exon 11 Mutation Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports B Sensitivity/Response This prospective study of 127 pretreatment patients with metastatic gastrointestinal stromal tumors (GISTs) examined the relationship between kinase (KIT and PDGFRA) genotype and treatment outcome for patients enrolled in a randomized phase II trial of imatinib (CSTI571B 2222). 85 patients harbored KIT exon 11 mutated GISTs: 71 had an in-frame deletion and 15 had unspecified point mutations (3 codon 557 cases, 3 codon 559 cases, 6 codon 560 cases and 2 codon 576 cases). Of patients harboring KIT exon 11 mutated GISTs, 71 (83.5%) had a partial response, 7 had stable disease, 4 had progressive disease and 3 were nonassessable. Patients with KIT exon 11 mutations were significantly more likely to have a partial response than those with KIT exon 9 mutations (P=.0006) or double WT kinases (WT KIT and WT PDGFRA; P < .0001). The presence of a KIT exon 11 mutation was the strongest predictor of response (Hazard ratio= 7.85). Patients harboring KIT exon 11 mutant GISTs experienced longer event free survival (median: 687 days) than those with KIT exon 9 mutant or double WT kinase GISTs (200 days and 82 days, respectively). Furthermore, patients whose tumors expressed an exon 11 mutant KIT had improved overall survival compared to patients whose tumor expressed an exon 9 mutant KIT (P = .0034) or double WT kinases (P <.0001). 14645423 PubMed Heinrich et al., 2003, J. Clin. Oncol. 4 accepted 654 66 29 4 55593582 55593708 ENST00000288135.5 75 GRCh37 c-KIT mutations in exon 11 lie within the juxtamembrane domain, and are very recurrent in gastrointestinal stromal tumors, often bearing a poorer prognosis than other KIT mutations. Cells harboring exon 11 mutations have shown sensitivity to the tyrosine kinase inhibitor imatinib, offering a better prognosis to patients treated with the drug in the first year. Small cohorts of melanoma patients harboring exon 11 KIT mutations have shown response to imatinib and sunitinib. Somatic 2019-02-23 00:11:27 UTC https://civicdb.org/links/evidence_items/654 https://civicdb.org/links/variants/66 https://civicdb.org/links/genes/29 false TERT 7015 C228T Thyroid Gland Papillary Carcinoma 3969 Prognostic Supports B Poor Outcome In patients with papillary thyroid cancer harboring both BRAF V600E and the TERT promotor mutation C228T, recurrence-free survival is worse than in patients harboring one of these mutations or no mutations in either gene. 25024077 PubMed Xing et al., 2014, J. Clin. Oncol. 5 accepted 655 248 79 5 1295228 1295228 G A ENST00000310581.5 75 GRCh37 Somatic 2015-11-17 01:26:21 UTC https://civicdb.org/links/evidence_items/655 https://civicdb.org/links/variants/248 https://civicdb.org/links/genes/79 false BRAF 673 V600E Thyroid Gland Papillary Carcinoma 3969 Prognostic Supports B Poor Outcome In patients with papillary thyroid cancer harboring both BRAF V600E and the TERT promotor mutation C228T (N=35), recurrence-free survival is worse than in patients harboring one of these mutations (N=159 BRAF, N=26 TERT promoter mutated) or no mutations in either gene (N=287)(P<0.001). 25024077 PubMed Xing et al., 2014, J. Clin. Oncol. 5 accepted 656 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-10-24 15:41:15 UTC https://civicdb.org/links/evidence_items/656 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false TERT 7015 Promoter Mutation Thyroid Gland Cancer 1781 Diagnostic Supports B Positive TERT promoter mutations are prevalent in aggressive sub-types of thyroid cancers. This work showed that TERT promoter mutations were significantly more prevalent in the tall cell papillary thyroid carcinoma (PTC) samples than in the conventional PTC and follicular variant PTC samples. 23766237 PubMed Liu et al., 2013, Endocr. Relat. Cancer 3 accepted 657 220 79 5 1295161 1295373 ENST00000310581.5 75 GRCh37 TERT promoter mutations are activating and commonly found at two hotspots within the TERT promoter region which occur 124 and 146 base pairs (hg19) upstream of the translation start site. These hotspots, termed C228T and C250T are observed in many cancer types and have a particularly high prevalence in glioblastoma (83%), melanoma (71%), bladder cancer (66%) and hepatocelluar carcinoma (HCC) (47%). The two mutations are usually heterozygous and mutually exclusive and result in an increased similarity to an ETS binding domain and may act as a binding site to an ETS transcription factor. These mutations are thought to be early events in tumorgenesis and aid in cellular immortality. Decreased overall survival in patients with these mutations have been observed in medulloblastoma, thyroid cancer, urogenital cancer, melanoma, and laryngeal tumors. The presence of these mutations has also been shown to be predictive of malignant/premalignant nodules in HCC and meningiomas. Somatic 2015-11-27 23:32:13 UTC https://civicdb.org/links/evidence_items/657 https://civicdb.org/links/variants/220 https://civicdb.org/links/genes/79 false TERT 7015 Promoter Mutation Thyroid Gland Cancer 1781 Prognostic Supports B Poor Outcome TERT promoter mutation C228T is significantly associated with BRAF V600E mutation, a marker of more aggressive tumors, in papillary thyroid cancer (PTC). Conversely, the BRAF V600E mutation is significantly more common in PTC cases with the TERT C228T mutation than in cases with the wild-type allele of TERT. TERT promoter mutations were also enriched in the more aggressive tall cell PTC compared to follicular or conventional PTC (30.8% vs 10.3%, P=0.046) and in the worse outcome anaplastic thyroid cancer than differentiated thyroid cancers (46.3% vs 12.2%, P=3×10−8). 23766237 PubMed Liu et al., 2013, Endocr. Relat. Cancer 3 accepted 658 220 79 5 1295161 1295373 ENST00000310581.5 75 GRCh37 TERT promoter mutations are activating and commonly found at two hotspots within the TERT promoter region which occur 124 and 146 base pairs (hg19) upstream of the translation start site. These hotspots, termed C228T and C250T are observed in many cancer types and have a particularly high prevalence in glioblastoma (83%), melanoma (71%), bladder cancer (66%) and hepatocelluar carcinoma (HCC) (47%). The two mutations are usually heterozygous and mutually exclusive and result in an increased similarity to an ETS binding domain and may act as a binding site to an ETS transcription factor. These mutations are thought to be early events in tumorgenesis and aid in cellular immortality. Decreased overall survival in patients with these mutations have been observed in medulloblastoma, thyroid cancer, urogenital cancer, melanoma, and laryngeal tumors. The presence of these mutations has also been shown to be predictive of malignant/premalignant nodules in HCC and meningiomas. Somatic 2018-10-24 20:15:52 UTC https://civicdb.org/links/evidence_items/658 https://civicdb.org/links/variants/220 https://civicdb.org/links/genes/79 false XRCC1 7515 R194W Lung Non-small Cell Carcinoma 3908 Docetaxel,Gemcitabine,Vinorelbine Substitutes Predictive Supports B Sensitivity/Response The XRCC1 R194W variant was shown to be correlated with increased chance of response to platinum-based chemotherapy in Stage IV Non-small Cell Lung Carcinoma (NSCLC). 82 patients with Stage IV NSCLC who had not previously been treated with chemotherapy were used in this study. 19157633 PubMed Sun et al., 2009, Lung Cancer 4 accepted 659 249 6144 19 44057574 44057574 G A ENST00000262887.5 75 GRCh37 Rare Germline 2015-12-22 15:27:10 UTC https://civicdb.org/links/evidence_items/659 https://civicdb.org/links/variants/249 https://civicdb.org/links/genes/6144 false GSTP1 2950 Deletion Ovarian Carcinoma 4001 Carboplatin,Paclitaxel,Cisplatin Substitutes Predictive Supports D Sensitivity/Response Stable GSTP1 knockdown in ovarian carcinoma A2780 cell lines showed increased sensitivity to platinum-based chemotherapy drugs carboplatin, cisplatinum, carboplatin, and paclitaxel. For each drug, 3 biological replicates were performed for this study, and effectiveness was evaluated using an MTT assay. There was not a significant difference in sensitivity to other chemotherapy drugs such as gemcitabine, topotecan, and doxorubicin. 25010864 PubMed Sawers et al., 2014, Br. J. Cancer 4 accepted 660 250 2473 11 67351066 67354131 ENST00000398606.3 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/660 https://civicdb.org/links/variants/250 https://civicdb.org/links/genes/2473 false BIRC7 79444 Amplification Colon Cancer 219 Cisplatin Predictive Supports D Resistance Livin (BIRC7) overexpression in two colon cancer cell lines (RKO and SW620) increased resistance of these cells to cisplatin. siRNA knockdown of Livin rendered the cells more sensitive to cisplatin. The study also further showed that cytoplasmic Livin levels increased in four colon cancer cell lines (RKO, SW620, HCT116, and KM12C) after cisplatin treatment in a dose-dependent manner. This study highlighted Livin as a potential player in colon cancer therapy. 23188704 PubMed Ding et al., 2013, Tumour Biol. 4 accepted 661 251 14842 20 61867235 61871859 ENST00000217169.3 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/661 https://civicdb.org/links/variants/251 https://civicdb.org/links/genes/14842 false EGFR 1956 Exon 4 Deletion Epithelial Ovarian Cancer 2152 Cisplatin Predictive Supports D Resistance A variant of EGFR with exon 4 deletion (de4 EGFR) enhanced the invasiveness and cisplatin resistance of epithelial ovarian cancer cell lines (SKOV3, CAOV3, ES2) in vitro when compared with wild-type EGFR. The three cell lines were infected with lentivirus for either EGFR or de4 EGFR, and lentivirus-infected cells were used to perform transwell migration assays, invasion assays, and cisplatin sensitivity assays. 23764753 PubMed Zhang et al., 2013, Carcinogenesis 4 accepted 662 252 19 7 55214299 55214433 ENST00000275493.2 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/662 https://civicdb.org/links/variants/252 https://civicdb.org/links/genes/19 false KRAS 3845 RS61764370 Epithelial Ovarian Cancer 2152 Paclitaxel,Carboplatin Substitutes Predictive Supports B Resistance The functional variant rs61764370 in the KRAS gene 3' UTR (KRAS-variant) was found to be correlated with platinum-based chemotherapy resistance in patients with Epithelial Ovarian Cancer (EOC). 291 EOC patients without BRCA mutations were used in this study. Furthermore, the researchers tested a KRAS-variant EOC cell line (BG1) and found it has much greater platinum-based chemotherapy resistance than a non-KRAS-variant cell line (CAOV3). 22139083 PubMed Ratner et al., 2012, Oncogene 3 accepted 664 254 30 12 25360224 25360224 A C ENST00000311936.3 75 GRCh37 Germline variant in the 3' UTR of KRAS that predicts resistance to platinum-based therapy. Common Germline 2016-02-13 04:02:23 UTC https://civicdb.org/links/evidence_items/664 https://civicdb.org/links/variants/254 https://civicdb.org/links/genes/30 false ERCC5 2073 RS751402 Parietal Lobe Ependymoma 0050903 Prognostic Supports B Poor Outcome The rs751402 polymorphism in the 5' UTR of ERCC5 was correlated with reduced progression free-survival in children with ependymoma that had been treated with platinum-based therapies. 55 post-operative frozen samples were used in this study. The results were also confirmed in vitro by treating neuroblastoma and B-cell lines expressing the wild-type or rs751402 polymorphism and finding that the rs751402 polymorphism was correlated with higher survival. 26338418 PubMed Somers et al., 2015, Genes Dev. 3 accepted 665 255 1741 13 103498198 103498198 A G ENST00000355739.4 75 GRCh37 Common Germline 2016-02-22 20:56:57 UTC https://civicdb.org/links/evidence_items/665 https://civicdb.org/links/variants/255 https://civicdb.org/links/genes/1741 false KIT 3815 rs17084733 Acral Lentiginous Melanoma 6367 Diagnostic Supports B Positive The rs17084733 variant in the 3' UTR of KIT was correlated with susceptibility to melanoma when comparing 70 melanoma patients to 94 healthy individuals from the same community. This variant was most strongly correlated with acral lentigious melanoma. 21119596 PubMed Godshalk et al., 2011, Oncogene 3 accepted 666 256 29 4 55604940 55604940 G A ENST00000288135.5 75 GRCh37 Common Germline 2016-02-22 20:38:11 UTC https://civicdb.org/links/evidence_items/666 https://civicdb.org/links/variants/256 https://civicdb.org/links/genes/29 false NT5C2 22978 K359Q Acute Lymphoblastic Leukemia 9952 Prognostic Supports B Poor Outcome The K359Q somatic mutation was significantly correlated with early disease recurrence and relapse in 103 T-cell ALL regardless of treatment course. The data was obtained from Berlin Frankfurt Münster Clinical Trials. 23377281 PubMed Tzoneva et al., 2013, Nat. Med. 4 accepted 667 239 9189 10 104852980 104852980 T G ENST00000343289.5 75 GRCh37 Somatic 2015-12-03 01:28:24 UTC https://civicdb.org/links/evidence_items/667 https://civicdb.org/links/variants/239 https://civicdb.org/links/genes/9189 false EZH2 2146 Intron 6 Mutation Colorectal Cancer 9256 Prognostic Supports B Poor Outcome The rs3757441 variant in Intron 6 of EZH2 (C/C versus C/T or T/T) was significantly correlated with lower progression free survival and overall survival in patients with metastatic Colorectal Cancer (mCRC). Blood samples from 106 patients with mCRC before and after treatment were used for this study. 21926398 PubMed Crea et al., 2012, Ann. Oncol. 4 accepted 668 257 63 7 148524752 148524752 C C ENST00000320356.2 75 GRCh37 Common Germline 2016-02-22 20:56:36 UTC https://civicdb.org/links/evidence_items/668 https://civicdb.org/links/variants/257 https://civicdb.org/links/genes/63 false MTHFR 4524 A222V Stomach Cancer 10534 Fluorouracil Predictive Supports B Sensitivity/Response The MTHFR C667T variant was associated with significantly lower relapse-free survival and overall survival in stomach cancer patients treated with 5-Fluorouracil-based therapies. 116 Chinese patients with histologically confirmed gastric cancer were used in this study, and all patients had radical surgery before treatment. 18704422 PubMed Huang et al., 2009, Cancer Chemother. Pharmacol. 3 accepted 669 258 3672 1 11856378 11856378 G A ENST00000376592.1 75 GRCh37 Common Germline 2022-02-24 21:31:43 UTC https://civicdb.org/links/evidence_items/669 https://civicdb.org/links/variants/258 https://civicdb.org/links/genes/3672 false GSTP1 2950 I105V Colorectal Cancer 9256 FOLFOX Regimen Predictive Supports B Sensitivity/Response Patients with the GSTP1 I105V variant had greater response to FOLFOX-4 treatment, longer progression-free survival, and longer overall survival. 166 Chinese patients with metastatic colorectal carcinoma who had been treated with FOLFOX-4 were used in this study. 19922504 PubMed Chen et al., 2010, Cancer Sci. 4 accepted 670 259 2473 11 67352689 67352689 A G ENST00000398606.3 75 GRCh37 Common Germline 2019-08-30 15:25:17 UTC https://civicdb.org/links/evidence_items/670 https://civicdb.org/links/variants/259 https://civicdb.org/links/genes/2473 false ABCG2 9429 Q141K Ovarian Cancer 2394 Prognostic Supports B Better Outcome The ABCG2 Q141K variant was correlated with higher progression-free survival and overall survival in 511 ovarian cancer patients treated with platinum + taxane-based chemotherapy. 22112610 PubMed Tian et al., 2012, Gynecol. Oncol. 3 accepted 671 260 7451 4 89052323 89052323 G T ENST00000237612.3 75 GRCh37 Common Germline 2016-02-22 19:52:51 UTC https://civicdb.org/links/evidence_items/671 https://civicdb.org/links/variants/260 https://civicdb.org/links/genes/7451 false XRCC1 7515 Q399R Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Better Outcome The XRCC1 R399Q variant was significantly correlated with higher overall survival in non-small cell lung carcinoma (NSCLC) patients treated with gemcitabine and platinum. 62 patients with either Stage IIIB or Stage IV NSCLC were used for this study. 22551904 PubMed Liao et al., 2012, J Thorac Oncol 4 accepted 672 261 6144 19 44055726 44055726 T C ENST00000262887.5 75 GRCh37 XRCC1 Q399R germline polymorphism (NM_006297.2:c.1196A>G) is associated with better outcome for patients with NSCLC and increased response to chemotherapy for patients with cervical cancer. Rare Germline 2015-12-09 21:24:38 UTC https://civicdb.org/links/evidence_items/672 https://civicdb.org/links/variants/261 https://civicdb.org/links/genes/6144 false XRCC1 7515 Q399R Cervical Cancer 4362 Cisplatin,Carboplatin Substitutes Predictive Supports B Sensitivity/Response The XRCC1 R399Q variant was correlated with increased response to platinum-based neoadjuvant chemotherapy in patients with cervical cancer. Tumor samples from 36 patients with Stage IB or IIA bulky (greater than 4 cm in size) cervical carcinomas were used in this study. 16875718 PubMed Chung et al., 2006, Gynecol. Oncol. 4 accepted 673 261 6144 19 44055726 44055726 T C ENST00000262887.5 75 GRCh37 XRCC1 Q399R germline polymorphism (NM_006297.2:c.1196A>G) is associated with better outcome for patients with NSCLC and increased response to chemotherapy for patients with cervical cancer. Rare Germline 2017-05-31 15:35:21 UTC https://civicdb.org/links/evidence_items/673 https://civicdb.org/links/variants/261 https://civicdb.org/links/genes/6144 false ABCB1 5243 S893T Ovarian Cancer 2394 Paclitaxel Predictive Supports B Sensitivity/Response The ABCB1 G2677T/A (S893T, rs2032582) homozygous variant was positively correlated with response to paclitaxel treatment in ovarian cancer patients. 51 epithelial and 2 fallopian tube frozen tumors were analyzed for this study. 16467099 PubMed Gréen et al., 2006, Clin. Cancer Res. 3 accepted 674 262 4244 7 87160618 87160618 A T ENST00000265724.3 75 GRCh37 Rare Germline 2015-12-22 15:22:19 UTC https://civicdb.org/links/evidence_items/674 https://civicdb.org/links/variants/262 https://civicdb.org/links/genes/4244 false ABCB1 5243 I1145I Lung Non-small Cell Carcinoma 3908 Cisplatin,Carboplatin Substitutes Predictive Supports B Sensitivity/Response The mutation at codon 3435 (C>T) correlated with a significantly higher response rate to platinum-based chemotherapy in patients with advanced non small cell lung cancer (NSCLC). 103 Chinese patients with NSCLC were evaluated in this study. However, there was not a significant correlation between the mutation and overall survival. 22296372 PubMed Yan et al., 2011, Asian Pac. J. Cancer Prev. 2 accepted 675 263 4244 7 87138645 87138645 A G ENST00000265724.3 75 GRCh37 ABCB1 I1145I is a germline polymorphism that has improved responses in cancer. Specifically, it can indicate sensitivity to platinum-based chemotherapies for patients with NSCLC or better outcome for HER2-positive metastatic breast cancer patients. Common Germline 2019-04-25 19:01:13 UTC https://civicdb.org/links/evidence_items/675 https://civicdb.org/links/variants/263 https://civicdb.org/links/genes/4244 false ERCC2 2068 K751Q Osteosarcoma 3347 Cisplatin Predictive Supports B Resistance The ERCC2 K751Q variant was significantly correlated with a lower response to cisplatin chemotherapy in osteosarcoma patients and shorter event-free survival. 91 osteosarcoma patients with a median age of 15 years were followed in this study. 19434073 PubMed Caronia et al., 2009, Pharmacogenomics J. 4 accepted 676 264 1736 19 45854919 45854919 T G ENST00000391945.4 75 GRCh37 Rare Germline 2016-10-02 15:11:45 UTC https://civicdb.org/links/evidence_items/676 https://civicdb.org/links/variants/264 https://civicdb.org/links/genes/1736 false ERCC2 2068 K751Q Lung Non-small Cell Carcinoma 3908 Carboplatin,Paclitaxel Combination Predictive Supports B Sensitivity/Response The ERCC2 K751Q variant is significantly correlated with increased response to paclitaxel and carboplatin therapies in non small cell lung cancer (NSCLC). The researchers utilized data from three previous clinical trials in Japan and the United States with a total of 526 NSCLC patients. 19470925 PubMed Gandara et al., 2009, J. Clin. Oncol. 3 accepted 677 264 1736 19 45854919 45854919 T G ENST00000391945.4 75 GRCh37 Rare Germline 2015-12-11 21:16:41 UTC https://civicdb.org/links/evidence_items/677 https://civicdb.org/links/variants/264 https://civicdb.org/links/genes/1736 false TYMS 7298 5' TANDEM REPEAT Colorectal Cancer 9256 Fluorouracil,Irinotecan Combination Predictive Supports B Resistance The TYMS 5' 3TPR germline variant was significantly correlated with lower response to irinotecan plus 5-fluorouracil treatment in colorectal cancer patients. 149 metastatic CRC patients treated with irinotecan/5FU as first-line chemotherapy were followed in this study. 20628391 PubMed Martinez-Balibrea et al., 2010, Br. J. Cancer 3 accepted 678 265 5971 18 657604 657742 ENST00000323274.10 75 GRCh37 Rare Germline 2015-12-11 21:15:59 UTC https://civicdb.org/links/evidence_items/678 https://civicdb.org/links/variants/265 https://civicdb.org/links/genes/5971 false LRP1B 53353 EXON 12-22 DELETION Ovarian Cancer 2394 Doxorubicin Predictive Supports D Resistance A minimum common region of deletion of 0.19Mb, encompassing exons 12–22 of LRP1B4 was observed in 4 patients exhibiting acquired treatment resistance. Transfection of mLRP1B4, a fully functional minigene of LRP1B, in IGROV1 and OVCAR4 ovarian cell lines with low expression of LRP1B4 increased sensitivity to liposomal doxorubicin but not doxorubicin. siRNA knockdown of LRP1B4 in JHOS3 and Kuramochi ovarian cancer cell lines decreased sensitivity to liposomal doxorubicin but not doxorubicin. 22896685 PubMed Cowin et al., 2012, Cancer Res. 3 accepted 679 266 12146 2 141665446 141777671 ENST00000389484.3 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/679 https://civicdb.org/links/variants/266 https://civicdb.org/links/genes/12146 false FGFR1 2260 Amplification Lung Squamous Cell Carcinoma 3907 PD173074 Predictive Supports D Sensitivity/Response Preclinical (in-vitro, in-vivo) evidence suggests predictive value of FGFR1 amplification for treatment with FGFR1-inhibitors. 4 of 83 cell lines exhibited FGFR1 amplification, and 3 of these were highly sensitive to PD173074. This sensitivity was confirmed in a mouse xenograft. Clinical trials are currently ongoing. 21160078 PubMed Weiss et al., 2010, Sci Transl Med 5 accepted 680 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/680 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false FGFR1 2260 Expression Lung Cancer 1324 Ponatinib Predictive Supports D Sensitivity/Response Preclinical evidence (in-vitro) for predictive value of FGFR1 mRNA and protein expression as well as mRNA expression of FGF2 and FGF9 for sensitivity to FGFR1 inhibition. The authors suggested that FGFR1 expression is a better predictive marker than FGFR1 amplification and proposes a connection between KRAS and PIK3CA mutations. This study used 58 cell lines, of which 14 exhibited ponatinib sensitivity. This sensitivity was correlated with FGFR1 mRNA and protein expression. 24771645 PubMed Wynes et al., 2014, Clin. Cancer Res. 4 accepted 681 268 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 high expression has been reported in 11.8% (178 patients) of oral squamous cell carcinoma patients, and was enriched in early stages (Freier et. al., 2007). Another study reports FGFR1 expression in 35% of primary HNSSC (353 patients) (Göke et. al., 2015). In both studies, FGFR1 gene amplification and expression do not correlate well with about 35% of samples with FGFR1 amplification overexpressing FGFR1 (Göke et. al., 2015). FGFR1 expression also correlated with sensitivity to FGFR1 inhibitors in preclinical models of lung cancer (Wynes et. al., 2014), HNSSC (Göke et. al., 2015) and urothelial carcinoma (Lamont et. al., 2011). N/A 2016-02-21 16:09:28 UTC https://civicdb.org/links/evidence_items/681 https://civicdb.org/links/variants/268 https://civicdb.org/links/genes/1885 false FGFR1 2260 Amplification Lung Squamous Cell Carcinoma 3907 Prognostic Supports B Poor Outcome In this study in surgically resected squamous cell lung cancer, FGFR1 amplification has been shown as an independent negative prognostic factor in Asian patients. FGFR1 amplification also correlates with cigarette smoking. 23182986 PubMed Kim et al., 2013, J. Clin. Oncol. 4 accepted 682 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). Somatic 2015-12-22 15:47:35 UTC https://civicdb.org/links/evidence_items/682 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false FGFR1 2260 Amplification Lung Squamous Cell Carcinoma 3907 Prognostic Supports B Poor Outcome This study shows an association of FGFR1 amplification with shorter overall and disease-free survival. However, no statistically significant association is seen on multivariate analysis. 25086725 PubMed Seo et al., 2014, Virchows Arch. 3 accepted 683 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). Somatic 2015-12-26 21:46:43 UTC https://civicdb.org/links/evidence_items/683 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false FGFR1 2260 Amplification Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Better Outcome This study shows a reduction in the risk of death for patients with FGFR1 copy-number between 4 and 6. No difference in survival is seen between amplified and non-amplified patients in general. 23806793 PubMed Tran et al., 2013, Lung Cancer 2 accepted 684 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). Somatic 2015-12-21 22:39:22 UTC https://civicdb.org/links/evidence_items/684 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false FGFR1 2260 Amplification Cancer 162 Prognostic Supports B Poor Outcome Meta-Analysis on prognostic value of FGFR1 amplification in different types of cancer shows significantly worse overall survival for patients with FGFR1 and FGFR2 amplification. However, larger studies are warranted for confirmation. 25171497 PubMed Chang et al., 2014, PLoS ONE 4 accepted 685 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). Somatic 2015-12-18 02:24:12 UTC https://civicdb.org/links/evidence_items/685 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false FGFR1 2260 Amplification Lung Non-small Cell Carcinoma 3908 PD173074 Predictive Supports D Sensitivity/Response Preclinical study showing FGFR1 amplification in NSCLC and efficacy of FGFR-1 inhibition in one amplified cell line. 21666749 PubMed Dutt et al., 2011, PLoS ONE 4 accepted 686 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/686 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false FGFR1 2260 Amplification Lung Squamous Cell Carcinoma 3907 Prognostic Does Not Support B Poor Outcome Effect of FGFR1 amplification on survival unclear, no significant correlation with PFS and OS seen in this meta-analysis. However, FGFR1 amplification is significantly correlated with lymph node metastasis. 25433983 PubMed Jiang et al., 2015, Lung Cancer 4 accepted 687 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). Somatic 2015-12-18 02:16:44 UTC https://civicdb.org/links/evidence_items/687 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false ROS1 6098 Rearrangement Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports B Sensitivity/Response An expansion cohort of a phase-1 Crizotinib study found a 72% objective response rate among 50 patients with ROS1 rearrangement. The study did not compare to patients without rearrangement that were treated with Crizotinib. Several different ROS1 fusion partners were identified, but no clinical differences in outcome were associated with the identity of the 5' partner. 25264305 PubMed Shaw et al., 2014, N. Engl. J. Med. NCT00585195 4 accepted 688 269 4941 6 117609463 117747018 ENST00000368508.3 75 GRCh37 ROS1 is a receptor tyrosine kinase that frequently forms gene fusions in several cancer types. Approximately 2% of NSCLC patients harbor a ROS1 gene fusion. Several fusion partners have been described with a constant ROS1-breakpoint, maintaining the kinase domain (Solomon B, 2015). Following case-studies and retrospective analyses, an expansion cohort of a phase-1 study showed clinical benefit of crizotinib in ROS1 rearranged NSCLC. The benefit was independent of the type of ROS1-rearrangement (Shaw et. al.,2014). Somatic 2015-12-27 21:58:34 UTC https://civicdb.org/links/evidence_items/688 https://civicdb.org/links/variants/269 https://civicdb.org/links/genes/4941 false MET 4233 Amplification Gastric Adenocarcinoma 3717 Onartuzumab Predictive Supports C Sensitivity/Response A case-study describing a patient with MET polysomy, MET over-expression and evidence of autocrine HGF-production (the growth factor ligand of MET). The patient initially achieved a complete response on MET-Inhibitor MetMAb (Onartuzumab) for 2 years and mixed response after recurrence with resistance in some of the newly developing metastases. 22389872 PubMed Catenacci et al., 2011, Cancer Discov 3 accepted 689 270 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/689 https://civicdb.org/links/variants/270 https://civicdb.org/links/genes/52 false ATR 545 I774FS Endometrial Cancer 1380 Prognostic Supports B Poor Outcome Extension and reduction of the ATR exon 10 A10 repeat (alters codon I774) was associated with poorer overall and disease-free survival in patients with endometrioid endometrial cancer when compared to patients with wildtype ATR and with or without microsatellite instability. These ATR mutations were observed in 12 of 248 patients (4.8%, 3 insertions, 9 deletions). 19470935 PubMed Zighelboim et al., 2009, J. Clin. Oncol. 4 accepted 690 271 524 3 142274740 142274740 ENST00000350721.4 75 GRCh37 Single A insertion or deletion in the 10 A mononucleotide run in exon 10 of ATR results in a frameshift of codon I774. In patients with endometrial cancer, this mutation has only been observed in patients with microsatellite instability. Somatic 2015-12-28 19:09:33 UTC https://civicdb.org/links/evidence_items/690 https://civicdb.org/links/variants/271 https://civicdb.org/links/genes/524 false EGFR 1956 Amplification Head And Neck Squamous Cell Carcinoma 5520 Fluorouracil,Platinum Compound,Cetuximab Combination Predictive Does Not Support B Sensitivity/Response EGFR amplification was not a predictor of response to cetuximab/5-FU/platinum in patients with recurrent or metastatic HNSSC from the EXTREME study. 21048039 PubMed Licitra et al., 2011, Ann. Oncol. 4 accepted 691 190 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2017-05-31 00:12:16 UTC https://civicdb.org/links/evidence_items/691 https://civicdb.org/links/variants/190 https://civicdb.org/links/genes/19 false EGFR 1956 Overexpression Head And Neck Squamous Cell Carcinoma 5520 Cetuximab Predictive Does Not Support B Sensitivity/Response EGFR expression level was not predicitive of response to cetuximab-containing first line regimens in recurrent or metastatic head and neck squamous cell carcinoma and KRAS-wild type colorectal carcinoma. 23265711 PubMed Licitra et al., 2013, Eur. J. Cancer NCT00122460,NCT00154102 4 accepted 692 193 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 N/A 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/692 https://civicdb.org/links/variants/193 https://civicdb.org/links/genes/19 false EGFR 1956 Overexpression Lung Non-small Cell Carcinoma 3908 Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Predictive Supports B Sensitivity/Response EGFR overexpression was correlated with longer overall survival in patients with advanced NSCLC treated with first line chemotherapy and cetuximab than those treated with first line chemotherapy alone. 22056021 PubMed Pirker et al., 2012, Lancet Oncol. NCT00148798 4 accepted 693 193 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 N/A 2020-10-20 06:02:35 UTC https://civicdb.org/links/evidence_items/693 https://civicdb.org/links/variants/193 https://civicdb.org/links/genes/19 false CDKN2A 1029 p16 Expression Head And Neck Squamous Cell Carcinoma 5520 Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Predictive Does Not Support B Resistance In this retrospective analysis of the SPECTRUM trial, p16 (CDKN2A) expression (and HPV-infection) was not predictive of response to EGFR-targeted therapy in combination with chemotherapy (n = 416 patient tumors). 24577117 PubMed Vermorken et al., 2014, Ann. Oncol. 3 accepted 694 272 14 9 21968055 21974865 ENST00000498124.1 75 GRCh37 CDKN2A (p16) expression is a surrogate marker of HPV infection in oropharyngeal squamous cell carcinoma. CDKN2A and p53 are inactivated through HPV proteins E6 and E7 and therefore not altered in expression level in HPV-associated carcinomas. However, there is no perfect overlap between p16 expression and HPV status with some 10-12.5% of HPV-negative tumors expressing p16. (Seiwert, T JCO, 2014). p16 positivity is a well-established positive prognostic factor in squamous cell cancer of the head and neck in the primary and, as increasing evidence suggests, recurrent/metastatic disease settings. Predictive information from HPV status have not been established to date. A lack of benefit from EGFR-inhibitors has been proposed by some studies. Other studies were not able to reproduce this finding. N/A 2020-10-30 07:16:59 UTC https://civicdb.org/links/evidence_items/694 https://civicdb.org/links/variants/272 https://civicdb.org/links/genes/14 false CDKN2A 1029 p16 Expression Head And Neck Squamous Cell Carcinoma 5520 Prognostic Supports B Better Outcome p16 positivity, as a surrogate marker for HPV-associated HNSSC was a favorable prognostic marker in recurrent or metastatic carcinoma. 24799460 PubMed Argiris et al., 2014, Ann. Oncol. NCT01487733 4 accepted 695 272 14 9 21968055 21974865 ENST00000498124.1 75 GRCh37 CDKN2A (p16) expression is a surrogate marker of HPV infection in oropharyngeal squamous cell carcinoma. CDKN2A and p53 are inactivated through HPV proteins E6 and E7 and therefore not altered in expression level in HPV-associated carcinomas. However, there is no perfect overlap between p16 expression and HPV status with some 10-12.5% of HPV-negative tumors expressing p16. (Seiwert, T JCO, 2014). p16 positivity is a well-established positive prognostic factor in squamous cell cancer of the head and neck in the primary and, as increasing evidence suggests, recurrent/metastatic disease settings. Predictive information from HPV status have not been established to date. A lack of benefit from EGFR-inhibitors has been proposed by some studies. Other studies were not able to reproduce this finding. N/A 2020-10-30 07:16:12 UTC https://civicdb.org/links/evidence_items/695 https://civicdb.org/links/variants/272 https://civicdb.org/links/genes/14 false CDKN2A 1029 p16 Expression Head And Neck Squamous Cell Carcinoma 5520 Panitumumab Predictive Supports B Resistance In this retrospective analysis of p16 status as surrogate marker for HPV in the SPECTRUM trial, p16 (CDKN2A) expression was not associated with improved response to EGFR-directed therapy (Panitumumab) in combination with chemotherapy compared to chemotherapy alone. 23746666 PubMed Vermorken et al., 2013, Lancet Oncol. NCT00460265 3 accepted 696 272 14 9 21968055 21974865 ENST00000498124.1 75 GRCh37 CDKN2A (p16) expression is a surrogate marker of HPV infection in oropharyngeal squamous cell carcinoma. CDKN2A and p53 are inactivated through HPV proteins E6 and E7 and therefore not altered in expression level in HPV-associated carcinomas. However, there is no perfect overlap between p16 expression and HPV status with some 10-12.5% of HPV-negative tumors expressing p16. (Seiwert, T JCO, 2014). p16 positivity is a well-established positive prognostic factor in squamous cell cancer of the head and neck in the primary and, as increasing evidence suggests, recurrent/metastatic disease settings. Predictive information from HPV status have not been established to date. A lack of benefit from EGFR-inhibitors has been proposed by some studies. Other studies were not able to reproduce this finding. N/A 2020-10-30 07:16:51 UTC https://civicdb.org/links/evidence_items/696 https://civicdb.org/links/variants/272 https://civicdb.org/links/genes/14 false CDKN2A 1029 p16 Expression Head And Neck Squamous Cell Carcinoma 5520 Cetuximab Predictive Does Not Support B Resistance In this study response to EGFR-inhibition by cetuximab was independent of HPV-status, represented by expression of p16 (CDKN2A, an established biomarker of HPV infection). Expression of p16 was assayed in 69 HNSCC patients by IHC. 24577089 PubMed Pogorzelski et al., 2014, Cell Death Dis 4 accepted 697 272 14 9 21968055 21974865 ENST00000498124.1 75 GRCh37 CDKN2A (p16) expression is a surrogate marker of HPV infection in oropharyngeal squamous cell carcinoma. CDKN2A and p53 are inactivated through HPV proteins E6 and E7 and therefore not altered in expression level in HPV-associated carcinomas. However, there is no perfect overlap between p16 expression and HPV status with some 10-12.5% of HPV-negative tumors expressing p16. (Seiwert, T JCO, 2014). p16 positivity is a well-established positive prognostic factor in squamous cell cancer of the head and neck in the primary and, as increasing evidence suggests, recurrent/metastatic disease settings. Predictive information from HPV status have not been established to date. A lack of benefit from EGFR-inhibitors has been proposed by some studies. Other studies were not able to reproduce this finding. N/A 2020-10-30 07:16:38 UTC https://civicdb.org/links/evidence_items/697 https://civicdb.org/links/variants/272 https://civicdb.org/links/genes/14 false RET 5979 KIF5B::RET Lung Adenocarcinoma 3910 Vandetanib Predictive Supports C Sensitivity/Response A case study of a patient with EGFR, KRAS, BRAF, HER2, ALK, ROS1 and MET negative adenocarcinoma of the lung. FISH analysis revealed a KIF5B-RET fusion. The RET inhibitor Vandetanib led to remission in the patient. 23584301 PubMed Gautschi et al., 2013, J Thorac Oncol 2 accepted 698 273 42 10 32306071 32345359 ENST00000302418.4 10 43609928 43625799 ENST00000355710.3 75 GRCh37 In a study by Takeuchi et. al. a fusion screen was performed in 1529 lung cancer samples. 14 adenocarcinomas with KIF5B-RET and CCDC6-RET fusions were identified. (Takeuchi K et. al., 2012) Somatic 2020-08-12 15:43:09 UTC https://civicdb.org/links/evidence_items/698 https://civicdb.org/links/variants/273 https://civicdb.org/links/genes/42 false HRAS 3265 G13D Colorectal Cancer 9256 Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Predictive Supports C Resistance Case report of a patient with metastatic colorectal carcinoma and a novel HRAS G13D mutation showed resistance to treatment with panitumumab. In vitro models of HRAS G13D confirmed resistance mechanism in the same study. 26561417 PubMed Boidot et al., 2016, Int J Colorectal Dis 3 accepted 699 274 2747 11 534285 534285 C T ENST00000451590.1 75 GRCh37 Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/699 https://civicdb.org/links/variants/274 https://civicdb.org/links/genes/2747 false HRAS 3265 Mutation Cancer 162 Binimetinib,MTOR Kinase Inhibitor AZD8055,Everolimus,Mirdametinib,Selumetinib Substitutes Predictive Supports D Sensitivity/Response A pre-clinical study in 10 solid cancer cell lines. HRAS mutations (Q61L, Q61R and G12V) sensitized cell lines toward MEK inhibitors (AZD6244/selumetinib, MEK162 and PD0325901) and mTOR inhibitors (Everolimus and AZD8055). 26544513 PubMed Kiessling et al., 2015, Oncotarget 3 accepted 700 275 2747 11 533873 534289 ENST00000451590.1 75 GRCh37 Somatic 2016-07-17 21:09:27 UTC https://civicdb.org/links/evidence_items/700 https://civicdb.org/links/variants/275 https://civicdb.org/links/genes/2747 false CD274 29126 Expression Lung Non-small Cell Carcinoma 3908 Prognostic Does Not Support B Poor Outcome This meta-analysis did not find a significant connection between expression of PD-L1 and overall survival in patients with NSCLC. 26664143 PubMed Zhong et al., 2015, Onco Targets Ther 4 accepted 701 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2020-10-21 04:32:11 UTC https://civicdb.org/links/evidence_items/701 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false CD274 29126 Expression Lung Squamous Cell Carcinoma 3907 Prognostic Supports B Better Outcome In this study, PD-L1 expression (measured by IHC) was associated with better overall survival in the subgroup of Lung Squamous Cell Carcinomas (149 of 321 patients in the study). 26313362 PubMed Schmidt et al., 2015, PLoS ONE 3 accepted 702 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2016-02-13 05:26:10 UTC https://civicdb.org/links/evidence_items/702 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false CD274 29126 Expression Ovarian Serous Carcinoma 0050933 Prognostic Supports B Better Outcome High expression of PD-L1 and PD-1 were associated with a favorable prognosis in patients with high grade serous ovarian carcinoma (n = 215 cases). 26625204 PubMed Darb-Esfahani et al., 2016, Oncotarget 3 accepted 703 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2016-02-13 05:31:36 UTC https://civicdb.org/links/evidence_items/703 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false CD274 29126 Expression Melanoma 1909 Pembrolizumab,Nivolumab Substitutes Predictive Supports B Sensitivity/Response Based on a meta-analysis of 20 trials (1475 patients), of which 7 studies (636 patients) included melanoma, PD-L1 expression was associated with a higher ORR rate in patients with melanoma. Active drugs were Nivolumab and Pembrolizumab, PD-1 receptor targeting antibodies. 26086854 PubMed Carbognin et al., 2015, PLoS ONE 4 accepted 704 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2016-02-13 05:32:27 UTC https://civicdb.org/links/evidence_items/704 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false MTOR 2475 Mutation Bladder Carcinoma 4007 Pazopanib,Everolimus Combination Predictive Supports C Sensitivity/Response A case-study of a patient with urothelial carcinoma reported exceptional response (14 months) in a phase 1 study of Everolimus and Pazopanib. Mutations E2014K and E2419K were shown to be activating in-vitro. 24625776 PubMed Wagle et al., 2014, Cancer Discov 3 accepted 705 277 2073 1 11166592 11322564 ENST00000361445.4 75 GRCh37 Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/705 https://civicdb.org/links/variants/277 https://civicdb.org/links/genes/2073 false AKT2 208 EXPRESSION Breast Cancer 1612 Trastuzumab Predictive Supports B Sensitivity/Response In HER2+ metastatic breast cancer treated with trastuzumab (n = 74 patients), the expression of AKT2 and pAkt-Thr308 and/or pAkt-Ser473 localized in nucleus+cytoplasm was associated with an improved time to progression (TTP) and overall survival (OS) compared to AKT2 negative tumors as measured by immunohistochemistry. 22842582 PubMed Grell et al., 2012, Int. J. Oncol. 3 accepted 706 278 254 19 40736224 40791302 ENST00000392038.2 75 GRCh37 N/A 2020-12-10 20:10:24 UTC https://civicdb.org/links/evidence_items/706 https://civicdb.org/links/variants/278 https://civicdb.org/links/genes/254 false AKT1 207 E17K Melanoma 1909 Uprosertib Predictive Supports D Sensitivity/Response A cell line with AKT E17K mutation was found to be sensitive to AKT inhibition with GSK2141795B in this study. 24735930 PubMed Lassen et al., 2014, Mol. Cancer 2 accepted 707 4 2 14 105246551 105246551 C T ENST00000407796.2 75 GRCh37 AKT1 E17K is a recurrent mutation that has been observed in breast, colorectal, lung, and ovarian cancer. It has been convincingly shown to be an activating mutation resulting in PI3K/AKT/mTOR pathway activity. It has been suggested that this mutation decreases the cell's sensitivity to AKT1 allosteric kinase inhibitors. This, and other AKT1 mutations, are the subject of much research and development for therapeutics. Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/707 https://civicdb.org/links/variants/4 https://civicdb.org/links/genes/2 false PTEN 5728 Loss Melanoma 1909 Uprosertib Predictive Supports D Sensitivity/Response Most BRAF mutant cell lines (mostly V600E) with PTEN mutation or loss of expression were among those sensitive to inhibition with AKT inhibitor GSK2141795B. 24735930 PubMed Lassen et al., 2014, Mol. Cancer 2 accepted 708 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/708 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false AKT1 207 E17K Breast Cancer 1612 Capivasertib Predictive Supports C Sensitivity/Response In a phase-I study of AZD5363, partial response was observed in 2 patients with breast and ovarian carcinoma, respectively, and AKT1 E17K mutations. While full study results have not yet been published, this paper highlights in vitro results that further confirm the role of AKT E17K mutation. 26351323 PubMed Davies et al., 2015, Mol. Cancer Ther. NCT01353781 3 accepted 709 4 2 14 105246551 105246551 C T ENST00000407796.2 75 GRCh37 AKT1 E17K is a recurrent mutation that has been observed in breast, colorectal, lung, and ovarian cancer. It has been convincingly shown to be an activating mutation resulting in PI3K/AKT/mTOR pathway activity. It has been suggested that this mutation decreases the cell's sensitivity to AKT1 allosteric kinase inhibitors. This, and other AKT1 mutations, are the subject of much research and development for therapeutics. Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/709 https://civicdb.org/links/variants/4 https://civicdb.org/links/genes/2 false PIK3CA 5290 E545K Breast Cancer 1612 Akt Inhibitor MK2206,Pictilisib Substitutes Predictive Supports D Sensitivity/Response PIK3CA E545K mutation increased sensitivity to AKT inhibitor MK-2206 and PI3K inhibitor GDC-0941 in a breast cancer cell line model. 23888070 PubMed Beaver et al., 2013, Clin. Cancer Res. 3 accepted 710 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/710 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false PTEN 5728 Loss Breast Cancer 1612 PI3Kbeta Inhibitor AZD8186 Predictive Supports D Sensitivity/Response Breast and prostate cancer cell lines responsive to AZD8186 were enriched for PTEN deficiency. 25398829 PubMed Hancox et al., 2015, Mol. Cancer Ther. 2 accepted 711 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/711 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false MTOR 2475 Mutation Melanoma 1909 Prognostic Supports B Poor Outcome Median overall survival of patients with nonsynonymous mutations in mTOR was shorter. 26490311 PubMed Kong et al., 2016, Clin. Cancer Res. 3 accepted 712 277 2073 1 11166592 11322564 ENST00000361445.4 75 GRCh37 Somatic 2015-12-24 22:47:55 UTC https://civicdb.org/links/evidence_items/712 https://civicdb.org/links/variants/277 https://civicdb.org/links/genes/2073 false MTOR 2475 H1968Y Melanoma 1909 PI3K/BET Inhibitor LY294002,Capivasertib Substitutes Predictive Supports D Sensitivity/Response In a cell line (HEK293T) with expression of H1968Y or P2213S mTOR mutations, LY294002 and AZD5363 were more effective than temsirolimus or BYL719 in suppressing cell growth. 26490311 PubMed Kong et al., 2016, Clin. Cancer Res. 3 accepted 713 283 2073 1 11188519 11188519 G A ENST00000361445.4 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/713 https://civicdb.org/links/variants/283 https://civicdb.org/links/genes/2073 false PTEN 5728 Loss Cancer 162 Carboplatin,Paclitaxel,Buparlisib Combination Predictive Supports B Sensitivity/Response All three patients with PTEN loss had benefit from adding Buparlisib to carboplatin+paclitaxel therapy in a phase I study in advanced solid cancers. 25672916 PubMed Hyman et al., 2015, Cancer Chemother. Pharmacol. NCT01297452 3 accepted 714 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2015-12-29 17:28:13 UTC https://civicdb.org/links/evidence_items/714 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false NF2 4771 K159fs Breast Cancer 1612 Temsirolimus Predictive Supports C Sensitivity/Response 23 patients were treated with temsirolimus containing regimens. 1 patient with a complete response >3 years had a K159fs*16 mutation in NF2. 2 patients were tested for NF2 mutations. 25878190 PubMed Moulder et al., 2015, Ann. Oncol. 3 accepted 715 279 3870 22 30050674 30050674 A ENST00000338641.4 75 GRCh37 Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/715 https://civicdb.org/links/variants/279 https://civicdb.org/links/genes/3870 false PTEN 5728 Loss Breast Cancer 1612 Alpelisib Predictive Supports D Resistance A case report described a responder to PI3K inhibitor BYL719 for a tumor with PIK3CA E542K mutation. After partial response for 9.5 months, resistance developed. Sequencing in this and other patients as well as preclinical models showed loss of PTEN as the probable mechanism of resistance. 25409150 PubMed Juric et al., 2015, Nature 4 accepted 716 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/716 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false EGFR 1956 S492R Colorectal Cancer 9256 Cetuximab Predictive Supports C Resistance In-vitro studies found this mutation to confer resistance to cetuximab. 2 of 10 patients studied also harbored EGFR S492R and were resistant to cetuximab therapy. Panitumumab was still active in-vitro and in one patient. 22270724 PubMed Montagut et al., 2012, Nat. Med. 4 accepted 717 453 19 7 55228009 55228009 C A ENST00000275493.2 75 GRCh37 Somatic 2016-08-15 20:02:53 UTC https://civicdb.org/links/evidence_items/717 https://civicdb.org/links/variants/453 https://civicdb.org/links/genes/19 false FBXW7 55294 Mutation Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Supports B Resistance 65 patients were retrospectively analyzed for mutational profiles predictive of response to EGFR-inhibitors (cetuximab or panitumumab). FBXW7 mutation was found to be more prevalent in non-responders (5 mutations) than responders (1 mutation). 26508446 PubMed Lupini et al., 2015, BMC Cancer 2 accepted 718 281 12903 4 153245446 153332714 ENST00000281708.4 75 GRCh37 Somatic 2016-02-19 22:46:00 UTC https://civicdb.org/links/evidence_items/718 https://civicdb.org/links/variants/281 https://civicdb.org/links/genes/12903 false SMAD4 4089 Mutation Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Supports B Resistance In a retrospective analysis of 65 patients with metastatic colorectal cancer, SMAD4 mutations were more common among patients with no benefit from EGFR-inhibition (cetuximab or panitumumab) (4 patients) than with patients with response to EGFR directed treatment (1 patient). 26508446 PubMed Lupini et al., 2015, BMC Cancer 2 accepted 719 216 77 18 48556583 48611409 ENST00000342988.3 75 GRCh37 Somatic 2016-02-19 22:48:42 UTC https://civicdb.org/links/evidence_items/719 https://civicdb.org/links/variants/216 https://civicdb.org/links/genes/77 false SMAD4 4089 Underexpression Head And Neck Squamous Cell Carcinoma 5520 Cetuximab Predictive Supports D Resistance In this study, SMAD4 underexpression was associated with an epithelial-to-mesenchymal transition and resistance to EGFR-directed treatment with Cetuximab. 26046389 PubMed Cheng et al., 2015, Cancer Biol. Ther. 3 accepted 720 282 77 18 48556583 48611409 ENST00000342988.3 75 GRCh37 Somatic 2016-02-17 19:50:06 UTC https://civicdb.org/links/evidence_items/720 https://civicdb.org/links/variants/282 https://civicdb.org/links/genes/77 false MTOR 2475 P2213S Melanoma 1909 PI3K/BET Inhibitor LY294002,Capivasertib Combination Predictive Supports D Sensitivity/Response In a cell line (HEK293T) with expression of H1968Y or P2213S mTOR mutations, LY294002 and AZD5363 were more effective than temsirolimus or BYL719 in suppressing cell growth. 26490311 PubMed Kong et al., 2016, Clin. Cancer Res. 3 accepted 722 284 2073 1 11184580 11184580 G A ENST00000361445.4 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/722 https://civicdb.org/links/variants/284 https://civicdb.org/links/genes/2073 false BRAF 673 AGK::BRAF Melanoma 1909 Sorafenib Predictive Supports C Sensitivity/Response BRAF fusion AGK-BRAF was associated with decreased sensitivity to vemurafenib and increased sensitivity to sorafenib in-vitro. A single patient with this fusion showed durable response to sorafenib. 23890088 PubMed Botton et al., 2013, Pigment Cell Melanoma Res 2 accepted 723 285 5 7 141250989 141255367 ENST00000355413.4 7 140434279 140494267 ENST00000288602.6 75 GRCh37 Somatic 2016-07-11 04:13:34 UTC https://civicdb.org/links/evidence_items/723 https://civicdb.org/links/variants/285 https://civicdb.org/links/genes/5 false BRAF 673 AGK::BRAF Melanoma 1909 Vemurafenib Predictive Supports D Resistance A melanoma cell line with AGK-BRAF in-frame fusion showed decreased sensitivity towards Vemurafenib in comparison with BRAF mutated (V600E) cell lines. 23890088 PubMed Botton et al., 2013, Pigment Cell Melanoma Res 2 accepted 724 285 5 7 141250989 141255367 ENST00000355413.4 7 140434279 140494267 ENST00000288602.6 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/724 https://civicdb.org/links/variants/285 https://civicdb.org/links/genes/5 false BRAF 673 PAPSS1::BRAF Melanoma 1909 Vemurafenib Predictive Supports D Resistance BRAF-fusion in "pan-negative" melanomas were identified in TCGA data. Cell-lines with PAPSS1-BRAF fusion were resistant to treatment with Vemurafenib. 24345920 PubMed Hutchinson et al., 2013, Clin. Cancer Res. 3 accepted 725 286 5 4 108603171 108641608 ENST00000265174.4 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/725 https://civicdb.org/links/variants/286 https://civicdb.org/links/genes/5 false BRAF 673 PAPSS1::BRAF Melanoma 1909 Trametinib Predictive Supports D Sensitivity/Response BRAF-fusion in "pan-negative" melanomas were identified in TCGA data. Cell-lines with a PAPSS1-BRAF fusion were resistant to treatment with Vemurafenib but sensitive to treatment with Trametinib. This fusion is believed to activate MAPK pathway signaling. 24345920 PubMed Hutchinson et al., 2013, Clin. Cancer Res. 3 accepted 726 286 5 4 108603171 108641608 ENST00000265174.4 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/726 https://civicdb.org/links/variants/286 https://civicdb.org/links/genes/5 false BRAF 673 TRIM24::BRAF Melanoma 1909 Trametinib Predictive Supports D Sensitivity/Response A TRIM24-BRAF fusion was identified in a single patient with metastatic melanoma that was "pan-negative" for driver mutations. A cell-line (293H) ectopically expressing the TRIM24-BRAF fusion was found to be sensitive to the MEK-inhibitor Trametinib. 24345920 PubMed Hutchinson et al., 2013, Clin. Cancer Res. 3 accepted 727 287 5 7 138145079 138239711 ENST00000343526.4 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2016-02-18 22:06:27 UTC https://civicdb.org/links/evidence_items/727 https://civicdb.org/links/variants/287 https://civicdb.org/links/genes/5 false BRAF 673 L597R Melanoma 1909 Vemurafenib Predictive Supports C Sensitivity/Response A case report of a patient with BRAF L597R mutation and clinical response to BRAF-inhibition (Vemurafenib) that correlated to in-vitro models. 23715574 PubMed Bahadoran et al., 2013, J. Clin. Oncol. 4 accepted 728 288 5 7 140453145 140453145 A C ENST00000288602.6 75 GRCh37 Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/728 https://civicdb.org/links/variants/288 https://civicdb.org/links/genes/5 false ERBB3 2065 Overexpression Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance High expression of ERBB3 (her3) was associated with shorter overall survival (OS) from Cetuximab treatment in patients with metastatic colorectal cancer. Gene expression measures (qRT-PCR) were available for 103 patients. 25520391 PubMed Cushman et al., 2015, Clin. Cancer Res. 4 accepted 729 289 1733 12 56473645 56497289 ENST00000267101.3 75 GRCh37 N/A 2020-10-07 02:43:57 UTC https://civicdb.org/links/evidence_items/729 https://civicdb.org/links/variants/289 https://civicdb.org/links/genes/1733 false NT5E 4907 Overexpression Colorectal Cancer 9256 Cetuximab Predictive Supports B Sensitivity/Response CD73 high expression was identified as a potential marker of improved PFS from cetuximab treatment in patients with metastatic CRC. 25520391 PubMed Cushman et al., 2015, Clin. Cancer Res. 3 accepted 730 290 3976 6 86159809 86205496 ENST00000257770.3 75 GRCh37 N/A 2020-11-24 07:13:24 UTC https://civicdb.org/links/evidence_items/730 https://civicdb.org/links/variants/290 https://civicdb.org/links/genes/3976 false EZH2 2146 Overexpression Cancer 162 Prognostic Supports B Poor Outcome High expression of EZH2 was associated with poorer outcome in a meta-analysis encompassing 51 studies and 9444 patients. 26683709 PubMed Jiang et al., 2016, Oncotarget 4 accepted 731 291 63 7 148504477 148581370 ENST00000320356.2 75 GRCh37 N/A 2020-10-24 06:40:29 UTC https://civicdb.org/links/evidence_items/731 https://civicdb.org/links/variants/291 https://civicdb.org/links/genes/63 false IDH1 3417 R132C Acute Myeloid Leukemia 9119 GSK321 Predictive Supports D Sensitivity/Response Newly developed allosteric inhibitors (GSK321) of IDH1 led to granulocytic differentiation in-vitro and in-vivo. 26436839 PubMed Okoye-Okafor et al., 2015, Nat. Chem. Biol. 3 accepted 732 59 26 2 209113113 209113113 G A ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes and acute myeloid leukemia (AML), IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/732 https://civicdb.org/links/variants/59 https://civicdb.org/links/genes/26 false MET 4233 Amplification Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports D Resistance In this study a gefitinib-sensitive cell-line (HCC827), acquired gefitinib resistance (HCC827 GR) by a focal amplification of MET. Resistance was conferred by the MET amplification driving ERBB3 (HER3)-dependent activation of PI3K. 17463250 PubMed Engelman et al., 2007, Science 4 accepted 733 270 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/733 https://civicdb.org/links/variants/270 https://civicdb.org/links/genes/52 false MYD88 4615 Overexpression Breast Cancer 1612 Paclitaxel Predictive Supports D Resistance In this retrospective analysis of 211 breast cancer tissues, MYD88 overexpression was correlated with poor survival. In-vitro experiments showed a decrease in sensitivity towards paclitaxel in cell-lines with high MYD88 expression. 26596839 PubMed Xiang et al., 2016, Tumour Biol. 2 accepted 734 292 3742 3 38179969 38184510 ENST00000417037.2 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/734 https://civicdb.org/links/variants/292 https://civicdb.org/links/genes/3742 false MET 4233 Amplification Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Sensitivity/Response A case-study of an ALK-negative patient with MET amplification (MET/CEP7 ratio >5.0) who achieved a durable partial response to MET/ALK-inhibitor crizotinib. 21623265 PubMed Ou et al., 2011, J Thorac Oncol NCT00585195 3 accepted 735 270 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/735 https://civicdb.org/links/variants/270 https://civicdb.org/links/genes/52 false MET 4233 EXON 14 SKIPPING MUTATION Cancer 162 Crizotinib Predictive Supports D Sensitivity/Response The creation of a cell line model (HEK293) with MET exon 14 deletion (using the CRISPR/Cas9 system) led to enhanced cellular growth and sensitivity to the MET inhibitor crizotinib. MET exon 14 deletion results in an in-frame deletion in the MET protein. Recurrent splice site mutations that result in exon 14 skipping have been observed in ~3% of all lung cancers. 26547802 PubMed Togashi et al., 2015, Lung Cancer 3 accepted 736 324 52 7 116411903 116412043 ENST00000318493.6 75 GRCh37 Exon 14 mutations have been observed in ~3% of patients with NSCLC (28/933 reported by Awad et al J Clin Onc 2016), confirmed to cause exon skipping when available, and associated with concurrent MET amplification. Responses to the c-MET inhibitor crizotinib have been reported in preclinical models and in individual case reports as well as a small-scale clinical trial (17 patients treated, Drilon et al., 2016 (suppl; abstr 108; ASCO ID 167889-176)). Larger studies are needed but enrollment of patients with MET exon 14 skipping mutation in trials with MET inhibitors or off-label treatment is encouraged (Paik et al., 2015 (suppl; abstr 8021)). Somatic 2016-02-24 11:44:37 UTC https://civicdb.org/links/evidence_items/736 https://civicdb.org/links/variants/324 https://civicdb.org/links/genes/52 false EGFR 1956 Overexpression Lung Non-small Cell Carcinoma 3908 Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Predictive Supports B Sensitivity/Response In this prospective study in 37 patients of whom 34 were treated with different EGFR inhibitors (gefitinib, erlotinib, afatinib), EGFR mutations and a higher relative expression of EGFR in comparison to MET expression were correlated with longer PFS. 26439803 PubMed Park et al., 2015, Oncotarget 3 accepted 737 193 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 N/A 2020-10-20 06:03:05 UTC https://civicdb.org/links/evidence_items/737 https://civicdb.org/links/variants/193 https://civicdb.org/links/genes/19 false PDGFRA 5156 D842V Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports B Resistance 823 patients with GIST under therapy with imatinib were genotyped for this study. 18 patients (2%) with PDGFRA mutations were identified. In D842V-mutant GISTs, PFS (median 3.8 months) and OS (median 25.2 months) were significantly poorer than Non-D842V mutated (PFS median 29.5 months OS median 59.8 months). 26130666 PubMed Yoo et al., 2016, Cancer Res Treat 4 accepted 738 99 38 4 55152093 55152093 A T ENST00000257290.5 75 GRCh37 PDGFRA D842 mutations are characterized broadly as imatinib resistance mutations. This is most well characterized in gastrointestinal stromal tumors, but other cell lines containing these mutations have been shown to be resistant as well. Exogenous expression of the A842V mutation resulted in constitutive tyrosine phosphorylation of PDGFRA in the absence of ligand in 293T cells and cytokine-independent proliferation of the IL-3-dependent Ba/F3 cell line, both evidence that this is an activating mutation. In imatinib resistant cell lines, a number of other therapeutics have demonstrated efficacy. These include; crenolanib, sirolimus, and midostaurin (PKC412). Somatic 2015-12-27 21:28:40 UTC https://civicdb.org/links/evidence_items/738 https://civicdb.org/links/variants/99 https://civicdb.org/links/genes/38 false PIK3CA 5290 P471L Merkel Cell Carcinoma 3965 Idelalisib Predictive Supports C Sensitivity/Response A case report of an 86-year old patient with metastasized Merkel cell carcinoma who achieved a complete clinical response under therapy with the PI3K-inhibitor Idelalisib. 26466009 PubMed Shiver et al., 2015, N. Engl. J. Med. 3 accepted 739 294 37 3 178928226 178928226 C T ENST00000263967.3 75 GRCh37 Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/739 https://civicdb.org/links/variants/294 https://civicdb.org/links/genes/37 false RET 5979 Overexpression Breast Cancer 1612 Vandetanib Predictive Supports D Sensitivity/Response Vandetanib was tested in 4 murine models of patient-derived xenografts. In xenografts with high expression of EGFR or RET, vandetanib led to tumor regression, in those without high expression, vandetanib slowed tumor growth. 26686064 PubMed Hatem et al., 2016, Int. J. Cancer 2 accepted 740 597 42 10 43572475 43625799 ENST00000355710.3 75 GRCh37 Somatic 2021-01-29 05:54:24 UTC https://civicdb.org/links/evidence_items/740 https://civicdb.org/links/variants/597 https://civicdb.org/links/genes/42 false RIT1 6016 OVEREXPRESSION Endometrial Cancer 1380 Prognostic Supports B Poor Outcome After preliminary studies in cell lines, GEO datasets and fresh frozen tissues, RIT1 expression was determined in 257 tumors and 31 normal tissues. Elevated expression of RIT1 was correlated with poorer overall survival, pathological type, clinical stage, grade and vascular invasion. 26617739 PubMed Xu et al., 2015, Int J Clin Exp Pathol 3 accepted 741 296 4875 1 155870065 155880706 ENST00000368322.3 75 GRCh37 Somatic 2015-12-27 21:35:30 UTC https://civicdb.org/links/evidence_items/741 https://civicdb.org/links/variants/296 https://civicdb.org/links/genes/4875 false RIT1 6016 Mutation Lung Adenocarcinoma 3910 Selumetinib,Pictilisib Substitutes Predictive Supports D Sensitivity/Response RIT1 mutations were identified in approx. 2% of lung adenocarcinomas (5/87 in the "oncogene negative" samples of TCGA - no RIT1 mutations were observed in 143 samples with a known driver mutation). GDC-0941 impaired tumor growth of NCI-H2110 (RIT1 M90I mutated) xenografts in nude mice. GDC-0941 and AZD-6244 (selumetinib) impaired colony formation in-vitro. Combined PI3K/MEK inhibition was more effective than single agent treatment in-vitro. 24469055 PubMed Berger et al., 2014, Oncogene 3 accepted 742 297 4875 1 155870065 155880706 ENST00000368322.3 75 GRCh37 Somatic 2020-08-12 15:43:09 UTC https://civicdb.org/links/evidence_items/742 https://civicdb.org/links/variants/297 https://civicdb.org/links/genes/4875 false CD274 29126 Expression Lung Non-small Cell Carcinoma 3908 Pembrolizumab,Nivolumab Substitutes Predictive Supports B Sensitivity/Response Based on a meta-analysis of 20 trials (1475 patients), PD-L1 expression was associated with a higher ORR rate in patients with NSCLC. Active drugs were Nivolumab and Pembrolizumab, PD-1 receptor targeting antibodies. 26086854 PubMed Carbognin et al., 2015, PLoS ONE 4 accepted 743 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2016-02-13 05:27:44 UTC https://civicdb.org/links/evidence_items/743 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false MYCN 4613 Amplification Neuroblastoma 769 FACT Complex-targeting Curaxin CBL0137 Predictive Supports D Sensitivity/Response The drug CBL0137 (a drug that interacts with SSRP1 aka FACT) exhibited a synergistic effect with standard chemotherapy (cyclophosphamide, etoposide, cisplatin, vincristine, etc.) by blocking repair of DNA damage caused by genotoxic drugs, thus creating a synthetic lethal environment in MYCN-amplified neuroblastoma cells. High MYCN expression was found to sensitize neuroblastoma cells to CBL0137. 26537256 PubMed Carter et al., 2015, Sci Transl Med 3 accepted 744 298 3741 2 16080686 16087129 ENST00000281043.3 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/744 https://civicdb.org/links/variants/298 https://civicdb.org/links/genes/3741 false SMO 6608 D473H Medulloblastoma 0050902 Vismodegib Predictive Supports C Resistance In this case report, the D473H mutation was reported as an acquired mechanism of resistance to the hedgehog pathway inhibitor GDC-0449 (vismodegib). 19726788 PubMed Yauch et al., 2009, Science 3 accepted 745 299 5365 7 128849189 128849189 G C ENST00000249373.3 75 GRCh37 Somatic 2020-11-20 16:16:34 UTC https://civicdb.org/links/evidence_items/745 https://civicdb.org/links/variants/299 https://civicdb.org/links/genes/5365 false SMO 6608 Mutation Basal Cell Carcinoma 2513 Vismodegib Predictive Supports B Resistance In basal cell carcinoma, H231R, D473G, W281C and Q477E mutations conferred resistance to SMO-inhibitor vismodegib. SMO mutations were identified in 22 of 44 resistant basal cell carcinomas in 15 patients. 25759020 PubMed Atwood et al., 2015, Cancer Cell 4 accepted 746 300 5365 7 128828713 128853386 ENST00000249373.3 75 GRCh37 Somatic 2015-12-29 00:00:12 UTC https://civicdb.org/links/evidence_items/746 https://civicdb.org/links/variants/300 https://civicdb.org/links/genes/5365 false SMO 6608 Mutation Basal Cell Carcinoma 2513 PSI,Arsenic Trioxide Substitutes Predictive Supports D Sensitivity/Response Basal cell carcinomas with ligand-binding pocket or constitutively active mutations in the SMO gene were sensitive to inhibition of downstream hedgehog signaling with PSI (aPKC-ι/λ/GLI inhibitor) or arsenic trioxide. 25759020 PubMed Atwood et al., 2015, Cancer Cell 4 accepted 747 300 5365 7 128828713 128853386 ENST00000249373.3 75 GRCh37 Somatic 2016-11-03 18:59:06 UTC https://civicdb.org/links/evidence_items/747 https://civicdb.org/links/variants/300 https://civicdb.org/links/genes/5365 false PTCH1 5727 Mutation Medulloblastoma 0050902 Sonidegib Predictive Supports B Sensitivity/Response 133 sonic-hedghog driven medulloblastomas were sequenced for alterations (WGS or WES). 60 cases exhibited PTCH1 mutations, most of which were likely loss-of-function (spread across the gene and of types including: stop gain, splice site, frameshift, etc.). Functional models also showed PTCH1 mutant xenografts to be sensitive to SHH inhibition with sonidegib. 24651015 PubMed Kool et al., 2014, Cancer Cell 4 accepted 748 301 4645 9 98205262 98270943 ENST00000331920.6 75 GRCh37 Somatic 2020-11-20 16:16:34 UTC https://civicdb.org/links/evidence_items/748 https://civicdb.org/links/variants/301 https://civicdb.org/links/genes/4645 false PTCH1 5727 LOH Medulloblastoma 0050902 Vismodegib Predictive Supports B Sensitivity/Response Loss-of-heterozygosity in SHH-driven medulloblastoma was associated with increased PFS under therapy with vismodegib (AKA HhAntag691, GDC0449, GDC-0449). 43 patients total were enrolled for this study. 26169613 PubMed Robinson et al., 2015, J. Clin. Oncol. NCT00939484,NCT01239316 2 accepted 749 302 4645 9 98205262 98270943 ENST00000331920.6 75 GRCh37 Somatic 2020-11-20 16:16:34 UTC https://civicdb.org/links/evidence_items/749 https://civicdb.org/links/variants/302 https://civicdb.org/links/genes/4645 false STK11 6794 EXON 1-2 MUTATION Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome In a retrospective analysis of 567 non-squamous, non-small cell lung cancer patients, Exon 1-2 mutations in STK11 were significantly associated with shorter OS (24 vs. 69 months) also after multivariate analysis. Results were validated in public datasets. 26625312 PubMed Pécuchet et al., 2015, Oncotarget 4 accepted 750 303 5534 19 1205740 1218499 ENST00000326873.7 75 GRCh37 Somatic 2015-12-28 23:25:20 UTC https://civicdb.org/links/evidence_items/750 https://civicdb.org/links/variants/303 https://civicdb.org/links/genes/5534 false STK11 6794 Underexpression Prostate Cancer 10283 SB202190 Predictive Supports D Sensitivity/Response STK11-deficient cells were sensitive to treatment with MAPK11 inhibitor SB202190. 26391455 PubMed Grossi et al., 2015, Autophagy 2 accepted 751 304 5534 19 1205740 1228428 ENST00000326873.7 75 GRCh37 Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/751 https://civicdb.org/links/variants/304 https://civicdb.org/links/genes/5534 false SYK 6850 OVEREXPRESSION Ovarian Cancer 2394 Paclitaxel Predictive Supports D Resistance Overexpression and high p-SYK/SYK ratio were associated with resistance to paclitaxel. Inhibition of SYK with R406 resensitized cell lines to paclitaxel. 26096845 PubMed Yu et al., 2015, Cancer Cell 3 accepted 752 305 5572 9 93564069 93660831 ENST00000375754.4 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/752 https://civicdb.org/links/variants/305 https://civicdb.org/links/genes/5572 false CDKN2A 1029 p16 Expression Head And Neck Squamous Cell Carcinoma 5520 Panitumumab Predictive Supports B Sensitivity/Response p16-negative patients (HPV negative) have a longer overall survival under panitumumab/chemotherapy in comparison to chemotherapy alone. 23746666 PubMed Vermorken et al., 2013, Lancet Oncol. NCT00460265 3 accepted 753 272 14 9 21968055 21974865 ENST00000498124.1 75 GRCh37 CDKN2A (p16) expression is a surrogate marker of HPV infection in oropharyngeal squamous cell carcinoma. CDKN2A and p53 are inactivated through HPV proteins E6 and E7 and therefore not altered in expression level in HPV-associated carcinomas. However, there is no perfect overlap between p16 expression and HPV status with some 10-12.5% of HPV-negative tumors expressing p16. (Seiwert, T JCO, 2014). p16 positivity is a well-established positive prognostic factor in squamous cell cancer of the head and neck in the primary and, as increasing evidence suggests, recurrent/metastatic disease settings. Predictive information from HPV status have not been established to date. A lack of benefit from EGFR-inhibitors has been proposed by some studies. Other studies were not able to reproduce this finding. Somatic 2015-12-29 18:04:18 UTC https://civicdb.org/links/evidence_items/753 https://civicdb.org/links/variants/272 https://civicdb.org/links/genes/14 false PRKACA 5566 DNAJB1::PRKACA Fibrolamellar Carcinoma 5015 Diagnostic Supports B Positive The DNAJB1-PRKACA fusion was detected in 79% (58/73) of fibrolamellar hepatocellular carcinomas assayed. 25557953 PubMed Cornella et al., 2015, Gastroenterology 4 accepted 754 31 17 19 14628951 14629232 ENST00000254322.2 19 14202500 14218221 ENST00000308677.4 75 GRCh37 This fusion has been found to be very recurrent in the rare form of adolescent liver cancer, fibrolamellar hepatocellular carcinoma. In one study, this fusion was observed in 15/15 FL-HCC cases examined and functional studies found that the fusion retained kinase activity. The presence of this fusion may be used as a diagnostic marker for this rare tumor type. Somatic 2015-12-30 04:33:34 UTC https://civicdb.org/links/evidence_items/754 https://civicdb.org/links/variants/31 https://civicdb.org/links/genes/17 false SMO 6608 D473H Basal Cell Carcinoma 2513 Vismodegib Predictive Supports D Resistance D473 mutations were identified in 5/30 resistant basal cell carcinomas. Crystal structure indicated this mutation interacts with a water molecule in the ligand binding pocket, putatively altering its interaction with the SMO inhibitor vismodegib. SMO-/- mouse embryonic fibroblasts expressing the SMO D473G mutant maintained hedgehog signaling in the presence of the drug and had IC50 values >40 fold higher than cells expressing wildtype SMO. 25759020 PubMed Atwood et al., 2015, Cancer Cell 3 accepted 755 299 5365 7 128849189 128849189 G C ENST00000249373.3 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/755 https://civicdb.org/links/variants/299 https://civicdb.org/links/genes/5365 false PIK3CA 5290 Amplification Epithelial Ovarian Cancer 2152 Pictilisib Predictive Supports C Sensitivity/Response One platinum-refractory epithelial ovarian cancer patient with PTEN loss and PIK3CA amplification had a partial response on treatment with PI3K inhibitor pictilisib (GDC-0941) in this phase 1 study. A total of 60 patients with advanced solid tumors were enrolled in this study. 25370471 PubMed Sarker et al., 2015, Clin. Cancer Res. 2 accepted 756 212 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/756 https://civicdb.org/links/variants/212 https://civicdb.org/links/genes/37 false BRAF 673 V600E Melanoma 1909 Pictilisib Predictive Supports C Sensitivity/Response One patient with BRAF V600E mutated melanoma (with no detected PI3K pathway deregulation) had a partial response on treatment with pictilisib, a PI3K inhibitor, for 9.5 months. Study was a phase-1 with 60 patients enrolled. 25370471 PubMed Sarker et al., 2015, Clin. Cancer Res. 2 accepted 757 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/757 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false CDKN2A 1029 p16 Expression Oropharynx Cancer 8557 Prognostic Supports A Better Outcome 720 patients with stage III/IV oropharyngeal cancer were retrospectively analyzed for p16 and HPV status. p16 and HPV-positivity correlated well and both showed improved overall-survival compared to patients with HPV-negative/p16 negative tumors. HPV/p16 status was shown to be a strong and independent risk factor in oropharyngeal carcinoma. 20530316 PubMed Ang et al., 2010, N. Engl. J. Med. NCT00047008 4 accepted 758 272 14 9 21968055 21974865 ENST00000498124.1 75 GRCh37 CDKN2A (p16) expression is a surrogate marker of HPV infection in oropharyngeal squamous cell carcinoma. CDKN2A and p53 are inactivated through HPV proteins E6 and E7 and therefore not altered in expression level in HPV-associated carcinomas. However, there is no perfect overlap between p16 expression and HPV status with some 10-12.5% of HPV-negative tumors expressing p16. (Seiwert, T JCO, 2014). p16 positivity is a well-established positive prognostic factor in squamous cell cancer of the head and neck in the primary and, as increasing evidence suggests, recurrent/metastatic disease settings. Predictive information from HPV status have not been established to date. A lack of benefit from EGFR-inhibitors has been proposed by some studies. Other studies were not able to reproduce this finding. N/A 2020-10-30 07:16:00 UTC https://civicdb.org/links/evidence_items/758 https://civicdb.org/links/variants/272 https://civicdb.org/links/genes/14 false CDKN2A 1029 p16 Expression Oropharynx Cancer 8557 Cetuximab Predictive Does Not Support B Resistance This study shows that benefit of EGFR inhibition in addition to radiotherapy was independent of p16/HPV status. 182 patients were evaluated. 26712222 PubMed Rosenthal et al., 2016, J. Clin. Oncol. 4 accepted 759 272 14 9 21968055 21974865 ENST00000498124.1 75 GRCh37 CDKN2A (p16) expression is a surrogate marker of HPV infection in oropharyngeal squamous cell carcinoma. CDKN2A and p53 are inactivated through HPV proteins E6 and E7 and therefore not altered in expression level in HPV-associated carcinomas. However, there is no perfect overlap between p16 expression and HPV status with some 10-12.5% of HPV-negative tumors expressing p16. (Seiwert, T JCO, 2014). p16 positivity is a well-established positive prognostic factor in squamous cell cancer of the head and neck in the primary and, as increasing evidence suggests, recurrent/metastatic disease settings. Predictive information from HPV status have not been established to date. A lack of benefit from EGFR-inhibitors has been proposed by some studies. Other studies were not able to reproduce this finding. N/A 2020-10-30 07:16:25 UTC https://civicdb.org/links/evidence_items/759 https://civicdb.org/links/variants/272 https://civicdb.org/links/genes/14 false ERBB2 2064 Amplification Breast Cancer 1612 AKTi-1/2 Predictive Supports D Sensitivity/Response Xenografts established from breast cancer cell lines with ERBB2 amplification and PIK3CA mutation (BT474) or PIK3CA mutation alone (MCF7) were effectively inhibited in-vivo with an AKT1/2-inhibitor (AKTi-1/2; naphthyridinone). 18725974 PubMed She et al., 2008, PLoS ONE 3 accepted 760 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-10-06 18:38:50 UTC https://civicdb.org/links/evidence_items/760 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Neratinib Predictive Supports B Sensitivity/Response Oral neratinib showed objective response rates of 24 and 56% respectively in prior-trastuzumab (n=63) and trastuzumab-naive (n=64) cohorts in a Phase II trial. As for the primary endpoint, the 16-week progression free survival was 59% in the prior-trastuzumab + neratibin patients and 78% in the trastuzumab-naive + neratinib patients. Overall, neratinib treatment results in substantial clinical activity and is well tolerated by patients. 20142587 PubMed Burstein et al., 2010, J. Clin. Oncol. 3 accepted 761 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2021-04-14 21:53:54 UTC https://civicdb.org/links/evidence_items/761 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Rociletinib Predictive Supports D Sensitivity/Response CO-1686 (Rociletinib) more effectively induced apoptosis in EGFR mutated (T790M and others) NSCLC cell lines than those harboring wildtype EGFR. CO-1686 also more effectively reduced tumor volume of mouse xenografts harboring the T790M than those with wildtype EGFR. 24065731 PubMed Walter et al., 2013, Cancer Discov 3 accepted 762 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/762 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false ALK 238 EML4::ALK L1152R Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Resistance Case-report of a patient with an acquired ALK L1152R mutation and resistance to crizotinib treatment. A cell line model also showed resistance against ALK inhibition. 21791641 PubMed Sasaki et al., 2011, Cancer Res. 4 accepted 763 307 1 2 29445270 29445270 A C ENST00000389048.3 75 GRCh37 Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/763 https://civicdb.org/links/variants/307 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK G1269A Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Resistance This study analyzed patients with non small cell lung cancer (NSCLC) who were positive for EML4-ALK fusions (ALK+) and progressed on crizotinib monotherapy. One ALK+ patient harbored the common E6;A20 fusion with ALK G1269A co-mutation in post-crizotinib progression biopsies. The presence of ALK G1269A pre-crizotinib could not be evaluated. This patient was a 21 year old non-smoking male with adenocarcinoma, wt for KRAS and EGFR, negative for ALK copy number gain, who experienced crizotinib as a 2nd line therapy. The patient's best response on crizotinib was stable disease (377 days on treatment). In vitro, Ba/F3 cell line expressing EML4-ALK fusion (E6a;A20, a known sensitizing alteration) and ALK G1269A co-mutation demonstrated resistance to crizotinib treatment (341 nmol/L vs. 22 nmol/L) compared to Ba/F3 cells expressing EML4-ALK fusion. Resistance was determined by assessing cell viability and colony formation. Levels of phosphorylation of ALK, ERK, STAT3, and AKT were higher in ALK+ G1269A mutant cells than ALK+ controls, by western blot. The authors note that ALK G1269A likely induces resistance by preventing crizotinib from accessing its binding pocket in the ALK kinase domain. 22235099 PubMed Doebele et al., 2012, Clin. Cancer Res. 4 accepted 764 308 1 2 29432682 29432682 C G ENST00000389048.3 75 GRCh37 The EML4-ALK G1269A mutation has been identified in non-small cell lung cancer patients resistant to crizotinib. Cell line data from multiple groups have shown this mutation enhances resistance to crizotinib treatment in vitro. Somatic 2021-04-27 16:26:57 UTC https://civicdb.org/links/evidence_items/764 https://civicdb.org/links/variants/308 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK G1269A Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Resistance 2 out of 7 patients with an acquired resistance to crizotinib had a G1269A mutation. One of these patients also harbored a L1196M mutation. In vitro follow-up showed reduced crizotinib-induced ALK dephosphorylation (293T) and apoptosis (Ba/F3) when EML4-ALK G1269A overexpression was compared to EML4-ALK overexpression in these cell lines. 23344087 PubMed Kim et al., 2013, J Thorac Oncol 3 accepted 765 308 1 2 29432682 29432682 C G ENST00000389048.3 75 GRCh37 The EML4-ALK G1269A mutation has been identified in non-small cell lung cancer patients resistant to crizotinib. Cell line data from multiple groups have shown this mutation enhances resistance to crizotinib treatment in vitro. Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/765 https://civicdb.org/links/variants/308 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK and Amplification Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Resistance This study analyzed patients with non small cell lung cancer (NSCLC) who were positive for EML4-ALK fusions (ALK+) and progressed on crizotinib monotherapy. One out of 11 patients with acquired crizotinib resistance showed >4-fold increase in rearranged ALK copy number between pre- and post- crizotinib biopsies as measured by FISH. This patient's tumor did not harbor ALK point mutations, and was wt for KRAS and EGFR. This patient was a 51 year old non-smoking male with adenocarcinoma, whose best response was partial response (454 days on crizotinib, 2 prior lines of therapy). The authors suggest that ALK copy number gain alone may induce crizotinib resistance. 22235099 PubMed Doebele et al., 2012, Clin. Cancer Res. 3 accepted 766 170 1 2 42396490 42528380 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Somatic 2021-10-08 18:52:43 UTC https://civicdb.org/links/evidence_items/766 https://civicdb.org/links/variants/170 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK and Amplification Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Resistance One patient with ALK-rearranged non-small cell lung cancer and an acquired resistance to crizotinib showed new ALK amplification (4.1 fold increase compared to pre-crizotinib specimen as measured by FISH) and harbored an EGFR L858R mutation. 23344087 PubMed Kim et al., 2013, J Thorac Oncol 2 accepted 767 170 1 2 42396490 42528380 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Somatic 2016-02-18 22:18:28 UTC https://civicdb.org/links/evidence_items/767 https://civicdb.org/links/variants/170 https://civicdb.org/links/genes/1 false ERBB4 2066 Mutation Melanoma 1909 Lapatinib Predictive Supports D Sensitivity/Response ERBB4 was the most commonly mutated protein tyrosine kinase in this study in melanoma (19% in 79 patients). Seven of the identified mutations in ERBB4 (E317K, E452K, E542K, R544W, E563K, E836K and E872K) were transforming and activating in-vitro. ERBB4 inhibition with shRNA or lapatinib led to reduced cell growth. 19718025 PubMed Prickett et al., 2009, Nat. Genet. 4 accepted 770 310 1734 2 212295697 212578308 ENST00000342788.4 75 GRCh37 ERBB4 mutations have been identified in melanoma, lung adenocarcinoma and medulloblastoma. In-vitro studies suggest that melanoma cell lines harboring an ERBB4 mutation are sensitive to ERBB4 inhibition with lapatinib. Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/770 https://civicdb.org/links/variants/310 https://civicdb.org/links/genes/1734 false PIK3CA 5290 Mutation Colorectal Cancer 9256 Cabozantinib Predictive Supports D Sensitivity/Response 20 patient-derived colorectal cancer xenografts were treated with cabozantinib, a c-MET and VEGFR2 inhibitor. 16 xenografts showed sensitivity (as defined by TGII: tumor growth of treated compared to control ≤ 20%). Among the genes tested for mutations (KRAS, TP53, PIK3CA, MET, VEGFR2, RET and AXL), PIK3CA mutations (4 PDTX) showed a significant enrichment in sensitive xenografts. PIK3CA mutations were observed in 4/5 of the most responsive tumors. Treating xenografts derived from isogenic PIK3CA wildtype or mutant cell lines corroborated this finding with PIK3CA mutant xenografts showing greater sensitivity to cabozantinib. 25242168 PubMed Song et al., 2015, Int. J. Cancer 3 accepted 771 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-02-22 20:32:23 UTC https://civicdb.org/links/evidence_items/771 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false EGFR 1956 VIII Glioblastoma 3068 Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Predictive Supports B Sensitivity/Response 49 patients (26 pretreatment tissues available for analysis) with recurrent glioblastomas who were treated with EGFR TKIs were analyzed in this study. Results were confirmed in an independent cohort of 33 patients. EGFRvIII and PTEN coexpression were associated with responsiveness to EGFR TKI. 16282176 PubMed Mellinghoff et al., 2005, N. Engl. J. Med. 4 accepted 772 312 19 7 55087058 55223523 ENST00000275493.2 75 GRCh37 The EGFRvIII variant is an oncogenic mutation that has been reported in several cancers including glioblastoma multiforme, breast, lung, head and neck, ovarian and prostate. In high-grade gliomas, EGFRvIII has been reported in about 30% of cases with EGFR amplification. The EGFRvIII mutation leads to deletion of the receptor ectodomain exons 2-7. The presence of this variant has been linked with clinical response to EGFR TKI. (Arteaga and Engelmann, 2014) Somatic 2016-02-03 17:26:05 UTC https://civicdb.org/links/evidence_items/772 https://civicdb.org/links/variants/312 https://civicdb.org/links/genes/19 false EGFR 1956 VIII Glioblastoma 3068 Afatinib Predictive Supports C Sensitivity/Response Case report of a 58-year old patient with disease progression after radiotherapy and three temozolomide cycles. Afatinib and temozolomide led to disease regression. At last assessment 63 treatment cycles had been completed and the patient had survived for about 5 years since recurrence. Identified EGFR aberrations included EGFRvIII positivity, EGFR gene amplification and three somatic EGFR mutations. 26423602 PubMed Alshami et al., 2015, Oncotarget 2 accepted 773 312 19 7 55087058 55223523 ENST00000275493.2 75 GRCh37 The EGFRvIII variant is an oncogenic mutation that has been reported in several cancers including glioblastoma multiforme, breast, lung, head and neck, ovarian and prostate. In high-grade gliomas, EGFRvIII has been reported in about 30% of cases with EGFR amplification. The EGFRvIII mutation leads to deletion of the receptor ectodomain exons 2-7. The presence of this variant has been linked with clinical response to EGFR TKI. (Arteaga and Engelmann, 2014) Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/773 https://civicdb.org/links/variants/312 https://civicdb.org/links/genes/19 false PTEN 5728 Expression Glioblastoma 3068 Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Predictive Supports B Sensitivity/Response 49 patients (26 pretreatment tissues available for analysis) with recurrent glioblastomas who were treated with EGFR TKIs were analyzed in this study. Results were confirmed in an independent cohort of 33 patients. EGFRvIII and PTEN coexpression were associated with responsiveness to EGFR TKI. 16282176 PubMed Mellinghoff et al., 2005, N. Engl. J. Med. 4 accepted 774 313 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 N/A 2020-10-20 06:09:21 UTC https://civicdb.org/links/evidence_items/774 https://civicdb.org/links/variants/313 https://civicdb.org/links/genes/41 false PTEN 5728 Expression Glioblastoma 3068 Dacomitinib Predictive Supports D Sensitivity/Response In this preclinical study, the EGFR inhibitor dacomitinib had an effect on cell viability, self-renewal and proliferation in EGFR amplified GBM cells in-vitro and in-vivo (with or without the EGFRvIII mutation). It was less effective in one cell-line with PTEN deletion. 25939761 PubMed Zahonero et al., 2015, Mol. Cancer Ther. 2 accepted 775 313 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 N/A 2020-10-20 06:09:07 UTC https://civicdb.org/links/evidence_items/775 https://civicdb.org/links/variants/313 https://civicdb.org/links/genes/41 false NRG1 3084 Expression Head And Neck Squamous Cell Carcinoma 5520 Lapatinib Predictive Supports D Sensitivity/Response In non-HER2 amplified cell lines, sensitivity to HER2 kinase inhibitor lapatinib was found mainly in cell-lines with elevated NRG1 expression and HER3 activation. This aberration was mainly identified in head and neck cancer cell lines. 21840482 PubMed Wilson et al., 2011, Cancer Cell 4 accepted 776 314 2593 8 31497942 32622294 ENST00000523534.1 75 GRCh37 N/A 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/776 https://civicdb.org/links/variants/314 https://civicdb.org/links/genes/2593 false NRG1 3084 Expression Colorectal Cancer 9256 Cetuximab Predictive Supports D Resistance NRG1 upregulation or ERBB2 amplification were the main causes of resistance to cetuximab in-vivo and in-vitro in this study. Inhibition of ERBB2/ERBB3 signaling restored cetuximab sensitivity. 21900593 PubMed Yonesaka et al., 2011, Sci Transl Med 4 accepted 777 314 2593 8 31497942 32622294 ENST00000523534.1 75 GRCh37 N/A 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/777 https://civicdb.org/links/variants/314 https://civicdb.org/links/genes/2593 false NRG1 3084 Expression Ovarian Cancer 2394 Seribantumab Predictive Supports D Sensitivity/Response An NRG1-ERBB3 autocrine signal-transducing loop was identified in a subset of ovarian cancers and cell lines. Disruption of this loop led to decreased cell-growth in-vitro and prolonged survival in-vivo. An ERBB3 directed antibody (MM-121) inhibited tumor-growth in-vivo. 20227043 PubMed Sheng et al., 2010, Cancer Cell 3 accepted 778 314 2593 8 31497942 32622294 ENST00000523534.1 75 GRCh37 N/A 2016-02-20 23:29:34 UTC https://civicdb.org/links/evidence_items/778 https://civicdb.org/links/variants/314 https://civicdb.org/links/genes/2593 false NRG1 3084 Expression Lung Non-small Cell Carcinoma 3908 Gemcitabine,Carboplatin,Paclitaxel,Cisplatin Substitutes Predictive Supports D Sensitivity/Response In-vivo studies of residual NSCLC tumors (xenografts of 5 cell lines) after chemotherapy found increased EGFR-family signaling and NRG1 expression. NRG1 inhibition (YW538.24.71 antibody) led to decreased tumor growth and enhanced magnitude and response to chemotherapy. 23390248 PubMed Hegde et al., 2013, Sci Transl Med 3 accepted 779 314 2593 8 31497942 32622294 ENST00000523534.1 75 GRCh37 N/A 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/779 https://civicdb.org/links/variants/314 https://civicdb.org/links/genes/2593 false AREG 374 Expression Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports D Resistance A cell line (DFCI076) with EML1-ALK fusion and resistance mutation L1152R showed no response to ALK inhibition with crizotinib or TAE684. There was co-dependancy on AKT and EGFR-signaling and inhibition of both pathways led to decreased cell-growth. Amphiregulin (AREG) production was identified as a potential mediator of EGFR-activation (no other alterations detectable). The same mechanism could be reproduced in a cell line (H3122) without EML1-ALK mutation and resistance to crizotinib that was acquired in-vitro. 21791641 PubMed Sasaki et al., 2011, Cancer Res. 3 accepted 780 315 389 4 75310851 75320726 ENST00000395748.3 75 GRCh37 N/A 2016-02-20 23:27:44 UTC https://civicdb.org/links/evidence_items/780 https://civicdb.org/links/variants/315 https://civicdb.org/links/genes/389 false AREG 374 Expression Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports B Resistance Five patients with acquired resistance to crizotinib showed high concentration of amphiregulin in malignant pleural effusions. 23344087 PubMed Kim et al., 2013, J Thorac Oncol 2 accepted 781 315 389 4 75310851 75320726 ENST00000395748.3 75 GRCh37 N/A 2016-02-08 19:41:26 UTC https://civicdb.org/links/evidence_items/781 https://civicdb.org/links/variants/315 https://civicdb.org/links/genes/389 false EGFR 1956 Overexpression Head And Neck Squamous Cell Carcinoma 5520 Prognostic Supports B Poor Outcome Primary tumors of 91 patients with head and neck squamous cell carcinoma were analyzed for expression of EGFR and TGF-alpha using IHC. Expression of EGFR or TGF-alpha were associated with reduced disease-free and cause-specific survival. 9625170 PubMed Rubin Grandis et al., 1998, J. Natl. Cancer Inst. 3 accepted 782 193 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 N/A 2016-07-26 14:48:43 UTC https://civicdb.org/links/evidence_items/782 https://civicdb.org/links/variants/193 https://civicdb.org/links/genes/19 false EGFR 1956 Overexpression Esophagus Squamous Cell Carcinoma 3748 Nimotuzumab Predictive Does Not Support B Sensitivity/Response 55 tumor samples were analyzed for EGFR expression using IHC. The objective response rate to anti-EGFR antibody nimotuzumab did not differ significantly between EGFR high- (18 pts) and EGFR low to moderate groups (37 pts). 26459251 PubMed Jia et al., 2016, Clin Transl Oncol 3 accepted 783 193 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 N/A 2020-10-20 06:03:43 UTC https://civicdb.org/links/evidence_items/783 https://civicdb.org/links/variants/193 https://civicdb.org/links/genes/19 false EGFR 1956 Overexpression Esophagus Squamous Cell Carcinoma 3748 Prognostic Supports B Poor Outcome 55 tumor samples were analyzed for EGFR expression using IHC. PFS and OS was shorter for the EGFR high expressing group (18 pts) than for the low to moderate expression group (37 pts). PFS: 5.8 ± 0.5 vs. 11.0 ± 2.8 months, P = 0.007; OS: 9.7 ± 0.5 vs. 21.5 ± 1.5 months, P = 0.03. 26459251 PubMed Jia et al., 2016, Clin Transl Oncol 3 accepted 784 193 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 N/A 2016-07-26 14:49:02 UTC https://civicdb.org/links/evidence_items/784 https://civicdb.org/links/variants/193 https://civicdb.org/links/genes/19 false TGFA 7039 EXPRESSION Head And Neck Squamous Cell Carcinoma 5520 Prognostic Supports B Poor Outcome Primary tumors of 91 patients with head and neck squamous cell carcinoma were analyzed for expression of EGFR and TGF-alpha using IHC. Expression of EGFR or TGF-alpha were associated with reduced disease-free and cause-specific survival. 9625170 PubMed Rubin Grandis et al., 1998, J. Natl. Cancer Inst. 3 accepted 785 316 5742 2 70674412 70781147 ENST00000295400.6 75 GRCh37 Somatic 2016-02-03 20:33:19 UTC https://civicdb.org/links/evidence_items/785 https://civicdb.org/links/variants/316 https://civicdb.org/links/genes/5742 false EGFR 1956 G724S Colorectal Cancer 9256 Cetuximab Predictive Supports D Sensitivity/Response Whole genome sequencing of a case of colon carcinoma revealed a G724S mutation in the EGFR gene. In-vitro, this mutation was shown to be oncogenic and sensitive to Cetuximab, yet relatively insensitive towards small molecules. 24894453 PubMed Cho et al., 2014, Mol. Cancer 4 accepted 786 317 19 7 55241722 55241722 G A ENST00000275493.2 75 GRCh37 Somatic 2016-02-21 16:18:46 UTC https://civicdb.org/links/evidence_items/786 https://civicdb.org/links/variants/317 https://civicdb.org/links/genes/19 false EGFR 1956 G719S Colorectal Cancer 9256 Cetuximab Predictive Supports D Sensitivity/Response Whole genome sequencing of a case of colon carcinoma revealed a G724S mutation in the EGFR gene. In-vitro, this mutation was shown to be oncogenic and sensitive to Cetuximab, yet relatively insensitive towards small molecules. The same in-vitro results could be reproduced for the G719S mutation. 24894453 PubMed Cho et al., 2014, Mol. Cancer 4 accepted 787 134 19 7 55241707 55241707 G A ENST00000275493.2 75 GRCh37 While not as recurrent as the L858R mutation, EGFR G719S has also been shown to be an activating mutation. In lung cancer cell lines, it also confers sensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib. Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/787 https://civicdb.org/links/variants/134 https://civicdb.org/links/genes/19 false AREG 374 Expression Colorectal Cancer 9256 Cetuximab Predictive Supports B Sensitivity/Response 226 cetuximab-treated patients with colorectal cancer (CRC) were analyzed for mRNA expression (by qPCR) of EGFR and its ligands (EGF, TGFA, AREG and EREG). High AREG mRNA expression in KRAS wild type tumours was a favorable predictor in a multivariate analysis (median survival 33 vs. 15 months, p=0.0005). Cetuximab-treated patients with AREG-low KRAS wild type CRC had poor survival, similar to KRAS mutated CRC. 23374602 PubMed Pentheroudakis et al., 2013, BMC Cancer 3 accepted 788 315 389 4 75310851 75320726 ENST00000395748.3 75 GRCh37 N/A 2016-02-17 01:16:43 UTC https://civicdb.org/links/evidence_items/788 https://civicdb.org/links/variants/315 https://civicdb.org/links/genes/389 false EREG 2069 EXPRESSION Colorectal Cancer 9256 Cetuximab Predictive Supports B Sensitivity/Response 226 cetuximab-treated patients with CRC were analyzed for mRNA expression of EGFR and its ligands. Favorable predictors in a multivariate analysis were high AREG mRNA in KRAS wild type tumours, high EREG mRNA and low Ephrin A2 receptor mRNA. 23374602 PubMed Pentheroudakis et al., 2013, BMC Cancer 3 accepted 789 318 1737 4 75230860 75254468 ENST00000244869.2 75 GRCh37 N/A 2016-02-16 15:02:59 UTC https://civicdb.org/links/evidence_items/789 https://civicdb.org/links/variants/318 https://civicdb.org/links/genes/1737 false MAPK1 5594 E322K Head And Neck Squamous Cell Carcinoma 5520 Erlotinib Predictive Supports C Sensitivity/Response Case report of a patient with stage IVA HNSCC with near-complete histologic response after 13 days of neoadjuvant erlotinib. Whole-exome sequencing of the pre-treatment tumor revealed a MAPK1 E322K mutation (allelic fraction 0.13). In-vitro studies in two HNSCC cell lines showed enhanced EGFR phosphorylation and erlotinib sensitivity in the mutant line compared with the wild-type line. 26181029 PubMed Van Allen et al., 2015, JAMA Oncol NCT00779389 4 accepted 791 320 4532 22 22127164 22127164 C T ENST00000215832.6 75 GRCh37 Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/791 https://civicdb.org/links/variants/320 https://civicdb.org/links/genes/4532 false MAPK1 5594 Amplification Lung Non-small Cell Carcinoma 3908 WZ4002 Predictive Supports D Resistance Resistance to WZ4002 was induced in cell lines. Amplification of MAPK1 or downregulation of ERK-pathway inhibitors led to resistance to EGFR inhibition with WZ4002. Chemical inhibition (MEK inhibition with either CI-1040 or GSK1120212) or shRNA knockdown of MAPK1 resensitized cells to EGFR inhibition with WZ4002 in-vitro. Additionally, MAPK1 amplification was identified in 1/21 erlotinib-resistant NSCLC patients. MAPK1 amplification was not observed in the pretreatment tumor, only the post-treatment resistant tumor which lacked other more common drug-resistance mechanisms EGFR T790M or MET amplification. 22961667 PubMed Ercan et al., 2012, Cancer Discov 4 accepted 792 321 4532 22 22108789 22221919 ENST00000215832.6 75 GRCh37 Somatic 2016-02-18 22:08:26 UTC https://civicdb.org/links/evidence_items/792 https://civicdb.org/links/variants/321 https://civicdb.org/links/genes/4532 false FGFR1 2260 Expression Breast Cancer 1612 Prognostic Supports B Poor Outcome FGFR1 expression, was assessed by IHC in 1,086 invasive breast cancers. FGFR1 expression was mainly associated with luminal cancer subtypes. Multivariate Cox regression analysis showed FGFR1 to be an independent poor prognostic marker in luminal A cancers for disease free survival (hazard ratio = 3.341, p = 0.008). In luminal A cancers, FGFR1 expression was also significantly associated with higher pN (lymph node metastases; p = 0.023) and pT (unfavorable tumor characteristics; p = 0.003) stages and lymphovascular invasion (p = 0.010). 26673008 PubMed Shi et al., 2016, Oncotarget 2 accepted 793 268 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 high expression has been reported in 11.8% (178 patients) of oral squamous cell carcinoma patients, and was enriched in early stages (Freier et. al., 2007). Another study reports FGFR1 expression in 35% of primary HNSSC (353 patients) (Göke et. al., 2015). In both studies, FGFR1 gene amplification and expression do not correlate well with about 35% of samples with FGFR1 amplification overexpressing FGFR1 (Göke et. al., 2015). FGFR1 expression also correlated with sensitivity to FGFR1 inhibitors in preclinical models of lung cancer (Wynes et. al., 2014), HNSSC (Göke et. al., 2015) and urothelial carcinoma (Lamont et. al., 2011). N/A 2020-11-24 20:28:27 UTC https://civicdb.org/links/evidence_items/793 https://civicdb.org/links/variants/268 https://civicdb.org/links/genes/1885 false KRAS 3845 A146V Lung Non-small Cell Carcinoma 3908 Abemaciclib Predictive Supports C Sensitivity/Response Case report of a patient with metastatic lung adenocarcinoma. Whole exome sequencing of the metastatic tumor revealed KRAS A146V, STK11 frameshift deletion and ATM alteration. Preclinical evidence led to administration of CDK4 inhibitor LY2835219. Specifically, the PHIAL algorithm nominated this variant as actionable on the basis of a predicted synthetic lethal relationship between activated KRAS and CDK4. The patient achieved stable disease and was on treatment for 16 weeks which was the patients best and only clinical response to any cancer-directed therapy. 24836576 PubMed Van Allen et al., 2014, Nat. Med. 2 accepted 794 322 30 12 25378561 25378561 G A ENST00000256078.4 75 GRCh37 Somatic 2016-02-22 20:30:50 UTC https://civicdb.org/links/evidence_items/794 https://civicdb.org/links/variants/322 https://civicdb.org/links/genes/30 false KRAS 3845 G12V Lung Non-small Cell Carcinoma 3908 Palbociclib Predictive Supports D Sensitivity/Response In vivo studies confirmed the activity of PD0332991 (CDK4 inhibitor) on KRAS G12V mutant tumors. 17% (2/12) of mice treated with PD0332991 developed detectable lesions, whereas 75% of mice (3/4) treated with vehicle developed lesions at the end of the treatment. 20609353 PubMed Puyol et al., 2010, Cancer Cell 1 accepted 795 425 30 12 25398284 25398284 C A ENST00000256078.4 75 GRCh37 KRAS mutations are the most common mutations in pancreatic cancer occurring in > 90% of cases. Of these the G12D activating mutation is the most prevalent and results in a loss of GTPase activity which in turn leads to a constitutively active form of KRAS. This is enough to cause pre-cancerous pancreatic intraepithelial lesions Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/795 https://civicdb.org/links/variants/425 https://civicdb.org/links/genes/30 false MET 4233 Mutation Papillary Renal Cell Carcinoma 4465 Foretinib Predictive Supports B Sensitivity/Response In a retrospective analysis of 74 patients with papillary renal cell carcinoma, treated with foretinib, MET germline mutation was associated with improved response rate. A response was observed in 5 of 10 (50%) vs. 5 of 57 (8.8%) patients with and without germline MET mutations, respectively. 23213094 PubMed Choueiri et al., 2013, J. Clin. Oncol. NCT00726323 3 accepted 796 323 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 Rare Germline 2016-02-13 05:14:18 UTC https://civicdb.org/links/evidence_items/796 https://civicdb.org/links/variants/323 https://civicdb.org/links/genes/52 false MET 4233 EXON 14 SKIPPING MUTATION Lung Adenocarcinoma 3910 Crizotinib Predictive Supports C Sensitivity/Response We now report responses to the MET inhibitors crizotinib and cabozantinib in four patients with stage IV lung adenocarcinomas harboring mutations leading to MET exon 14 skipping. 25971939 PubMed Paik et al., 2015, Cancer Discov 3 accepted 797 324 52 7 116411903 116412043 ENST00000318493.6 75 GRCh37 Exon 14 mutations have been observed in ~3% of patients with NSCLC (28/933 reported by Awad et al J Clin Onc 2016), confirmed to cause exon skipping when available, and associated with concurrent MET amplification. Responses to the c-MET inhibitor crizotinib have been reported in preclinical models and in individual case reports as well as a small-scale clinical trial (17 patients treated, Drilon et al., 2016 (suppl; abstr 108; ASCO ID 167889-176)). Larger studies are needed but enrollment of patients with MET exon 14 skipping mutation in trials with MET inhibitors or off-label treatment is encouraged (Paik et al., 2015 (suppl; abstr 8021)). Somatic 2020-08-12 15:43:09 UTC https://civicdb.org/links/evidence_items/797 https://civicdb.org/links/variants/324 https://civicdb.org/links/genes/52 false FGFR1 2260 Expression Head And Neck Squamous Cell Carcinoma 5520 Prognostic Does Not Support B Poor Outcome This review identified 12 studies that addressed the prognostic role of FGFRs in HNSSC. Evidence was found for the expression of FGFR1 in cancer-associated fibroblasts, other results were conflicting. Significant risk of bias was reported for the included studies. 26115874 PubMed Ipenburg et al., 2016, Target Oncol 2 accepted 798 268 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 high expression has been reported in 11.8% (178 patients) of oral squamous cell carcinoma patients, and was enriched in early stages (Freier et. al., 2007). Another study reports FGFR1 expression in 35% of primary HNSSC (353 patients) (Göke et. al., 2015). In both studies, FGFR1 gene amplification and expression do not correlate well with about 35% of samples with FGFR1 amplification overexpressing FGFR1 (Göke et. al., 2015). FGFR1 expression also correlated with sensitivity to FGFR1 inhibitors in preclinical models of lung cancer (Wynes et. al., 2014), HNSSC (Göke et. al., 2015) and urothelial carcinoma (Lamont et. al., 2011). N/A 2020-11-24 20:28:57 UTC https://civicdb.org/links/evidence_items/798 https://civicdb.org/links/variants/268 https://civicdb.org/links/genes/1885 false FGFR1 2260 Expression Head And Neck Squamous Cell Carcinoma 5520 Infigratinib Predictive Supports D Sensitivity/Response FGFR1 mRNA expression, rather than copy number alterations, were predictive of response to FGFR inhibitor BGJ398 in cell lines and patient derived xenografts. 26015511 PubMed Göke et al., 2015, Clin. Cancer Res. 3 accepted 799 268 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 high expression has been reported in 11.8% (178 patients) of oral squamous cell carcinoma patients, and was enriched in early stages (Freier et. al., 2007). Another study reports FGFR1 expression in 35% of primary HNSSC (353 patients) (Göke et. al., 2015). In both studies, FGFR1 gene amplification and expression do not correlate well with about 35% of samples with FGFR1 amplification overexpressing FGFR1 (Göke et. al., 2015). FGFR1 expression also correlated with sensitivity to FGFR1 inhibitors in preclinical models of lung cancer (Wynes et. al., 2014), HNSSC (Göke et. al., 2015) and urothelial carcinoma (Lamont et. al., 2011). N/A 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/799 https://civicdb.org/links/variants/268 https://civicdb.org/links/genes/1885 false FGFR1 2260 Expression Gastric Adenocarcinoma 3717 Infigratinib Predictive Supports D Sensitivity/Response FGFR inhibitor BGJ398 was most effective in a gastric cancer cell line model with high expression of FGFR1 and FGFR2IIIc. 26637881 PubMed Schmidt et al., 2015, Anticancer Res. 2 accepted 800 268 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 high expression has been reported in 11.8% (178 patients) of oral squamous cell carcinoma patients, and was enriched in early stages (Freier et. al., 2007). Another study reports FGFR1 expression in 35% of primary HNSSC (353 patients) (Göke et. al., 2015). In both studies, FGFR1 gene amplification and expression do not correlate well with about 35% of samples with FGFR1 amplification overexpressing FGFR1 (Göke et. al., 2015). FGFR1 expression also correlated with sensitivity to FGFR1 inhibitors in preclinical models of lung cancer (Wynes et. al., 2014), HNSSC (Göke et. al., 2015) and urothelial carcinoma (Lamont et. al., 2011). N/A 2016-02-21 17:44:14 UTC https://civicdb.org/links/evidence_items/800 https://civicdb.org/links/variants/268 https://civicdb.org/links/genes/1885 false FGFR1 2260 Expression Bladder Carcinoma 4007 Dovitinib,PD173074 Substitutes Predictive Supports D Sensitivity/Response One urothelial cell line (JMSU1) with high expression of FGFR1 was sensitive to treatment with FGFR inhibitors (SU5402, TKI258 or PD173074). IC50 values for PD173074 and TKI-258 (Dovitinib) were in nanomolar range compared with micromolar concentration for SU5402. 21119661 PubMed Lamont et al., 2011, Br. J. Cancer 2 accepted 801 268 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 high expression has been reported in 11.8% (178 patients) of oral squamous cell carcinoma patients, and was enriched in early stages (Freier et. al., 2007). Another study reports FGFR1 expression in 35% of primary HNSSC (353 patients) (Göke et. al., 2015). In both studies, FGFR1 gene amplification and expression do not correlate well with about 35% of samples with FGFR1 amplification overexpressing FGFR1 (Göke et. al., 2015). FGFR1 expression also correlated with sensitivity to FGFR1 inhibitors in preclinical models of lung cancer (Wynes et. al., 2014), HNSSC (Göke et. al., 2015) and urothelial carcinoma (Lamont et. al., 2011). N/A 2019-08-23 14:34:47 UTC https://civicdb.org/links/evidence_items/801 https://civicdb.org/links/variants/268 https://civicdb.org/links/genes/1885 false FGFR3 2261 Overexpression Bladder Carcinoma 4007 Tyrosine Kinase Inhibitor SU5402,Dovitinib,PD173074 Substitutes Predictive Supports D Sensitivity/Response The effects of FGFR inhibitors (PD173074, TKI-258 and SU5402) in bladder carcinoma cell lines were related to FGFR3 (and/or FGFR1) expression. 21119661 PubMed Lamont et al., 2011, Br. J. Cancer 3 accepted 803 325 23 4 1795039 1810599 ENST00000440486.2 75 GRCh37 N/A 2016-02-21 16:30:44 UTC https://civicdb.org/links/evidence_items/803 https://civicdb.org/links/variants/325 https://civicdb.org/links/genes/23 false CDKN2A 1029 p16 Expression Head And Neck Squamous Cell Carcinoma 5520 Prognostic Supports B Better Outcome Patients from three studies (RTOG 0129, 0234, and 0522; 85, 95 and 142 patients, respectively) were retrospectively analyzed for p16 (CDKN2A) expression (IHC) and HPV-high risk status (ISH). p16 expression in non-oropharyngeal HNSSC was also prognostic and associated with a better outcome. However, p16-positive oropharyngeal HNSSC still had better PFS and OS than p16-positive non-oropharyngeal HNSSC. 25267748 PubMed Chung et al., 2014, J. Clin. Oncol. 3 accepted 804 272 14 9 21968055 21974865 ENST00000498124.1 75 GRCh37 CDKN2A (p16) expression is a surrogate marker of HPV infection in oropharyngeal squamous cell carcinoma. CDKN2A and p53 are inactivated through HPV proteins E6 and E7 and therefore not altered in expression level in HPV-associated carcinomas. However, there is no perfect overlap between p16 expression and HPV status with some 10-12.5% of HPV-negative tumors expressing p16. (Seiwert, T JCO, 2014). p16 positivity is a well-established positive prognostic factor in squamous cell cancer of the head and neck in the primary and, as increasing evidence suggests, recurrent/metastatic disease settings. Predictive information from HPV status have not been established to date. A lack of benefit from EGFR-inhibitors has been proposed by some studies. Other studies were not able to reproduce this finding. N/A 2020-10-30 07:17:05 UTC https://civicdb.org/links/evidence_items/804 https://civicdb.org/links/variants/272 https://civicdb.org/links/genes/14 false CBLC 23624 EXPRESSION Cancer 162 Olaparib Predictive Supports D Resistance The E3 ubiquitin ligase, CBLC, was identified as a candidate biomarker for olaparib sensitivity in a siRNA screen and further validated in-vitro. In other words, expression of CBLC is predicted to confer resistance to olaparib. 25883215 PubMed Frankum et al., 2015, Oncotarget 2 accepted 805 326 9705 19 45281126 45303891 ENST00000270279.3 75 GRCh37 N/A 2016-02-22 20:35:40 UTC https://civicdb.org/links/evidence_items/805 https://civicdb.org/links/variants/326 https://civicdb.org/links/genes/9705 false KRAS 3845 G13D Colorectal Cancer 9256 Cetuximab Predictive Does Not Support B Resistance This is a retrospective analysis of 98 patients with metastatic colorectal cancer and KRAS mutations. 23 (23.5%) had KRAS p.G13D-mutated tumors. Of the 98 patients, 31 patients received cetuximab, of these, 9 (29.0%) had KRAS p.G13D mutations. Univariate analysis did not show any differences between these groups. Multivariate analysis showed a trend towards better PFS among patients with a G13D mutation (PFS: HR=0.29; 95% CI: 0.08-1.10; P=0.07; OS: HR=0.23; 95% CI: 0.04-1.54; P=0.13). 26623049 PubMed Osumi et al., 2015, Mol Clin Oncol 2 accepted 806 81 30 12 25398281 25398281 C T ENST00000256078.4 75 GRCh37 While the KRAS G13 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort. This mutation, along with the mutations affecting the neighboring G12 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, results are conflicting with retrospective analyses suggesting a better response to EGFR-Inhibition. A recent prospective phase-II study (12 patients, Schirripa et. al. 2015) could not reproduce this finding and another prospective phase II trial is currently ongoing. Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/806 https://civicdb.org/links/variants/81 https://civicdb.org/links/genes/30 false PTPRD 5789 Mutation Head And Neck Carcinoma 1542 JSI-124 Predictive Supports D Sensitivity/Response In this preclinical study, loss-of-function of PTPRD was mainly caused by mutation in head and neck cancer, as identified in TCGA data. PTPRD mutated cell-lines were more sensitive to STAT3 inhibition (JSI-124) than wild-type cells. The authors generated several representative HNSCC-derived PTPRD mutants by site-directed mutagenesis (S384R, K1502M, T1100M and L1147F). 26267899 PubMed Peyser et al., 2015, PLoS ONE 3 accepted 807 327 4692 9 8314246 10033790 ENST00000381196.4 75 GRCh37 Somatic 2016-02-21 16:52:14 UTC https://civicdb.org/links/evidence_items/807 https://civicdb.org/links/variants/327 https://civicdb.org/links/genes/4692 false DEFA1 1667 EXPRESSION Prostate Cancer 10283 Docetaxel Predictive Supports B Sensitivity/Response Blood mRNA levels of DEFA1, DEFA1B and DEFA3 were associated with response to docetaxel treatment in castration resistant prostate cancer. The discovery cohort consisted of 6 patients, results were validated in 10 patients. 26261420 PubMed Kohli et al., 2015, Onco Targets Ther 2 accepted 808 328 1428 8 6835172 6837602 ENST00000382692.2 75 GRCh37 N/A 2016-02-20 02:51:43 UTC https://civicdb.org/links/evidence_items/808 https://civicdb.org/links/variants/328 https://civicdb.org/links/genes/1428 false ERCC1 2067 Expression Bladder Carcinoma 4007 Cisplatin Predictive Does Not Support B Sensitivity/Response Immunhistochemistry of ERCC1 expression in 432 patients revealed no correlation to response to cisplatin based chemotherapy. In-vitro studies also did not show any effects. 26162296 PubMed Klatte et al., 2015, J. Urol. 4 accepted 809 329 1735 19 45916692 45926824 ENST00000013807.5 75 GRCh37 N/A 2016-02-13 05:40:15 UTC https://civicdb.org/links/evidence_items/809 https://civicdb.org/links/variants/329 https://civicdb.org/links/genes/1735 false ERCC1 2067 Expression Bladder Carcinoma 4007 Prognostic Supports B Better Outcome ERCC1 expression as evaluated by IHC in 432 patients was associated with better disease-free survival (HR 0.70, p = 0.028) and cancer specific survival (HR 0.70, p = 0.032) on multivariable analysis. 26162296 PubMed Klatte et al., 2015, J. Urol. 2 accepted 810 329 1735 19 45916692 45926824 ENST00000013807.5 75 GRCh37 N/A 2016-02-17 01:42:45 UTC https://civicdb.org/links/evidence_items/810 https://civicdb.org/links/variants/329 https://civicdb.org/links/genes/1735 false NOTCH1 4851 Amplification Colorectal Cancer 9256 NOTCH1 Antibody (PF-06293622) Predictive Supports D Sensitivity/Response NOTCH1 copy-number gain in a patient-derived tumor xenograft model of colorectal cancer, was associated with increased NOTCH1 and JAG1 activity and response to a NOTCH1-targeting antibody (PF-06293622). 26152787 PubMed Arcaroli et al., 2016, Int. J. Cancer 2 accepted 811 330 50 9 139388896 139440314 ENST00000277541.6 75 GRCh37 Somatic 2016-02-21 18:43:28 UTC https://civicdb.org/links/evidence_items/811 https://civicdb.org/links/variants/330 https://civicdb.org/links/genes/50 false NOTCH1 4851 Amplification Colorectal Cancer 9256 Prognostic Supports B Poor Outcome NOTCH1 amplifications (as determined by FISH) were significantly (log-rank p = 0.025) associated with worse survival in a cohort of 116 patients with colorectal cancer. 26152787 PubMed Arcaroli et al., 2016, Int. J. Cancer 2 accepted 812 330 50 9 139388896 139440314 ENST00000277541.6 75 GRCh37 Somatic 2016-02-18 18:26:12 UTC https://civicdb.org/links/evidence_items/812 https://civicdb.org/links/variants/330 https://civicdb.org/links/genes/50 false NRG1 3084 Expression Lung Non-small Cell Carcinoma 3908 Patritumab Predictive Supports B Sensitivity/Response In this phase-2 study, 215 patients were randomized to either erlotinib and placebo or erlotinib and HER3 monoclonal antibody patritumab. HRG (NRG1) expression was retrospectively defined as predictive biomarker but prospectively assessed in 102 patients before unblinding. NRG1-high groups demonstrated clinical benefit from additional patritumab with hazard ratios of 0.37 (P = 0.0283) and 0.29 (P = 0.0027) in the high- and low-dose patritumab arms, respectively. 26137564 PubMed Mendell et al., 2015, EBioMedicine 4 accepted 813 314 2593 8 31497942 32622294 ENST00000523534.1 75 GRCh37 N/A 2020-11-24 07:10:24 UTC https://civicdb.org/links/evidence_items/813 https://civicdb.org/links/variants/314 https://civicdb.org/links/genes/2593 false WEE1 7465 RS3910384 Lung Non-small Cell Carcinoma 3908 Gemcitabine,Platinum Compound Combination Predictive Supports B Sensitivity/Response The presence of the WEE1 polymorphism rs3910384 correlated with OS and PFS of NSCLC patients treated with platinum-based chemotherapy. Especially the combination of two DNA-damaging agents was associated with efficacy. 663 patients were tested. The authors showed that rs3910384 is closely linked with the putative functional WEE1 promoter at SNPs rs6486433, rs3763869 and rs3763868. 26057002 PubMed Liu et al., 2015, Sci Rep 3 accepted 814 331 6104 11 9599943 9599943 A G ENST00000450114.2 75 GRCh37 Common Germline 2016-02-21 22:37:16 UTC https://civicdb.org/links/evidence_items/814 https://civicdb.org/links/variants/331 https://civicdb.org/links/genes/6104 false FNTB 2342 RS11623866 Ovarian Cancer 2394 Lonafarnib Predictive Supports B Resistance 57 from 105 patients in the AGo-OVAR-15 trial were retrospectively genotyped for FNTB polymorphisms. Resistance to lonafarnib-containing treatment was limited to patients with a FNTB rs11623866 (c.-609G > C) GG genotype (HRPFS 6.2, 95%CI = 2.01, 19.41, P = 0.002; HROS 9.6, 95%CI = 1.89, 48.54, P = 0.006). 26033044 PubMed Bachmann et al., 2015, Br J Clin Pharmacol 2 accepted 815 332 1950 14 65453063 65453063 G C ENST00000246166.2 75 GRCh37 Common Germline 2016-02-16 15:13:01 UTC https://civicdb.org/links/evidence_items/815 https://civicdb.org/links/variants/332 https://civicdb.org/links/genes/1950 false BRAF 673 V600E Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Does Not Support B Resistance This meta-analysis of 7 randomized control trials evaluating overall survival (OS) (8 for progression free survival) could not definitely state that survival benefit of anti-EGFR monoclonal antibodies is limited to patients with wild type BRAF. In other words, the authors believe that there is insufficient data to justify the exclusion of anti-EGFR monoclonal antibody therapy for patients with mutant BRAF. In these studies, mutant BRAF specifically meant the V600E mutation. 25989278 PubMed Rowland et al., 2015, Br. J. Cancer 4 accepted 816 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-02-18 19:56:58 UTC https://civicdb.org/links/evidence_items/816 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false PTPRT 11122 Promoter Hypermethylation Head And Neck Squamous Cell Carcinoma 5520 Stattic,JSI-124 Substitutes Predictive Supports D Sensitivity/Response PTPRT promoter hypermethylation was associated with increased sensitivity to STAT3 inhibition in this preclinical study in HNSCC. The authors found that PTPRT promoter methylation and sensitivity to Stattic (a STAT3 SH2 domain inhibitor) or JSI-124 (a JAK/STAT3 pathway inhibitor) are significantly correlated (P<0.05). 25982282 PubMed Peyser et al., 2016, Oncogene 2 accepted 817 333 8878 Somatic 2016-02-22 02:21:18 UTC https://civicdb.org/links/evidence_items/817 https://civicdb.org/links/variants/333 https://civicdb.org/links/genes/8878 false VEGFA 7422 Decreased Peri-therapeutic Expression Colorectal Cancer 9256 Irinotecan,Bevacizumab,Levoleucovorin,Fluorouracil Combination Predictive Supports B Sensitivity/Response Decreased peri- and post-therapeutic expression of VEGFA were significantly associated with response to FOLFIRI plus bevacizumab in 57 patients with metastatic CRC. 25973082 PubMed Tsai et al., 2015, Int J Clin Exp Pathol 2 accepted 818 334 6071 6 43738444 43752346 ENST00000372055.4 75 GRCh37 N/A 2016-02-13 05:45:41 UTC https://civicdb.org/links/evidence_items/818 https://civicdb.org/links/variants/334 https://civicdb.org/links/genes/6071 false DNMT1 1786 EXPRESSION Ovarian Cancer 2394 Decitabine Predictive Supports D Sensitivity/Response DNMT1 expression (mRNA expression from an independent study) correlated with sensitivity to decitabine (ρ, −0.443, Pearson regression analysis) in this preclinical study of 45 solid tumor cell lines. DNMT1 protein expression was also evaluated in two KRAS-mutant ovarian cancer cell lines pre and post-decitabine treatment showing downregulation following treatment. 25968887 PubMed Stewart et al., 2015, Cancer Res. 3 accepted 819 335 1510 19 10244022 10305811 ENST00000340748.4 75 GRCh37 N/A 2016-02-22 20:34:44 UTC https://civicdb.org/links/evidence_items/819 https://civicdb.org/links/variants/335 https://civicdb.org/links/genes/1510 false KRAS 3845 Mutation Ovarian Cancer 2394 Decitabine Predictive Supports D Sensitivity/Response KRAS mutation or amplification predicted sensitivity to decitabine in ovarian cancer cell lines. The authors profiled the response of 45 ovarian, melanoma, and breast cancer cell lines over 9 days of treatment with decitabine. 4 ovarian lines with KRAS mutation were among the most sensitive to decitabine. 25968887 PubMed Stewart et al., 2015, Cancer Res. 3 accepted 820 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-02-21 16:24:24 UTC https://civicdb.org/links/evidence_items/820 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false PDCD4 27250 EXPRESSION Lung Cancer 1324 Paclitaxel Predictive Supports B Sensitivity/Response PDCD4 expression was associated with response to paclitaxel in a retrospective analysis of 77 patients after preclinical validation and mechanistic analysis of the biomarker. 25928036 PubMed Xu et al., 2015, J. Proteome Res. 4 accepted 821 337 10573 10 112631596 112659763 ENST00000393104.2 75 GRCh37 A new study, a retrospective analysis of 77 patients, has implicated PDCD4 expression in the sensitivity to paclitaxel. However, this finding came from a large proteome screen and has not yet been replicated in independent patient sets. N/A 2020-11-24 07:10:11 UTC https://civicdb.org/links/evidence_items/821 https://civicdb.org/links/variants/337 https://civicdb.org/links/genes/10573 false MGMT 4255 RS16906252 Glioblastoma 3068 Temozolomide Predictive Supports B Sensitivity/Response The T allele of the rs16906252 SNP was associated with MGMT methylation and low protein expression. Germline presence of the T allele increased the risk of glioblastoma development (adjusted odds ratio, 1.96; P = .013). Temozolomide treatment led to better survival in patients with the rs16906252 T genotype irrespective of methylation status. 25910840 PubMed Rapkins et al., 2015, Neuro-oncology 3 accepted 822 338 34 10 131265545 131265545 C T ENST00000306010.7 75 GRCh37 Common Germline 2016-02-13 05:49:42 UTC https://civicdb.org/links/evidence_items/822 https://civicdb.org/links/variants/338 https://civicdb.org/links/genes/34 false TFF3 7033 EXPRESSION Breast Cancer 1612 Tamoxifen,Aminoglutethimide Substitutes Predictive Supports B Sensitivity/Response TFF3 expression was assessed by IHC in 75 patients, 187 patients were identified for the validation cohort. TFF3 expression was associated with response to endocrine therapy (tamoxifen, aminoglutethimide or oophorectomy) and outperformed ER, PR and TFF1 as biomarkers. 25900183 PubMed May et al., 2015, Endocr. Relat. Cancer 3 accepted 823 339 5737 21 43731777 43735761 ENST00000518498.1 75 GRCh37 N/A 2016-02-17 01:18:20 UTC https://civicdb.org/links/evidence_items/823 https://civicdb.org/links/variants/339 https://civicdb.org/links/genes/5737 false DKK1 22943 NUCLEAR EXPRESSION Colorectal Cancer 9256 Fluorouracil,Oxaliplatin,Levoleucovorin,Irinotecan Combination Predictive Supports B Resistance Nuclear expression of DICKKOPF-1 was identified in 15% of 699 patients with colorectal cancer and was associated with decreased progression-free survival (PFS) and overall survival (OS) after chemotherapy (FOLFOX, FOLFIRI, or 5-FU) [adjusted HR, 1.65; 95% confidence interval (CI), 1.23-2.21; P = 0.002)]. 25788273 PubMed Aguilera et al., 2015, Oncotarget 3 accepted 824 340 9171 10 54074056 54077417 ENST00000373970.3 75 GRCh37 N/A 2016-02-20 20:11:54 UTC https://civicdb.org/links/evidence_items/824 https://civicdb.org/links/variants/340 https://civicdb.org/links/genes/9171 false CD44 960 CD44s Expression Cancer 162 RG7356 Predictive Supports D Sensitivity/Response CD44 isoform expression (especially CD44s) was identified to predict response to CD44 antibody RG7356 preclinically. Retrospective evaluation of 13 patients from a phase 1 study, treated with RG7356, identified 3 patients with CD44s isoform. 2/3 patients with CD44s had SD as best response. Overall, 5 patients had an OR. 25762343 PubMed Birzele et al., 2015, Clin. Cancer Res. 3 accepted 825 341 855 11 35160728 35251574 ENST00000428726.2 75 GRCh37 N/A 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/825 https://civicdb.org/links/variants/341 https://civicdb.org/links/genes/855 false EGF 1950 EXPRESSION Head And Neck Squamous Cell Carcinoma 5520 Cetuximab Predictive Supports D Resistance 3 tongue cancer cell lines were used for this study. Addition of recombinant human EGF led to increased cetuximab resistance. EGF downregulation suppressed proliferation of cell lines. Results for amphiregulin and epiregulin were inconclusive. 25677871 PubMed Ansell et al., 2016, J. Oral Pathol. Med. 3 accepted 826 342 1634 4 110834047 110933422 ENST00000265171.5 75 GRCh37 N/A 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/826 https://civicdb.org/links/variants/342 https://civicdb.org/links/genes/1634 false MDM2 4193 EXPRESSION Malignant Pleural Mesothelioma 7474 Pemetrexed,Cisplatin Combination Predictive Supports B Resistance 72 patients with malignant pleural mesothelioma were analyzed, MDM2 immunoexpression was assessed in 65 patients. MDM2 mRNA and protein expression correlated with poor OS and PFS for patients treated with cisplatin and pemetrexed (standard of care therapy). 25668009 PubMed Walter et al., 2015, Br. J. Cancer 1 accepted 827 343 3465 12 69201956 69239214 ENST00000462284.1 75 GRCh37 N/A 2016-03-11 01:49:58 UTC https://civicdb.org/links/evidence_items/827 https://civicdb.org/links/variants/343 https://civicdb.org/links/genes/3465 false MDM2 4193 EXPRESSION Malignant Pleural Mesothelioma 7474 Prognostic Supports B Poor Outcome 72 patients with malignant pleural mesothelioma were analyzed, MDM2 immunoexpression was assessed in 65 patients. MDM2 mRNA and protein expression correlated with poor OS and PFS for patients treated with standard of care therapy (cisplatin and pemetrexed). 25668009 PubMed Walter et al., 2015, Br. J. Cancer 3 accepted 828 343 3465 12 69201956 69239214 ENST00000462284.1 75 GRCh37 Somatic 2016-02-18 22:11:48 UTC https://civicdb.org/links/evidence_items/828 https://civicdb.org/links/variants/343 https://civicdb.org/links/genes/3465 false HMOX1 3162 EXPRESSION Renal Cell Carcinoma 4450 Sunitinib,Sorafenib Substitutes Predictive Supports B Resistance In 66 patients with advanced renal cell carcinoma, high expression of heme oxygenase-1 (HO-1) was associated with poor overall response rate (2.6% versus 53.6%, P<0.01), clinical benefit rate (47.4% versus 92.9%, P<0.01), shorter progression-free survival (4.4 versus 42 months, P=0.022) and poor overall survival (χ (2)=4.775, P=0.029) in patients receiving sorafenib or sunitinib. 26309414 PubMed Zheng et al., 2015, Onco Targets Ther 3 accepted 829 344 2657 22 35776828 35790207 ENST00000216117.8 75 GRCh37 N/A 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/829 https://civicdb.org/links/variants/344 https://civicdb.org/links/genes/2657 false SPHK1 8877 OVEREXPRESSION Cervical Cancer 4362 Prognostic Supports B Poor Outcome SPHK1 protein expression was assessed in 287 cervical cancer and 5 normal cervical tissue samples using IHC. Univariate analysis for OS showed SPHK1 expression (p = 0.033; Figure 1C), tumor size (p = 0.033), and lymph node metastasis (p = 0.008) as associated with OS. SPHK1 expression did not directly predict OS. High SPHK1 expression was also associated with larger tumor size (p < 0.001), deeper invasion depth (p < 0.001), presence of lymph node metastasis (p = 0.029), higher FIGO stage (p = 0.029), presence of lymphovascular invasion (p = 0.045), and higher preoperative squamous cell carcinoma (SCC) antigen level (p = 0.009). 26311741 PubMed Kim et al., 2015, Oncotarget 2 accepted 830 345 7041 17 74380731 74383936 ENST00000323374.4 75 GRCh37 Somatic 2016-02-07 04:15:24 UTC https://civicdb.org/links/evidence_items/830 https://civicdb.org/links/variants/345 https://civicdb.org/links/genes/7041 false CASP8 841 Overexpression Ewing Sarcoma Of Bone 3368 Conatumumab Predictive Supports D Sensitivity/Response In-vitro and in-vivo sensitivity to DR5 antibody conatumumab was correlated with expression of caspase-8. 26291055 PubMed Kang et al., 2015, Br. J. Cancer 3 accepted 831 346 761 2 202122759 202152434 ENST00000358485.4 75 GRCh37 N/A 2016-02-21 16:51:23 UTC https://civicdb.org/links/evidence_items/831 https://civicdb.org/links/variants/346 https://civicdb.org/links/genes/761 false TYMS 7298 Overexpression Lung Non-small Cell Carcinoma 3908 Pemetrexed Predictive Supports B Resistance mRNA expression of thymidylate synthase (TYMS) in 62 NSCLC patients correlated with response rate to pemetrexed mono- or combination therapy. Response rate with low TYMS expression was 0.29 compared with 0.03 in patients with overexpression (P = 0.025). Patients with low expression exhibited a benefit in time to progression (average TTP = 56 vs. 23 months, P = 0.001) and in overall survival (average OS = 60 vs. 25 months, P = 0.002). 26502926 PubMed Chamizo et al., 2015, BMC Pulm Med 3 accepted 832 347 5971 18 657604 673578 ENST00000323274.10 75 GRCh37 N/A 2016-02-13 03:47:19 UTC https://civicdb.org/links/evidence_items/832 https://civicdb.org/links/variants/347 https://civicdb.org/links/genes/5971 false PBK 55872 OVEREXPRESSION Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports D Resistance TOPK (PBK) silencing sensitized lung cancer cells to gefitinib in preclinical xenograft models. Over-expression was also associated with resistance in various lung cancer cell lines. 26745678 PubMed Li et al., 2016, Oncotarget 3 accepted 835 348 13276 8 27667137 27695612 ENST00000301905.4 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/835 https://civicdb.org/links/variants/348 https://civicdb.org/links/genes/13276 false MET 4233 Amplification Lung Adenocarcinoma 3910 Crizotinib Predictive Supports C Sensitivity/Response Case report of a patient with MET amplification without high-level MET/CEP7 ratio, MET exon 14 mutation or overexpression who achieved rapid response to crizotinib. 26724472 PubMed Zhang et al., 2016, J Thorac Oncol 2 accepted 836 270 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/836 https://civicdb.org/links/variants/270 https://civicdb.org/links/genes/52 false SMARCA4 6597 Underexpression Lung Non-small Cell Carcinoma 3908 Cisplatin,Vinorelbine Combination Predictive Supports B Sensitivity/Response SMARCA4 expression was determined with gene expression microarray in 133 patients. Improved five-year disease-specific survival (DSS) was noted only in patients with low SMARCA4 expression when treated with adjuvant cisplatin/vinorelbine (n=36) (HR=0.1, 95% CI: 0.0-0.5, P=0.002 [low]; HR 1.0, 95% CI: 0.5-2.3, P=0.92 [high]) compared to patients in the observation arm (N=30). 26671993 PubMed Bell et al., 2016, Clin. Cancer Res. 3 accepted 837 349 78 19 11071598 11172958 ENST00000358026.2 75 GRCh37 N/A 2020-12-10 20:09:55 UTC https://civicdb.org/links/evidence_items/837 https://civicdb.org/links/variants/349 https://civicdb.org/links/genes/78 false SMARCA4 6597 Underexpression Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome SMARCA4 expression was determined with gene expression microarray in 133 patients. Reduced overall survival was observed in patients with low SMARCA4 expression compared to intermediate (P<0 .001) or high expression (P=0.009). In multivariate analysis, compared to low, high SMARCA4 expression predicted a decrease in risk of death (HR=0.6, 95% CI: 0.4-0.8, P=0.002). 26671993 PubMed Bell et al., 2016, Clin. Cancer Res. 3 accepted 838 349 78 19 11071598 11172958 ENST00000358026.2 75 GRCh37 Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/838 https://civicdb.org/links/variants/349 https://civicdb.org/links/genes/78 false SETBP1 26040 Exon 4 Mutation Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative 0060597 Prognostic Supports B Poor Outcome Atypical Chronic Myeloid Leukemia has the same symptoms as CML, but it lacks the BCR-ABL1 fusion. Targeted sequencing of 70 aCML patients identified SETBP1 mutations between codons 858 and 871 in 24.3% of the patients. Patients with this mutation had a 22 month median survival compared to 77 months in aCML patients without the mutation (P=.01). 23222956 PubMed Piazza et al., 2013, Nat. Genet. 3 accepted 839 350 10024 18 42531877 42531918 ENST00000282030.5 75 GRCh37 Somatic 2021-02-27 01:03:57 UTC https://civicdb.org/links/evidence_items/839 https://civicdb.org/links/variants/350 https://civicdb.org/links/genes/10024 false SETBP1 26040 G870S Chronic Myeloid Leukemia 8552 Prognostic Supports D Poor Outcome Atypical Chronic Myeloid Leukemia has the same symptoms as CML, but it lacks the BCR-ABL1 fusion. The researchers transfected 293T cells with SETBP1 G870S, a variant found to be associated with poor prognosis in aCML, and found those cells had higher proliferation and higher expression of SET and SETBP1 proteins. This may be linked to the mutation abrogating a ubiquitination site. 23222956 PubMed Piazza et al., 2013, Nat. Genet. 3 accepted 840 351 10024 18 42531913 42531913 G A ENST00000282030.5 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/840 https://civicdb.org/links/variants/351 https://civicdb.org/links/genes/10024 false ALK 238 EML4::ALK C1156Y Lung Non-small Cell Carcinoma 3908 Crizotinib,Luminespib,Ceritinib Sequential Predictive Supports C Resistance In this case report, a patient with metastatic, ALK-rearranged NSCLC with C1156Y mutation had tumor progression under sequential treatment with first crizotinib, then ceritinib and finally AUY922. Subsequent chemotherapy (carboplatin–pemetrexed) was administered and the patient had a response for 6 months before progression. Exome sequencing revealed the C1156Y mutation was present in <7% of the pretreatment tumor and in ~50% of the crizotinib tumor prior to ceritinib therapy. 26698910 PubMed Shaw et al., 2016, N. Engl. J. Med. NCT01970865 3 accepted 841 6 1 2 29445258 29445258 C T ENST00000389048.3 75 GRCh37 In patients with non-small cell lung cancer exhibiting EML4-ALK fusion, C1156Y has been shown to confer resistance to crizotinib. Case reports indicate that secondary mutations can modulate drug sensitivity. EML4-ALK C1156Y/L1196M maintained crizotinib resistance while the lorlatinib resistant combination EML4-ALK C1156Y/L1198F re-sensitized the tumor to crizotinib treatment. Somatic 2016-02-18 18:45:46 UTC https://civicdb.org/links/evidence_items/841 https://civicdb.org/links/variants/6 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK C1156Y Lung Non-small Cell Carcinoma 3908 Lorlatinib Predictive Supports C Sensitivity/Response Case report of a patient with metastatic ALK-rearranged NSCLC after progression under sequential crizotinib, ceritinib, HSP90 inhibitor AUY922 and chemotherapy followed by crizotinib again. Third generation ALK inhibitor lorlatinib led to a partial response that lasted for 8 months. The C1156Y mutation was confirmed in a sample prior to initial crizotinib (<7% of cells), following crizotinib treatment (~50% of cells) and following lorlatinib resistance (100% of cells). However, a second ALK mutation (C1156Y & L1198F) was detected in the lorlatinib resistant tumor. 26698910 PubMed Shaw et al., 2016, N. Engl. J. Med. NCT01970865 3 accepted 842 6 1 2 29445258 29445258 C T ENST00000389048.3 75 GRCh37 In patients with non-small cell lung cancer exhibiting EML4-ALK fusion, C1156Y has been shown to confer resistance to crizotinib. Case reports indicate that secondary mutations can modulate drug sensitivity. EML4-ALK C1156Y/L1196M maintained crizotinib resistance while the lorlatinib resistant combination EML4-ALK C1156Y/L1198F re-sensitized the tumor to crizotinib treatment. Somatic 2016-02-18 18:44:15 UTC https://civicdb.org/links/evidence_items/842 https://civicdb.org/links/variants/6 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK C1156Y-L1198F Lung Non-small Cell Carcinoma 3908 Lorlatinib Predictive Supports C Resistance Case report of a patient with metastatic ALK-rearranged NSCLC. After developing resistance to first and second line ALK inhibitors mediated by a C1156Y mutation, the patient had a partial response with the third generation ALK-inhibitor lorlatinib. The patient progressed on lorlatinib after 8 months, at which point whole exome sequencing revealed an EML4-ALK C1156Y–L1198F double mutation. In vitro, the double mutation was resistant to lorlatinib but sensitive to crizotinib. The patient was started on crizotinib again and had a clinical response that lasted for 6 months. 26698910 PubMed Shaw et al., 2016, N. Engl. J. Med. NCT01970865 4 accepted 843 352 1 2 29443625 29445258 ENST00000389048.3 75 GRCh37 EML4-ALK C1156Y alone is resistant to crizotinib in non-small cell lung cancer (NSCLC) which has been shown to be modulated (both increased sensitivity and resistance) by additional ALK mutations. A case report showed that an NSCLC harboring EML4-ALK C1156Y-L1198F was resistant to lorlatinib but this second mutation re-sensitized this tumor to crizotinib. Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/843 https://civicdb.org/links/variants/352 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK C1156Y-L1198F Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Sensitivity/Response Case report of a patient with metastatic ALK-rearranged NSCLC. After developing resistance to first and second line ALK inhibitors mediated by a C1156Y mutation, the patient had a partial response with the third generation ALK-inhibitor lorlatinib. The patient progressed on lorlatinib after 8 months, at which point whole exome sequencing revealed an EML4-ALK C1156Y–L1198F double mutation. In vitro, the double mutation was resistant to lorlatinib but sensitive to crizotinib. The patient was started on crizotinib again and had a clinical response that lasted for 6 months. 26698910 PubMed Shaw et al., 2016, N. Engl. J. Med. NCT01970865 4 accepted 844 352 1 2 29443625 29445258 ENST00000389048.3 75 GRCh37 EML4-ALK C1156Y alone is resistant to crizotinib in non-small cell lung cancer (NSCLC) which has been shown to be modulated (both increased sensitivity and resistance) by additional ALK mutations. A case report showed that an NSCLC harboring EML4-ALK C1156Y-L1198F was resistant to lorlatinib but this second mutation re-sensitized this tumor to crizotinib. Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/844 https://civicdb.org/links/variants/352 https://civicdb.org/links/genes/1 false BRCA1 672 Loss-of-function Prostate Cancer 10283 Olaparib Predictive Supports C Sensitivity/Response 1/1 patients with BRCA1 homozygous deletion had a response to olaparib in this phase 2 study. 26510020 PubMed Mateo et al., 2015, N. Engl. J. Med. NCT01682772 2 accepted 845 131 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 BRCA1 loss of function mutations have been shown to increase risk of breast and ovarian cancer in those carrying the allele in their germline. Treating BRCA mutant patients with PARP inhibitors such as Olaparib has led to significant response. Somatic 2016-09-06 02:00:48 UTC https://civicdb.org/links/evidence_items/845 https://civicdb.org/links/variants/131 https://civicdb.org/links/genes/6 false AREG 374 Expression Head And Neck Squamous Cell Carcinoma 5520 Cetuximab,Docetaxel Combination Predictive Supports B Resistance 47 HNSCC patients treated with cetuximab/docetaxel were retrospectively analyzed for EGFRvIII, EGFR and AREG expression with IHC. 45% of cases expressed high level of AREG. High AREG expression in tumor cells was associated with reduced overall survival (hazard ratio: 2.2, P = 0.002) and progression free survival (hazard ratio: 2.2, P = 0.016) compared to patients with low AREG expression score. AREG was an independent prognosticator of OS in multivariate Cox analysis. High EGFRvIII and AREG expression levels identified SCCHN (squamous cell carcinoma, head and neck) patients that were less likely to benefit from combination treatment with cetuximab and docetaxel. 21653686 PubMed Tinhofer et al., 2011, Clin. Cancer Res. 2 accepted 846 315 389 4 75310851 75320726 ENST00000395748.3 75 GRCh37 N/A 2016-02-20 02:51:20 UTC https://civicdb.org/links/evidence_items/846 https://civicdb.org/links/variants/315 https://civicdb.org/links/genes/389 false EGFR 1956 VIII Head And Neck Squamous Cell Carcinoma 5520 Cetuximab,Docetaxel Combination Predictive Supports B Resistance 47 HNSCC patients treated with cetuximab/docetaxel were retrospectively analyzed for EGFRvIII, EGFR, and AREG expression by IHC. 17% of cases expressed high levels of EGFRvIII. High vIII expression was associated with reduced disease control rate (DCR) and shortened progression free survival (PFS) (HR: 3.3, P = 0.005) but not with OS. 21653686 PubMed Tinhofer et al., 2011, Clin. Cancer Res. 2 accepted 848 312 19 7 55087058 55223523 ENST00000275493.2 75 GRCh37 The EGFRvIII variant is an oncogenic mutation that has been reported in several cancers including glioblastoma multiforme, breast, lung, head and neck, ovarian and prostate. In high-grade gliomas, EGFRvIII has been reported in about 30% of cases with EGFR amplification. The EGFRvIII mutation leads to deletion of the receptor ectodomain exons 2-7. The presence of this variant has been linked with clinical response to EGFR TKI. (Arteaga and Engelmann, 2014) Somatic 2016-02-13 04:37:08 UTC https://civicdb.org/links/evidence_items/848 https://civicdb.org/links/variants/312 https://civicdb.org/links/genes/19 false EGFR 1956 Overexpression Head And Neck Squamous Cell Carcinoma 5520 Cetuximab,Docetaxel Combination Predictive Does Not Support B Sensitivity/Response 47 HNSCC patients treated with cetuximab/docetaxel were retrospectively analyzed for EGFRvIII, EGFR and AREG expression with IHC. 73 % of cases expressed high level of EGFR. EGFR expression had no impact on PFS (P=0.73) or OS (P=0.75). 21653686 PubMed Tinhofer et al., 2011, Clin. Cancer Res. 3 accepted 849 193 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 N/A 2020-10-06 16:37:34 UTC https://civicdb.org/links/evidence_items/849 https://civicdb.org/links/variants/193 https://civicdb.org/links/genes/19 false TP53 7157 Mutation Gastric Adenocarcinoma 3717 Chemotherapy Predictive Supports B Sensitivity/Response In this meta-analysis of 13 studies (564 patients) p53 positivity as defined by high protein expression and/or p53 mutation was associated with improved response to chemotherapy (risk ratio [RR] = 0.704; 95% confidence intervals [CI] = 0.550-0.903; P = 0.006). 24740294 PubMed Xu et al., 2014, PLoS ONE 3 accepted 850 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2016-02-09 00:03:38 UTC https://civicdb.org/links/evidence_items/850 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false TP53 7157 Mutation Breast Cancer 1612 Doxorubicin Predictive Supports D Sensitivity/Response In this preclinical study, MMTV-Wnt1 mammary tumors with mutant TP53 showed a better clinical response to chemotherapy (doxorubicin) than TP53 wild-type tumors. This was mediated by wild-type TP53-induced cell-arrest under chemotherapy even in the context of heterozygous TP53 point mutations or absence of p21. Thus the status of both TP53 alleles should be assessed because even one copy of wild-type TP53 may contribute to poor response to chemotherapy. 22698404 PubMed Jackson et al., 2012, Cancer Cell 4 accepted 851 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2016-02-21 16:07:30 UTC https://civicdb.org/links/evidence_items/851 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false CDKN1A 1026 EXPRESSION Colorectal Cancer 9256 Fluorouracil Predictive Supports B Resistance 112 patients with rectal cancer who received 5-FU based chemotherapy and surgery were retrospectively analyzed for expression of Ki67, TS, BAX, EpCAM, p53, p21, EGFR, CD44, CD133, CD166, HIF1α and ALDH1. High pretreatment p21 (CDKN1A) expression was significantly associated with non-pCR (p = 0.022) and poor disease free survival (median DFS - low vs high p21: 75.8 vs 58.1 months, p = 0.002). Multivariate analysis was also significant (p = 0.001, HR 6.14; 95% CI 2.03, 18.55). 24708484 PubMed Sim et al., 2014, BMC Cancer 3 accepted 852 355 913 6 36646487 36655108 ENST00000405375.1 75 GRCh37 N/A 2016-02-16 14:58:21 UTC https://civicdb.org/links/evidence_items/852 https://civicdb.org/links/variants/355 https://civicdb.org/links/genes/913 false ALCAM 214 EXPRESSION Colorectal Cancer 9256 Fluorouracil Predictive Supports B Resistance 112 patients with rectal cancer who received 5-FU based chemotherapy and surgery were retrospectively analyzed for expression of Ki67, TS, BAX, EpCAM, p53, p21, EGFR, CD44, CD133, CD166, HIF1α and ALDH1. Pretreatment CD166 (ALCAM) expression level was associated with poor disease free survival (p = 0.003; HR 5.61; 95% CI 1.81, 17.35). 24708484 PubMed Sim et al., 2014, BMC Cancer 3 accepted 853 356 259 3 105085753 105295744 ENST00000306107.5 75 GRCh37 N/A 2016-02-14 00:24:47 UTC https://civicdb.org/links/evidence_items/853 https://civicdb.org/links/variants/356 https://civicdb.org/links/genes/259 false EGFR 1956 Amplification Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Supports B Sensitivity/Response In this meta-analysis (14 studies, 1021 patients), EGFR gene copy number (GCN) was predictive of improved progression free survival (PFS) and overall survival (OS) with cetuximab or panitumumab regardless of KRAS status. For the pooled analysis, the objective response rate (ORR) was 65.2% (167/256) in patients with high EFGR GCN, while in patients with low EFGR GCN, the pooled ORR was 12.2% (44/361). The odds ratio (OR) was 6.905 (95% CI: 4.489-10.620; Z=8.79, P=0.000). In wild type KRAS patients, the pooled OR was 8.133 (95% CI: 4.316-15.326; Z=6.48, P=0.000). 24653627 PubMed Shen et al., 2014, Chin. J. Cancer Res. 3 accepted 854 190 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2016-02-18 22:50:59 UTC https://civicdb.org/links/evidence_items/854 https://civicdb.org/links/variants/190 https://civicdb.org/links/genes/19 false STMN1 3925 EXPRESSION Endometrial Carcinoma 2871 Paclitaxel Predictive Supports B Resistance 33 patients were retrospectively analyzed for Stathmin expression by IHC. High protein expression was correlated with poor response to paclitaxel but not other chemotherapy. The authors supported this conclusion with pre-clinical studies that showed that knock-down of stathmin improved sensitivity to paclitaxel in endometrial carcinoma cell lines with both naturally higher and lower sensitivity to paclitaxel. 24587245 PubMed Werner et al., 2014, PLoS ONE 3 accepted 855 357 3255 1 26211931 26232957 ENST00000426559.2 75 GRCh37 N/A 2016-02-14 00:23:25 UTC https://civicdb.org/links/evidence_items/855 https://civicdb.org/links/variants/357 https://civicdb.org/links/genes/3255 false CCND1 595 Overexpression Estrogen-receptor Positive Breast Cancer 0060075 Tamoxifen Predictive Supports B Resistance The authors performed a tissue microarray analysis of 167 postmenopausal breast cancers that had been randomized to treatment with or without tamoxifen. ER +ve patients with high CCND1 tumor expression did not show any difference in survival between tamoxifen and no treatment. 15138475 PubMed Stendahl et al., 2004, Br. J. Cancer 3 accepted 856 20 8 11 69455855 69469242 ENST00000227507.2 75 GRCh37 Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK's) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, and range from genomic amplification to promoter methylation changes. While Cyclin D2 has only been found to be significantly misregulated in glioma, Cyclin D1 in particular seems to be a pan-cancer actor. Cyclin D misregulation has been shown to lead to poorer outcomes in a number of studies, and currently there are no FDA-approved targeted therapies. N/A 2016-02-18 18:33:17 UTC https://civicdb.org/links/evidence_items/856 https://civicdb.org/links/variants/20 https://civicdb.org/links/genes/8 false RSF1 51773 Amplification Breast Cancer 1612 Tamoxifen Predictive Supports B Resistance In retrospective study, 413 patients were assessed for RSF1 amplification. 28 patients with RSF1 amplification did not show a benefit from adjuvant tamoxifen compared to placebo (12 treated vs 16 placebo). 381 patients without amplification did show a benefit compared to placebo (187 treated vs 194 placebo). 24367492 PubMed Keilty et al., 2013, PLoS ONE 2 accepted 857 358 12121 11 77371041 77532063 ENST00000308488.6 75 GRCh37 Somatic 2016-02-20 02:50:11 UTC https://civicdb.org/links/evidence_items/857 https://civicdb.org/links/variants/358 https://civicdb.org/links/genes/12121 false CCND1 595 Amplification Breast Cancer 1612 Tamoxifen Predictive Does Not Support B Resistance In this retrospective analysis, CCND1 amplification was analyzed in 442 patients. No interaction with treatment was observed. 24367492 PubMed Keilty et al., 2013, PLoS ONE 3 accepted 858 18 8 11 69455855 69469242 ENST00000227507.2 75 GRCh37 CCND1 amplification has been implicated in poorer prognosis in non-small cell lung cancer. Somatic 2016-02-10 16:39:05 UTC https://civicdb.org/links/evidence_items/858 https://civicdb.org/links/variants/18 https://civicdb.org/links/genes/8 false AR 367 OVEREXPRESSION Breast Cancer 1612 Dactolisib Predictive Supports D Sensitivity/Response In-vitro and xenograft studies of response of breast cancer cell lines to PI3K/mTOR inhibitor NVP-BEZ235 showed that sensitivity correlated with expression of the androgen receptor (AR). Reintroduction of AR expression resensitized nonresponsive AR-negative cells to NVP-BEZ235. A dihydrotestosterone (DHT) and NVP-BEZ235 combination achieved tumor regression and complete response in AR/ER expressing tumors (xenografts). 24356815 PubMed Wang et al., 2014, Mol. Cancer Ther. 3 accepted 859 359 67 X 66764465 66950461 ENST00000374690.3 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/859 https://civicdb.org/links/variants/359 https://civicdb.org/links/genes/67 false CDKN1B 1027 CYTOPLASMIC MISLOCALIZATION Breast Cancer 1612 Lapatinib Predictive Supports D Resistance Cytoplasmic localization of p27 (CDKN1B) leads to lapatinib resistance in HER2+ breast cancer cell lines. p27 knockout resensitiuzed cells to lapatinib. 25587029 PubMed Zhao et al., 2014, Oncotarget 3 accepted 860 360 914 12 12870058 12875305 ENST00000228872.4 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/860 https://civicdb.org/links/variants/360 https://civicdb.org/links/genes/914 false NRG1 3084 Expression Cancer 162 Anti-ErbB3 Monoclonal Antibody AV-203 Predictive Supports D Sensitivity/Response This screening study in various tumor xenografts identified NRG1 expression to correlate with sensivity to ERBB3 inhibitory antibody AV-203. ERBB3 expression was not predictive of response. 25542901 PubMed Meetze et al., 2015, Clin. Cancer Res. 3 accepted 861 314 2593 8 31497942 32622294 ENST00000523534.1 75 GRCh37 N/A 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/861 https://civicdb.org/links/variants/314 https://civicdb.org/links/genes/2593 false ERBB3 2065 EXPRESSION Cancer 162 Anti-ErbB3 Monoclonal Antibody AV-203 Predictive Does Not Support D Sensitivity/Response The authors conducted an in vivo efficacy study of AV-203 (ERBB3 inhibitory antibody) using a panel of 32 xenograft models representing 12 human cancer types. To identify biomarkers that can predict response to AV-203, the relationship between tumor growth inhibition (TGI) by AV-203 and the expression levels of ERBB3 and NRG1 were evaluated in these tumor models. ERBB3 expression was not predictive of response. 25542901 PubMed Meetze et al., 2015, Clin. Cancer Res. 3 accepted 862 361 1733 12 56473645 56497289 ENST00000267101.3 75 GRCh37 N/A 2016-02-21 16:31:39 UTC https://civicdb.org/links/evidence_items/862 https://civicdb.org/links/variants/361 https://civicdb.org/links/genes/1733 false AR 367 V7 EXPRESSION Prostate Cancer 10283 Abiraterone,Enzalutamide Substitutes Predictive Supports B Resistance Detection of AR-V7 in circulating tumor cells of 62 patients treated with either enzalitamide (n=31) or arbiraterone (n=31), was correlated with lower PSA response rates and PSA PFS in men receiving enzalutamide or abiraterone. 25184630 PubMed Antonarakis et al., 2014, N. Engl. J. Med. 3 accepted 863 362 67 X 66764662 66915917 ENST00000504326.1 75 GRCh37 N/A 2016-02-08 19:54:16 UTC https://civicdb.org/links/evidence_items/863 https://civicdb.org/links/variants/362 https://civicdb.org/links/genes/67 false PTEN 5728 Loss Gastric Adenocarcinoma 3717 Trastuzumab,Lapatinib Substitutes Predictive Supports B Resistance In 48 patients with advanced gastric cancer, retrospectively analyzed for PTEN expression using IHC, PTEN loss was associated with a shorter duration of response (median 4.2 vs. 6.1 months, p = 0.04) to HER2-targeted therapy (trastuzumab, N=39; lapatinib, N=9). Response rates did not differ between groups. 25300346 PubMed Zhang et al., 2015, Oncology 2 accepted 864 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 N/A 2016-02-22 20:27:37 UTC https://civicdb.org/links/evidence_items/864 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false ERBB3 2065 EXPRESSION Pancreatic Ductal Adenocarcinoma 3498 9F7-F11,Pertuzumab Combination Predictive Supports D Sensitivity/Response In mice xenografts expressing ERBB3 (HER3) the combination of ERBB2 (HER2) and ERBB3 inhibitors pertuzumab and 9F7-F11enhanced tumor inhibition and the median survival time. Sensitivity to single-agent pertuzumab might also be increased through ERBB3 expression. 25216528 PubMed Thomas et al., 2014, Oncotarget 3 accepted 865 361 1733 12 56473645 56497289 ENST00000267101.3 75 GRCh37 N/A 2016-02-21 04:47:39 UTC https://civicdb.org/links/evidence_items/865 https://civicdb.org/links/variants/361 https://civicdb.org/links/genes/1733 false UGT1A 7361 EXPRESSION Colorectal Cancer 9256 Ganetespib Predictive Supports D Resistance Colorectal cancer cell lines were evaluated for response to the HSP90 inhibitor ganetespib. Correlating cell line-specific IC50s with the corresponding gene expression patterns revealed a possible relationship to UGT1A expression. High UGT1A expression was correlated with ganetespib resistance. Knockdown of UGT1A sensitized HT29 cells to HSP90 inhibition. HCT116 and SW480 cell lines became resistant through UGT1A overexpression. 25210794 PubMed Landmann et al., 2014, Cell Death Dis 3 accepted 866 363 6023 2 234526291 234681956 ENST00000373450.4 75 GRCh37 N/A 2016-02-22 03:01:10 UTC https://civicdb.org/links/evidence_items/866 https://civicdb.org/links/variants/363 https://civicdb.org/links/genes/6023 false ERBB4 2066 NUCLEAR TRANSLOCATION Breast Cancer 1612 Trastuzumab Predictive Supports D Resistance HER4 nuclear translocation was identified as a mediator of trastuzumab resistance in HER2 positive breast cancer cell lines. Increased nuclear staining was also identified in xenograft and patient samples after trastuzumab treatment. 25153719 PubMed Mohd Nafi et al., 2014, Oncotarget 2 accepted 867 364 1734 2 212240446 213403565 ENST00000342788.4 75 GRCh37 N/A 2016-02-21 04:48:57 UTC https://civicdb.org/links/evidence_items/867 https://civicdb.org/links/variants/364 https://civicdb.org/links/genes/1734 false ERBB4 2066 EXPRESSION Breast Cancer 1612 Trastuzumab Predictive Supports D Resistance siRNA knockdown of HER4 or inhibition with neratinib enhanced trastuzumab response in breast cancer cell lines. 25153719 PubMed Mohd Nafi et al., 2014, Oncotarget 2 accepted 868 365 1734 2 212240446 213403565 ENST00000342788.4 75 GRCh37 N/A 2017-10-12 21:20:20 UTC https://civicdb.org/links/evidence_items/868 https://civicdb.org/links/variants/365 https://civicdb.org/links/genes/1734 false ERBB4 2066 EXPRESSION Breast Cancer 1612 Lapatinib Predictive Supports D Resistance ERBB4 protein expression was identified in breast cancer cell lines with acquired lapatinib resistance. Genetic ablation of ERBB4 (not ERBB1-3) led to apoptosis in trastuzumab- and lapatinib resistant cells, probably through a decrease in the PI3K/Akt pathway. 25590338 PubMed Canfield et al., 2015, Cell Cycle 3 accepted 869 365 1734 2 212240446 213403565 ENST00000342788.4 75 GRCh37 N/A 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/869 https://civicdb.org/links/variants/365 https://civicdb.org/links/genes/1734 false SLFN11 91607 EXPRESSION Colorectal Cancer 9256 7-Ethyl-10-Hydroxycamptothecin Predictive Supports D Sensitivity/Response In this study, SLFN11 expression was associated with sensitivity to SN-38 (an active metabolite of topoisomerase inhibitor irinotecan). 25089570 PubMed Tian et al., 2014, Anticancer Drugs 2 accepted 870 366 16872 17 33677324 33700639 ENST00000394566.1 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/870 https://civicdb.org/links/variants/366 https://civicdb.org/links/genes/16872 false AURKA 6790 Overexpression Lung Non-small Cell Carcinoma 3908 Cisplatin Predictive Supports B Resistance High levels of Aurora-A expression (retrospectively assessed by IHC in 102 NSCLC patients) predicted poorer overall survival and progression free survival in a population treated with surgery and cisplatin-based chemotherapy. In-vitro data confirmed these results and overexpression or knockdown of AURKA decreased or increased in-vitro sensitivity to cisplatin. 25082261 PubMed Xu et al., 2014, J Transl Med 4 accepted 871 181 61 20 54944446 54967393 ENST00000395913.3 75 GRCh37 N/A 2016-02-16 19:52:36 UTC https://civicdb.org/links/evidence_items/871 https://civicdb.org/links/variants/181 https://civicdb.org/links/genes/61 false KRAS 3845 RS61764370 Head And Neck Squamous Cell Carcinoma 5520 Cisplatin Predictive Supports B Resistance In the retrospective analysis of 103 HNSSC, the TG/GG rs61764370 variant was associated with poor response to cisplatin (log-rank P = 0.002).There seemed to be some improvement when cetuximab was added to their platinum-based regimen (log-rank P = 0.04). 25081901 PubMed Chung et al., 2014, Ann. Oncol. NCT00003809,NCT00425750,NCT00503997 3 accepted 872 254 30 12 25360224 25360224 A C ENST00000311936.3 75 GRCh37 Germline variant in the 3' UTR of KRAS that predicts resistance to platinum-based therapy. Common Germline 2016-02-13 04:02:42 UTC https://civicdb.org/links/evidence_items/872 https://civicdb.org/links/variants/254 https://civicdb.org/links/genes/30 false RAC1 5879 P29S Melanoma 1909 Vemurafenib,Dabrafenib Substitutes Predictive Supports D Resistance Melanoma cell lines harboring the RAC1 P29S hotspot mutation were shown to be resistant to BRAF inhibition with vemurafenib or dabrafenib and knock-in or knock-out of this mutation decreased and increased sensitivity to these drugs. 25056119 PubMed Watson et al., 2014, Cancer Res. 4 accepted 873 367 4753 7 6426892 6426892 C T ENST00000356142.4 75 GRCh37 Somatic 2016-02-20 23:28:17 UTC https://civicdb.org/links/evidence_items/873 https://civicdb.org/links/variants/367 https://civicdb.org/links/genes/4753 false BIRC5 332 NUCLEAR EXPRESSION Lung Non-small Cell Carcinoma 3908 Taxane Compound,Platinum Compound Combination Predictive Supports B Sensitivity/Response Patients with nuclear survivin (BIRC5) expression had significantly better responses to taxane-platinum chemotherapy than those with low tumor N-survivin expression (P < 0.001) in a retrospective analysis of 48 patients with non-small cell lung cancer. 24961465 PubMed Wu et al., 2014, Med. Oncol. 3 accepted 874 368 355 17 76210267 76221717 ENST00000301633.4 75 GRCh37 N/A 2016-02-16 14:48:00 UTC https://civicdb.org/links/evidence_items/874 https://civicdb.org/links/variants/368 https://civicdb.org/links/genes/355 false TP53 7157 Wildtype Colorectal Cancer 9256 Capecitabine,Cetuximab,Oxaliplatin Combination Predictive Supports B Sensitivity/Response In this retrospective biomarker analysis of the EXPERT-C trial, patients with TP53 wild-type status had a statistically significant better progression free survival (PFS) (89.3% vs 65.0% at 5 years; hazard ratio [HR] = 0.23; 95% confidence interval [CI] = 0.07 to 0.78; two-sided P = .02 by Cox regression) and overall survival (OS) (92.7% vs 67.5% at 5 years; HR = 0.16; 95% CI = 0.04 to 0.70; two-sided P = .02 by Cox regression) when treated with Cetuximab + CAPOX (Capecitabine, Oxaliplatin) than in the control arm without Cetuximab. 24957073 PubMed Sclafani et al., 2014, J. Natl. Cancer Inst. 3 accepted 875 369 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 N/A 2016-02-12 23:34:03 UTC https://civicdb.org/links/evidence_items/875 https://civicdb.org/links/variants/369 https://civicdb.org/links/genes/45 false MRE11 4361 Loss Endometrial Cancer 1380 Talazoparib Predictive Supports D Sensitivity/Response One endometrial cell line with decreased MRE11 expression caused by a homozygous poly(T) mutation exhibited increased sensitivity to the PARP inhibitor BMN-673. Loss of MRE11 was identified in 30.7% of endometrial tumors (N=521). 24927325 PubMed Koppensteiner et al., 2014, PLoS ONE 2 accepted 876 370 3586 11 94152895 94227074 ENST00000323929.3 75 GRCh37 N/A 2016-02-21 17:48:52 UTC https://civicdb.org/links/evidence_items/876 https://civicdb.org/links/variants/370 https://civicdb.org/links/genes/3586 false ATM 472 Underexpression Gastric Adenocarcinoma 3717 Olaparib Predictive Supports D Sensitivity/Response Low ATM protein expression led to sensitivity to PARP inhibitors in TP53 -ve gastric cancer cell lines (8 lines were used for various aspects of this study). 24841718 PubMed Kubota et al., 2014, Cell Cycle 4 accepted 878 179 69 11 108093559 108239826 ENST00000278616.4 75 GRCh37 N/A 2016-02-21 17:47:42 UTC https://civicdb.org/links/evidence_items/878 https://civicdb.org/links/variants/179 https://civicdb.org/links/genes/69 false EGFR 1956 L858R Lung Adenocarcinoma 3910 Afatinib Predictive Supports B Sensitivity/Response A phase III clinical trial (NCT00949650) found that median progression free survival among patients with exon 19 deletions or L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = 0.001). 23816960 PubMed Sequist et al., 2013, J. Clin. Oncol. NCT00949650 4 accepted 879 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/879 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 Exon 19 Deletion Lung Adenocarcinoma 3910 Afatinib Predictive Supports B Sensitivity/Response A phase III clinical trial (NCT00949650) found that median progression free survival among patients with EGFR exon 19 deletion was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). 308 patients had either exon 19 or L858 mutations. 23816960 PubMed Sequist et al., 2013, J. Clin. Oncol. NCT00949650 4 accepted 880 133 19 7 55242415 55242513 ENST00000275493.2 75 GRCh37 Deletions within exon 19 of EGFR are most common in lung cancer. These deletions, in non-small cell lung cancer, have been shown to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib, afatinib, and erlotinib. There is also data to suggest that this event is a good prognostic marker in lung adenocarcinoma. Examples of exon 19 deletions include: p.746_A750delELREA, p.747_753delinsS, p.747_752delLREATS, and p.747_751delLREAT. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/880 https://civicdb.org/links/variants/133 https://civicdb.org/links/genes/19 false EGFR 1956 Exon 19 Deletion Lung Non-small Cell Carcinoma 3908 Afatinib Predictive Supports D Sensitivity/Response Stable HEK293 cell lines expressing mutant EGFR cDNAs were created (using a pQCLIN retroviral vector) and their drug sensitivities to afatinib were examined by MTT assay. Phorphorylation of EGFR was assayed by Western blot. The 50% inhibitory concentration (IC50) of afatinib was significantly lower in cells harboring EGFR exon 19 deletion than in cells harboring EGFR L858R. 25862853 PubMed Banno et al., 2015, Anticancer Res. 2 accepted 881 133 19 7 55242415 55242513 ENST00000275493.2 75 GRCh37 Deletions within exon 19 of EGFR are most common in lung cancer. These deletions, in non-small cell lung cancer, have been shown to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib, afatinib, and erlotinib. There is also data to suggest that this event is a good prognostic marker in lung adenocarcinoma. Examples of exon 19 deletions include: p.746_A750delELREA, p.747_753delinsS, p.747_752delLREATS, and p.747_751delLREAT. Somatic 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/881 https://civicdb.org/links/variants/133 https://civicdb.org/links/genes/19 false EGFR 1956 Exon 19 Deletion Lung Adenocarcinoma 3910 Afatinib Predictive Supports B Sensitivity/Response In a phase 2 study (NCT00525148), patients with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) and EGFR mutations, treated with afatinib, were assessed by objective response. In total, 129 patients were treated with afatinib. 66% of the 106 patients with two common activating EGFR mutations (exon 19 deletion or L858R) had an objective response compared to 39% of 23 patients with less common EGFR mutations. 22452895 PubMed Yang et al., 2012, Lancet Oncol. NCT00525148 3 accepted 882 133 19 7 55242415 55242513 ENST00000275493.2 75 GRCh37 Deletions within exon 19 of EGFR are most common in lung cancer. These deletions, in non-small cell lung cancer, have been shown to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib, afatinib, and erlotinib. There is also data to suggest that this event is a good prognostic marker in lung adenocarcinoma. Examples of exon 19 deletions include: p.746_A750delELREA, p.747_753delinsS, p.747_752delLREATS, and p.747_751delLREAT. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/882 https://civicdb.org/links/variants/133 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Adenocarcinoma 3910 Afatinib Predictive Supports B Sensitivity/Response In a phase 2 study of patients with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) and EGFR mutations, treated with afatinib were assessed by objective response. 129 patients were treated with afatinib. 66% of the 106 patients with two common activating EGFR mutations (deletion 19 or L858R) had an objective response compared to 39% of 23 patients with less common mutations. 22452895 PubMed Yang et al., 2012, Lancet Oncol. NCT00525148 3 accepted 883 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/883 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 Exon 19 Deletion Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports B Sensitivity/Response A randomized phase 3 trial involving 173 NSCLC patients with EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease. Patients were randomly allocated (1:1) to receive either erlotinib or standard chemotherapy. The primary endpoint was progression-free survival (PFS). Median PFS was 9.7 months in the erlotinib group, compared with 5.2 months in the standard chemotherapy group. 22285168 PubMed Rosell et al., 2012, Lancet Oncol. NCT00446225 3 accepted 884 133 19 7 55242415 55242513 ENST00000275493.2 75 GRCh37 Deletions within exon 19 of EGFR are most common in lung cancer. These deletions, in non-small cell lung cancer, have been shown to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib, afatinib, and erlotinib. There is also data to suggest that this event is a good prognostic marker in lung adenocarcinoma. Examples of exon 19 deletions include: p.746_A750delELREA, p.747_753delinsS, p.747_752delLREATS, and p.747_751delLREAT. Somatic 2016-02-10 23:14:51 UTC https://civicdb.org/links/evidence_items/884 https://civicdb.org/links/variants/133 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports B Sensitivity/Response A randomized phase 3 trial (NCT00446225) involving 173 NSCLC patients with EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease. Patients were randomly allocated (1:1) to receive either erlotinib or standard chemotherapy. The primary endpoint was progression-free survival (PFS). Median PFS was 9.7 months in the erlotinib group, compared with 5.2 months in the standard chemotherapy group. 22285168 PubMed Rosell et al., 2012, Lancet Oncol. NCT00446225 3 accepted 885 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2016-02-18 18:40:33 UTC https://civicdb.org/links/evidence_items/885 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false ERBB2 2064 Amplification Uterine Corpus Endometrial Carcinoma 0050939 Afatinib Predictive Supports D Sensitivity/Response Eight uterine cancer cell lines (four with ERBB2 amplification and four without) were treated with scalar concentrations of afatinib. Primary chemotherapy-resistant USC cell lines harbouring ERBB2 gene amplification were sensitive to afatinib exposure and significantly more sensitive than non-amplified cell lines. 25268372 PubMed Schwab et al., 2014, Br. J. Cancer 2 accepted 886 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/886 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Afatinib,Lapatinib,Trastuzumab Substitutes Predictive Supports B Sensitivity/Response In this phase 2 trial, treatment-naive, ERBB2-positive (by IHC) breast cancer patients with stage IIIA, B, C or inflammatory disease were randomized 1:1:1 to afatinib (n = 10), lapatinib (n = 8), or trastuzumab (n = 11). The primary end point was objective response rate. Objective response was seen in 8 afatinib-, 6 lapatinib-, and 4 trastuzumab-treated patients. Afatinib demonstrated clinical activity that compared favorably to trastuzumab and lapatinib for neoadjuvant treatment of HER2-positive breast cancer. 25537159 PubMed Rimawi et al., 2015, Clin. Breast Cancer 2 accepted 887 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-02-18 04:13:55 UTC https://civicdb.org/links/evidence_items/887 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false TOP1 7150 Amplification Colorectal Cancer 9256 Irinotecan Predictive Supports B Sensitivity/Response FFPE tumor samples from 78 patients with colorectal cancer, who had received irinotecan monotherapy were analyzed with a FISH dual-probe. TOP1 gain was nonsignificantly associated with objective response to irinotecan Odds ratio (OR): 1.62; p = 0.07. 24256029 PubMed Nygård et al., 2014, Scand. J. Gastroenterol. 1 accepted 888 371 5845 20 39657458 39753127 ENST00000361337.2 75 GRCh37 Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/888 https://civicdb.org/links/variants/371 https://civicdb.org/links/genes/5845 false CDKN1B 1027 EXPRESSION Head And Neck Squamous Cell Carcinoma 5520 Fluorouracil,Cisplatin Combination Predictive Supports B Sensitivity/Response 41 HNSSC were analyzed by IHC for expression of EGFR, p53, CCND1, p16, p21, p27 (CDKN2B), p-AKT, HIF-1a, Caspase 3 and BCL2. p27 was the only protein that served as a predictive biomarker of response after multivariate analysis (p=0.025; n=41 patients). 24239278 PubMed Moreno-Galindo et al., 2014, Oral Oncol. 2 accepted 889 372 914 12 12870058 12875305 ENST00000228872.4 75 GRCh37 N/A 2016-02-13 05:34:27 UTC https://civicdb.org/links/evidence_items/889 https://civicdb.org/links/variants/372 https://civicdb.org/links/genes/914 false MET 4233 Amplification Lung Squamous Cell Carcinoma 3907 Crizotinib Predictive Supports C Sensitivity/Response Case report of a 73 year old patient with advanced squamous cell carcinoma of the lung that tested negative for EGFR, KRAS and PIK3CA mutations and ALK and ROS1 rearrangements. c-MET amplification was detected by FISH. Crizotinib led to a partial response. 24192513 PubMed Schwab et al., 2014, Lung Cancer 2 accepted 890 270 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 Somatic 2016-02-21 18:48:51 UTC https://civicdb.org/links/evidence_items/890 https://civicdb.org/links/variants/270 https://civicdb.org/links/genes/52 false AGR2 10551 EXPRESSION Breast Cancer 1612 Tamoxifen Predictive Supports B Resistance mRNA expression of AGR2 in 61 patients with tamoxifen treated postmenopausal breast cancer was determined by qRT-PCR and was inversely associated with treatment response and progression free survival (p= 0.0011, p = 0.0366 respectively). AGR2 protein expression as assessed by IHC was not significantly associated with treatment outcome. 24167368 PubMed Hrstka et al., 2013, Dis. Markers 1 accepted 891 373 8407 7 16831435 16844704 ENST00000419304.2 75 GRCh37 N/A 2016-02-21 17:46:45 UTC https://civicdb.org/links/evidence_items/891 https://civicdb.org/links/variants/373 https://civicdb.org/links/genes/8407 false PIK3CA 5290 Mutation Endometrial Cancer 1380 Temsirolimus,Ridaforolimus Substitutes Predictive Does Not Support B Sensitivity/Response 94 endometrial cancer samples of women who had been treated with single agent mTOR inhibitors temsirolimus or ridaforolimus were retrospectively analyzed. No predictive biomarkers were identified, including PIK3CA mutations (N=21/73), KRAS mutations (10/73) or PTEN loss. 24166148 PubMed Mackay et al., 2014, Cancer 3 accepted 892 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-02-07 04:26:11 UTC https://civicdb.org/links/evidence_items/892 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PTEN 5728 Loss Endometrial Cancer 1380 Ridaforolimus,Temsirolimus Substitutes Predictive Does Not Support B Resistance 94 endometrial cancer samples of women who had been treated with single agent mTOR inhibitors temsirolimus or ridaforolimus were retrospectively analyzed. No predictive biomarkers were identified, including PIK3CA mutations, KRAS mutations or PTEN loss. 24166148 PubMed Mackay et al., 2014, Cancer 3 accepted 893 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-02-10 17:07:21 UTC https://civicdb.org/links/evidence_items/893 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false KRAS 3845 Mutation Endometrial Cancer 1380 Ridaforolimus,Temsirolimus Substitutes Predictive Does Not Support B Sensitivity/Response 94 endometrial cancer samples of women who had been treated with single agent mTOR inhibitors temsirolimus or ridaforolimus were retrospectively analyzed. Mutations were found in 32 of 73 analyzed tumors, 10 of which were KRAS mutations. No predictive biomarkers were identified, including PIK3CA mutations, KRAS mutations or PTEN loss. 24166148 PubMed Mackay et al., 2014, Cancer 2 accepted 894 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-02-13 19:33:54 UTC https://civicdb.org/links/evidence_items/894 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false ERBB2 2064 Amplification Colorectal Cancer 9256 Oxaliplatin,Cetuximab,Capecitabine Combination Predictive Does Not Support B Resistance 141 patients were analyzed for ERBB2 (HER2) positivity by FISH and/or IHC. Only 6 (4.3%) were ERBB2 positive. These patients did not show a difference in outcome after capecitabine, oxaliplatin and chemoradiotherapy, with or without cetuximab. 24146218 PubMed Sclafani et al., 2013, Ann. Oncol. 1 accepted 895 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. N/A 2016-10-06 18:38:50 UTC https://civicdb.org/links/evidence_items/895 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false FGFR1 2260 Expression Colorectal Cancer 9256 Infigratinib Predictive Supports D Sensitivity/Response In vitro studies showed efficacy of FGFR inhibitor NVP-BGJ398 in cell lines exhibiting high FGFR1 protein. Three cell lines (SNU-C1, HDC9, HCT116) were analyzed. FGFR1 amplification (24/454, assessed by FISH) and/or activated pFGFR1 protein (18/99, assessed by mRNA in situ hybridization) was identified in primary CRC tissue samples. 24135816 PubMed Göke et al., 2013, Digestion 2 accepted 896 268 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 high expression has been reported in 11.8% (178 patients) of oral squamous cell carcinoma patients, and was enriched in early stages (Freier et. al., 2007). Another study reports FGFR1 expression in 35% of primary HNSSC (353 patients) (Göke et. al., 2015). In both studies, FGFR1 gene amplification and expression do not correlate well with about 35% of samples with FGFR1 amplification overexpressing FGFR1 (Göke et. al., 2015). FGFR1 expression also correlated with sensitivity to FGFR1 inhibitors in preclinical models of lung cancer (Wynes et. al., 2014), HNSSC (Göke et. al., 2015) and urothelial carcinoma (Lamont et. al., 2011). N/A 2016-02-21 18:50:39 UTC https://civicdb.org/links/evidence_items/896 https://civicdb.org/links/variants/268 https://civicdb.org/links/genes/1885 false NAPRT 93100 Promoter Hypermethylation Cancer 162 GNE-617 Predictive Supports D Sensitivity/Response Tumor-specific promoter hypermethylation of NAPRT1 led to loss of NAPRT1 expression in most tumor types sensitive to treatment with Nampt inhibitor GNE-617 and nicotinic acid. 24097869 PubMed Shames et al., 2013, Clin. Cancer Res. 3 accepted 897 374 17016 Somatic 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/897 https://civicdb.org/links/variants/374 https://civicdb.org/links/genes/17016 false EGFR 1956 Exon 18 Overexpression Lung Non-small Cell Carcinoma 3908 Bevacizumab,Erlotinib Combination Predictive Supports B Sensitivity/Response Overexpression of EGFR exon 18 (Affymetrix Human Exon 1.0 ST) in tumor or blood samples was associated with tumor shrinkage, independently of EGFR mutational status in NSCLC treated with bevacizumab and erlotinib. 76 patients were analyzed for this study. 24039832 PubMed Baty et al., 2013, PLoS ONE 2 accepted 898 375 19 7 55237999 55238735 ENST00000344576.2 75 GRCh37 N/A 2016-02-22 20:26:59 UTC https://civicdb.org/links/evidence_items/898 https://civicdb.org/links/variants/375 https://civicdb.org/links/genes/19 false ZEB1 6935 Expression Mantle Cell Lymphoma 0050746 Doxorubicin,Gemcitabine,Cytarabine Substitutes Predictive Supports D Resistance Downregulation of ZEB1 expression in mantle cell lymphoma cell lines and mouse xenografts led to enhanced sensitivity towards treatment with doxorubicin, cytarabin and gemcitabine. 24013721 PubMed Sánchez-Tilló et al., 2014, Cell Death Differ. 2 accepted 899 376 5649 10 31608101 31818741 ENST00000361642.5 75 GRCh37 N/A 2016-02-21 17:39:29 UTC https://civicdb.org/links/evidence_items/899 https://civicdb.org/links/variants/376 https://civicdb.org/links/genes/5649 false ZEB1 6935 Expression Mantle Cell Lymphoma 0050746 Salinomycin,Doxorubicin Combination Predictive Supports D Sensitivity/Response Downregulation of ZEB1 expression in mantle cell lymphoma cell lines and mouse xenografts led to enhanced sensitivity towards treatment with doxorubicin, cytarabin and gemcitabine. the combination of salinomycin (downregulating ZEB1) and doxorubicin was syngergistic. 24013721 PubMed Sánchez-Tilló et al., 2014, Cell Death Differ. 3 accepted 900 376 5649 10 31608101 31818741 ENST00000361642.5 75 GRCh37 Somatic 2017-04-21 18:58:16 UTC https://civicdb.org/links/evidence_items/900 https://civicdb.org/links/variants/376 https://civicdb.org/links/genes/5649 false TIMP1 7076 Overexpression Breast Cancer 1612 Fulvestrant Predictive Supports D Resistance TIMP1 overexpression was associated with resistance to fulvestrant in breast cancer cell lines. 23881388 PubMed Bjerre et al., 2013, Tumour Biol. 2 accepted 901 377 5777 X 47441712 47446188 ENST00000218388.4 75 GRCh37 N/A 2016-02-17 23:00:11 UTC https://civicdb.org/links/evidence_items/901 https://civicdb.org/links/variants/377 https://civicdb.org/links/genes/5777 false PTP4A3 11156 OVEREXPRESSION Colorectal Cancer 9256 Cetuximab Predictive Supports D Sensitivity/Response In-vitro studies linked PRL-3 (PP4A3) expression to hyperactivation and dependence on EGFR signaling (through downregulation of PTP1B, an inhibitory phosphatase of EGFR). Retrospective analysis of 68 patients showed improved clinical response to the EGFR inhibitor cetuximab in tumors expressing PRL-3. 23867504 PubMed Al-Aidaroos et al., 2013, J. Clin. Invest. 3 accepted 902 378 8908 8 142402093 142441394 ENST00000521578.1 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/902 https://civicdb.org/links/variants/378 https://civicdb.org/links/genes/8908 false TYMS 7298 Amplification Lung Adenocarcinoma 3910 Pemetrexed Predictive Supports B Resistance TYMS copy number was lower in clinical samples responding to pemetrexed in combination with platinum (n=25). The same was found in 17 cell lines. 23645741 PubMed Kasai et al., 2013, Anticancer Res. 3 accepted 903 379 5971 18 657604 673578 ENST00000323274.10 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/903 https://civicdb.org/links/variants/379 https://civicdb.org/links/genes/5971 false IGF1R 3480 EXPRESSION Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports D Resistance Expression of IGF1R in NSCLC cell lines (n=17) was associated with resistance to EGFR inhibitor gefitinib, however, knock-in or knock-out of IGF1R did not affect gefitinib sensitivity. IGF1R expression was also higher in patients with disease progression after gefitinib therapy in a clinical cohort (n=98). 23619944 PubMed Peled et al., 2013, Cell Oncol (Dordr) 2 accepted 904 380 2899 15 99192200 99507759 ENST00000268035.6 75 GRCh37 N/A 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/904 https://civicdb.org/links/variants/380 https://civicdb.org/links/genes/2899 false EPHB4 2050 EXPRESSION Colorectal Cancer 9256 Bevacizumab Predictive Supports B Resistance EPHB4 expression, as assessed by quantitative RT-PCR in 13 colorectal cancer patients treated with bevacizumab, was higher in non-responders (p = 0.048). No difference was observed in a control group without bevacizumab treatment. qRT-PCR results were also shown to correlate with protein expression measured by IHC. 23579861 PubMed Guijarro-Muñoz et al., 2013, Med. Oncol. 2 accepted 905 381 1721 7 100400187 100425121 ENST00000358173.3 75 GRCh37 N/A 2016-02-22 20:28:42 UTC https://civicdb.org/links/evidence_items/905 https://civicdb.org/links/variants/381 https://civicdb.org/links/genes/1721 false TP53 7157 Wildtype Esophageal Carcinoma 1107 Chemotherapy Predictive Supports B Sensitivity/Response Patients with p53 wild type (as defined by low expression and/or wild-type tp53 gene) had a higher response rate to chemotherapy-based treatment (total major response [MR]: risk ratio [RR] = 1.09, 95 % CI = 1.03-1.16, P = .003; pathological MR: RR = 1.15, 95 % CI = 1.06-1.25, P = .001; total complete response [CR]: RR = 1.08, 95 % CI = 1.00-1.17, P = .040) in this meta-analysis (28 studies, 1497 cases). 23515910 PubMed Zhang et al., 2013, Ann. Surg. Oncol. 3 accepted 906 369 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 N/A 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/906 https://civicdb.org/links/variants/369 https://civicdb.org/links/genes/45 false TYMS 7298 Underexpression Lung Non-small Cell Carcinoma 3908 Pemetrexed Predictive Supports B Sensitivity/Response 49 tumor specimens from 268 NSCLC patients treated with pemetrexed were evaluated for expression of TYMS and DHFR by IHC and compared to treatment outcomes. Patients with low TS (≤150) expression had a longer median progression-free survival (PFS) than those with high TS (>150) expression (4.8 vs. 3.4 months; p=0.01). 21367480 PubMed Chen et al., 2011, Lung Cancer 3 accepted 907 382 5971 18 657604 673578 ENST00000323274.10 75 GRCh37 N/A 2016-02-13 03:48:15 UTC https://civicdb.org/links/evidence_items/907 https://civicdb.org/links/variants/382 https://civicdb.org/links/genes/5971 false TYMS 7298 Underexpression Prostate Cancer 10283 Pemetrexed Predictive Supports C Sensitivity/Response Case report of a patient with metastatic prostate cancer and underexpression of TYMS who showed a nonspecified response to pemetrexed for at least 4 months. 24782778 PubMed Russell et al., 2014, Front Pharmacol 2 accepted 908 382 5971 18 657604 673578 ENST00000323274.10 75 GRCh37 N/A 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/908 https://civicdb.org/links/variants/382 https://civicdb.org/links/genes/5971 false TOP2A 7153 EXPRESSION Breast Cancer 1612 Doxorubicin Predictive Supports B Sensitivity/Response In a retrospective study, TOP2A expression was assessed by IHC for 108 breast cancer patients (from TAX 303 trial). TOP2A expression was associated with a higher probability of response in doxorubicin treated but not in docetaxel treated breast cancer patients. 15486187 PubMed Durbecq et al., 2004, Mol. Cancer Ther. 2 accepted 909 383 5848 17 38544768 38574202 ENST00000423485.1 75 GRCh37 N/A 2016-02-18 18:42:18 UTC https://civicdb.org/links/evidence_items/909 https://civicdb.org/links/variants/383 https://civicdb.org/links/genes/5848 false TOP1 7150 EXPRESSION Ovarian Cancer 2394 Cyclophosphamide,Carboplatin,Topotecan Combination Predictive Supports B Sensitivity/Response Shorter progression free survival was observed in patients with low expression (IHC) of topoisomerase 1 in 16 patients with relapsed or persistent ovarian or peritoneal carcinoma after treatment with topotecan, cyclophosphamide and carboplatin followed by an autologous hematopoietic stem cell transplant. 19648970 PubMed Litzow et al., 2010, Bone Marrow Transplant. NCT00652691 2 accepted 910 384 5845 20 39657458 39753127 ENST00000361337.2 75 GRCh37 N/A 2016-02-24 00:21:14 UTC https://civicdb.org/links/evidence_items/910 https://civicdb.org/links/variants/384 https://civicdb.org/links/genes/5845 false EGFR 1956 Amplification Colorectal Cancer 9256 Cetuximab Predictive Supports B Sensitivity/Response 87 patients with metastatic colorectal cancer treated with cetuximab were retrospectively analyzed for EGFR amplifications by FISH. In multivariate analysis, EGFR amplification predicted response and overall survival independent of KRAS status. 18794099 PubMed Personeni et al., 2008, Clin. Cancer Res. 3 accepted 911 190 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2016-01-27 00:50:57 UTC https://civicdb.org/links/evidence_items/911 https://civicdb.org/links/variants/190 https://civicdb.org/links/genes/19 false TOP1 7150 EXPRESSION Colorectal Cancer 9256 Irinotecan Predictive Supports B Sensitivity/Response 498 patients were retrospectively analyzed for topoisomerase 1 expression (IHC). In the subgroup of patients treated with irinotecan (38% of the 498), those patients expressing Topoisomerase I had a better overall survival according to multivariate analysis (HR = 0.47, 95% CI 0.23-0.94, p = 0.033). 19775480 PubMed Kostopoulos et al., 2009, BMC Cancer 3 accepted 912 384 5845 20 39657458 39753127 ENST00000361337.2 75 GRCh37 N/A 2016-02-20 00:35:07 UTC https://civicdb.org/links/evidence_items/912 https://civicdb.org/links/variants/384 https://civicdb.org/links/genes/5845 false PRKAA2 5563 T172 PHOSPHORYLATION Cancer 162 ACLY SiRNA Predictive Supports E Sensitivity/Response Low levels of baseline p-AMPK (PRKAA2, measured at Thr172) were predictive of efficacy of ACLY inhibition by siRNA in cell lines of various cancer histologies. 23506848 PubMed Migita et al., 2013, Am. J. Pathol. 2 accepted 913 385 4503 1 57159476 57159478 ENST00000371244.4 75 GRCh37 N/A 2016-02-22 20:41:27 UTC https://civicdb.org/links/evidence_items/913 https://civicdb.org/links/variants/385 https://civicdb.org/links/genes/4503 false HSPA5 3309 EXPRESSION Colorectal Cancer 9256 Fluorouracil Predictive Supports B Sensitivity/Response Expression of GRP78 (HSPA5) in colorectal cancer patients (n=396, by IHC) showed improved benefit from adjuvant chemotherapy in stage III patients (52% vs. 28%; p = 0.026). In vitro, GRP78 inhibition reduced response to 5-FU. 23456958 PubMed Thornton et al., 2013, Int. J. Cancer 4 accepted 914 386 2778 9 127997132 128003609 ENST00000324460.6 75 GRCh37 N/A 2016-02-14 00:35:45 UTC https://civicdb.org/links/evidence_items/914 https://civicdb.org/links/variants/386 https://civicdb.org/links/genes/2778 false PIK3CA 5290 Mutation Colorectal Cancer 9256 Anti-EGFR Monoclonal Antibody Predictive Supports B Resistance A meta-analysis of 8 metastatic colorectal cancer studies (839 patients) was performed. PIK3CA mutations were significantly associated with shorter PFS and OS following therapy with anti-EGFR monoclonal antibodies (PFS: 8 studies, 839 patients; HR = 1.53; 95 % confidence interval (CI) 1.28-1.84; P < 0.001; OS: 5 studies; 587 patients; HR = 1.28; 95 % CI 1.05-1.56; P = 0.015). 23435830 PubMed Wu et al., 2013, J. Cancer Res. Clin. Oncol. 4 accepted 915 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-02-14 00:26:17 UTC https://civicdb.org/links/evidence_items/915 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false KRAS 3845 Exon 2 Mutation Pancreatic Carcinoma 4905 Erlotinib Predictive Does Not Support B Resistance KRAS exon 2 was mutated in 121 of 173 (70%) patients with advanced pancreatic cancer and did not show an association with response to erlotinib treatment. 23435671 PubMed Boeck et al., 2013, J. Gastroenterol. 3 accepted 916 75 30 12 25398208 25398329 ENST00000256078.4 75 GRCh37 Exon 2 mutations have been associated with reduced response rates or resistance to EGFR inhibitors in non-small cell lung and colorectal cancer. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. Somatic 2016-02-13 04:06:29 UTC https://civicdb.org/links/evidence_items/916 https://civicdb.org/links/variants/75 https://civicdb.org/links/genes/30 false KRAS 3845 Exon 2 Mutation Pancreatic Carcinoma 4905 Prognostic Supports B Poor Outcome KRAS exon 2 was mutated in 121 of 173 patients with advanced pancreatic cancer. Patients with KRAS wildtype had an improved OS (HR 1.68, p = 0.005). 23435671 PubMed Boeck et al., 2013, J. Gastroenterol. 3 accepted 917 75 30 12 25398208 25398329 ENST00000256078.4 75 GRCh37 Exon 2 mutations have been associated with reduced response rates or resistance to EGFR inhibitors in non-small cell lung and colorectal cancer. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. Somatic 2016-02-08 21:26:48 UTC https://civicdb.org/links/evidence_items/917 https://civicdb.org/links/variants/75 https://civicdb.org/links/genes/30 false EIF4EBP1 1978 PHOSPHORYLATION Gastric Adenocarcinoma 3717 Everolimus Predictive Supports D Sensitivity/Response 8 gastric cancer cell lines were treated with the MTOR inhibitor everolimus. Cell proliferation was effectively inhibited in 3 cell lines by everolimus. Phosphorylated EIF4EBP1 (T37/46, T70) levels were higher in cell lines and xenografts sensitive to everolimus. 23340172 PubMed Nishi et al., 2013, Cancer Lett. 2 accepted 918 387 1655 8 37888200 37914663 ENST00000338825.4 75 GRCh37 N/A 2016-02-22 20:38:35 UTC https://civicdb.org/links/evidence_items/918 https://civicdb.org/links/variants/387 https://civicdb.org/links/genes/1655 false KIT 3815 Mutation Gastrointestinal Stromal Tumor 9253 Pictilisib,Imatinib Combination Predictive Supports D Sensitivity/Response Human GISTs with different KIT mutations were grafted in 136 nude muce. Mice were then treated with control, imatinib, GDC-0941, or GDC-0941 + imatinib. The combination showed superior antitumor efficacy that was sustained after treatment withdrawal. 23231951 PubMed Floris et al., 2013, Clin. Cancer Res. 2 accepted 919 388 29 4 55524085 55606881 ENST00000288135.5 75 GRCh37 Somatic 2016-02-21 16:08:21 UTC https://civicdb.org/links/evidence_items/919 https://civicdb.org/links/variants/388 https://civicdb.org/links/genes/29 false TUBB3 10381 EXPRESSION Cancer 162 Paclitaxel Predictive Supports D Resistance High expression of class 3 beta-tubulin led to decreased effect of paclitaxel on cell motility in HeLa, MCF-7 and CHO cell lines. 21576762 PubMed Ganguly et al., 2011, Oncotarget 2 accepted 920 389 8262 16 89989687 90002505 ENST00000315491.7 75 GRCh37 N/A 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/920 https://civicdb.org/links/variants/389 https://civicdb.org/links/genes/8262 false TUBB3 10381 EXPRESSION Breast Cancer 1612 Taxane Compound Predictive Supports B Sensitivity/Response High expression of betaIII-tubulin, as assessed in 85 breast cancers by IHC, was associated with better pathological response. 23218766 PubMed Wang et al., 2013, Clin. Breast Cancer 2 accepted 921 389 8262 16 89989687 90002505 ENST00000315491.7 75 GRCh37 N/A 2016-02-20 21:53:48 UTC https://civicdb.org/links/evidence_items/921 https://civicdb.org/links/variants/389 https://civicdb.org/links/genes/8262 false TYMS 7298 Overexpression Lung Non-small Cell Carcinoma 3908 Pemetrexed Predictive Supports B Resistance mRNA levels of TYMS, DHFR and GARFT were assessed (rt-PCR) in 50 patient samples of NSCLC. TYMS mRNA levels were lower in responders compared to non-responders to pemetrexed (1.671 ± 0.844 versus 5.978 ± 1.895, p=0.0142). 23060591 PubMed Shimizu et al., 2012, Anticancer Res. 3 accepted 922 347 5971 18 657604 673578 ENST00000323274.10 75 GRCh37 N/A 2016-02-13 03:47:34 UTC https://civicdb.org/links/evidence_items/922 https://civicdb.org/links/variants/347 https://civicdb.org/links/genes/5971 false EGFR 1956 Y1092 PHOSPHORYLATION Lung Non-small Cell Carcinoma 3908 Erlotinib,Gefitinib Substitutes Predictive Supports B Sensitivity/Response While EGFR mutation is a strong predictive factor for EGFR inhibition, some patients with EGFR wild-type also respond. The authors investigated whether phosphorylated EGFR could be a potential predictive biomarker in patients with wild-type EGFR. Phosphorylation of Y1068 (assessed by IHC) was associated with improved progression free survival (PFS) in 205 patients with stage IIb and IV NSCLC treated with EGFR tyrosine kinase inhibitors (gefitinib or erlotinib) compared to phospho-Y1068 negative patients (median PFS 7.0 months vs. 1.2 months, P < 0.001). In this group, 92 (44.9%) were EGFR mutant. In a subgroup of patients with wild-type EGFR, phospho-Y1068 expression positive patients had a significantly prolonged PFS (4.2 months vs.1.2 months P < 0.001) compared with those without phospho-Y1068 expression. 22901364 PubMed Wang et al., 2012, J. Exp. Clin. Cancer Res. 3 accepted 923 390 19 7 55272951 55272953 ENST00000275493.2 75 GRCh37 Although referred to as Y1068 in the literature, based on the recognition peptide described, this tyrosine occurs at Y1039 (ENST00000454757.2 v75) or Y1092 (ENST00000275493.2 v75). N/A 2016-02-18 18:32:19 UTC https://civicdb.org/links/evidence_items/923 https://civicdb.org/links/variants/390 https://civicdb.org/links/genes/19 false IGF1R 3480 NUCLEAR EXPRESSION Sarcoma 1115 IGF1R Monoclonal Antibody Predictive Supports B Sensitivity/Response IGF-1R nuclear immunostaining (IHC) was observed in 9 out of 16 samples of patients with different sarcomas (osteosarcoma, ewing sarcoma, liposarcoma, synovialsarcoma, desmoplastic tumor, rhabdomyosarcoma). Exclusive nuclear immunostaining was associated with better progression free survival and overall survival after therapy with IGF1R antibodies (R1507, IMC-A12, SCH 717454 and CP-751.871). 22682017 PubMed Asmane et al., 2012, Eur. J. Cancer NCT00474760,NCT00617890,NCT00642941,NCT00668148 2 accepted 924 391 2899 15 99192200 99507759 ENST00000268035.6 75 GRCh37 N/A 2016-02-20 03:01:05 UTC https://civicdb.org/links/evidence_items/924 https://civicdb.org/links/variants/391 https://civicdb.org/links/genes/2899 false CFLAR 8837 EXPRESSION Prostate Cancer 10283 Bicalutamide Predictive Supports D Resistance Expression of c-FLIP (CFLAR) in 50 prostate specimens (assessed by IHC) was increased in castrate-resistant prostate cancer. In-vitro, silencing of CFLAR led to sensitization of two cell lines to bicalutamide. 22623731 PubMed McCourt et al., 2012, Clin. Cancer Res. 3 accepted 925 392 7009 2 201980827 202041410 ENST00000309955.3 75 GRCh37 N/A 2016-02-21 16:27:54 UTC https://civicdb.org/links/evidence_items/925 https://civicdb.org/links/variants/392 https://civicdb.org/links/genes/7009 false PROM1 8842 EXPRESSION Hepatocellular Carcinoma 684 Sorafenib Predictive Supports B Resistance CD133 (PROM1) expression in 39 samples of hepatocellular carcinomas was correlated with JNK activity. Both were more highly expressed in patients not responding to sorafenib. CD133+ cells (sorted) were xenografted into mice, producing larger, more JNK inhibitor responsive tumors than CD133- xenografts. 22596232 PubMed Hagiwara et al., 2012, Br. J. Cancer 2 accepted 926 393 7014 4 15969857 16085324 ENST00000510224.1 75 GRCh37 N/A 2016-02-21 16:45:56 UTC https://civicdb.org/links/evidence_items/926 https://civicdb.org/links/variants/393 https://civicdb.org/links/genes/7014 false TIMP1 7076 Overexpression Breast Cancer 1612 Paclitaxel Predictive Supports B Resistance High expression of TIMP-1 was assessed by IHC in 99 primary breast cancers that had not spread beyond the breast after 6 postoperative courses of paclitaxel-based chemotherapy. High TIMP1 levels were associated with worse 5-year disease free survival (71.1%) than low levels (88.5 %; P = 0.020). High TIMP-1 levels were also associated with worse 5-year overall survival (78.9 %) than low levels (96.7 %; P = 0.004). 22544540 PubMed Zhu et al., 2012, Med. Oncol. 2 accepted 927 377 5777 X 47441712 47446188 ENST00000218388.4 75 GRCh37 N/A 2016-02-20 02:26:47 UTC https://civicdb.org/links/evidence_items/927 https://civicdb.org/links/variants/377 https://civicdb.org/links/genes/5777 false FOXP3 50943 EXPRESSION Breast Cancer 1612 Epirubicin Predictive Supports B Sensitivity/Response 1,097 patients with breast cancer were evaluated for FOXP3 expression by IHC. FOXP3 expression was found in 405 tumor samples and associated with improved OS in patients treated with anthracycline-based adjuvant chemotherapy (6 cycles of 'FEC100' aka epirubicin + cyclophosphamide + 5-fluorouracil) but not in patients treated with sequential anthracycline->taxane (3 cycles of FEC100 followed by 3 cycles of docetaxel). In-vitro experiments confirmed that FOXP3 expression enhance anthracycline efficacy. The in vitro data consisted of testing the sensitivity of various breast cancer cell lines to anthracyclines after treatment with valproic acid (which increases FOXP3 expression). The authors observed that, while valproic acid has no intrinsic cytotoxic effect on tumor cells, it enhanced the cytotoxic effect of epirubicin specifically in cell lines where FOXP3 expression was increased. 22431701 PubMed Ladoire et al., 2012, Ann. Oncol. 4 accepted 928 394 11587 X 49106897 49121288 ENST00000376207.4 75 GRCh37 N/A 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/928 https://civicdb.org/links/variants/394 https://civicdb.org/links/genes/11587 false TYMS 7298 Overexpression Gastric Adenocarcinoma 3717 Raltitrexed Predictive Supports B Resistance In 125 gastric tumors, plasma and tissue mRNA levels of TYMS were lower in the raltitrexed sensitive group compared to the resistant group (p = 0.007 and 0.013, respectively). 22422354 PubMed Shen et al., 2012, Int. J. Cancer 2 accepted 929 347 5971 18 657604 673578 ENST00000323274.10 75 GRCh37 N/A 2016-02-22 20:30:29 UTC https://civicdb.org/links/evidence_items/929 https://civicdb.org/links/variants/347 https://civicdb.org/links/genes/5971 false RPS6 6194 PHOSPHORYLATION Gastric Adenocarcinoma 3717 Everolimus Predictive Supports D Sensitivity/Response 54 patients with advanced gastric cancer were treated with everolimus. Two patient responsed and potential biomarkers were explored. High pre-treatment expression of phosphorylated RPS6 (pS6; at Ser240/4) was associated with higher disease control rate and progression free survival (P=0.043, P=0.001 respectively; N=28). 22343617 PubMed Yoon et al., 2012, Br. J. Cancer 2 accepted 930 395 5013 9 19376309 19376323 ENST00000380394.4 75 GRCh37 N/A 2016-02-22 23:46:50 UTC https://civicdb.org/links/evidence_items/930 https://civicdb.org/links/variants/395 https://civicdb.org/links/genes/5013 false JAK1 3716 OVEREXPRESSION Lung Non-small Cell Carcinoma 3908 Enzastaurin Predictive Supports D Sensitivity/Response Overexpression of JAK1 in 22 lung cancer cell lines was associated with sensitivity to PKC-inhibitor enzastaurin. Silencing of JAK1 (by small molecule JAK 1/2/3 inhibitor) led to resistance. Overexpression of JAK1 (lentiviral mediated) led to sensitivity to enzastaurin. 22333600 PubMed Shimokawa et al., 2012, Br. J. Cancer 4 accepted 931 396 3090 1 65298912 65432187 ENST00000342505.4 75 GRCh37 N/A 2016-02-21 16:18:02 UTC https://civicdb.org/links/evidence_items/931 https://civicdb.org/links/variants/396 https://civicdb.org/links/genes/3090 false EIF4EBP1 1978 PHOSPHORYLATION Colorectal Cancer 9256 Dactolisib,WYE354,MTOR Kinase Inhibitor PP242 Substitutes Predictive Supports D Resistance 12 CRC cell lines were evaluated. 40% of these were intrinsically resistant to mTOR inhibition with BEZ235, PP242 or WYE354. mTOR independent phosphorylation of EIF4EBP1 (T37/46) was associated with resistance to mTOR inhibitors in one analyzed cell line (SW620). 22262166 PubMed Zhang et al., 2012, Cell Cycle 2 accepted 932 387 1655 8 37888200 37914663 ENST00000338825.4 75 GRCh37 N/A 2016-02-22 20:36:59 UTC https://civicdb.org/links/evidence_items/932 https://civicdb.org/links/variants/387 https://civicdb.org/links/genes/1655 false BRCA1 672 Expression Malignant Mesothelioma 1790 Vinorelbine Predictive Supports D Sensitivity/Response Expression of BRCA1 in 6 mesothelioma cell lines was associated with sensitivity to vinorelbine in functional studies. 22190288 PubMed Busacca et al., 2012, J. Pathol. 2 accepted 933 397 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 N/A 2016-02-21 16:47:25 UTC https://civicdb.org/links/evidence_items/933 https://civicdb.org/links/variants/397 https://civicdb.org/links/genes/6 false DUSP6 1848 EXPRESSION Cancer 162 Trametinib Predictive Supports D Sensitivity/Response Expression of DUSP6 was associated with sensitivity to MEK inhibitor GSK1120212 (Sensitivity: 79%; specificity: 82%: P = 0.0027) in 218 solid cancer cell lines. 22169769 PubMed Jing et al., 2012, Mol. Cancer Ther. 3 accepted 934 398 1567 12 89741009 89747048 ENST00000279488.7 75 GRCh37 N/A 2016-02-20 23:26:51 UTC https://civicdb.org/links/evidence_items/934 https://civicdb.org/links/variants/398 https://civicdb.org/links/genes/1567 false KRAS 3845 Mutation Cancer 162 Trametinib Predictive Supports D Sensitivity/Response In this screen of 218 solid cancer cell lines, KRAS and BRAF mutations were predictive of response to MEK inhibitor GSK1120212. 40 cell lines harbored a KRAS mutation. In RAF/RAS mutant colon cancer cell lines, co-occurring PIK3CA/PTEN mutations led to a cytostatic (9/10 cell lines) response rather than a cytotoxic response (1/10 cell lines). 22169769 PubMed Jing et al., 2012, Mol. Cancer Ther. 4 accepted 935 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/935 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false BRAF 673 Mutation Cancer 162 Trametinib Predictive Supports D Sensitivity/Response In this screen of 218 solid cancer cell lines, BRAF mutations were predictive of response to the MEK inhibitor GSK1120212. 26 of these cell lines had the BRAF V600E mutation, one cell line had a G469A mutation, one had G596R mutation and one had an unspecified mutation. Also of note, in RAF/RAS mutant colon cancer cell lines, co-occurring PIK3CA/PTEN mutations led to a cytostatic response rather than a cytotoxic response. 22169769 PubMed Jing et al., 2012, Mol. Cancer Ther. 4 accepted 936 399 5 7 140453136 140481403 ENST00000288602.6 75 GRCh37 Somatic 2016-02-18 18:35:39 UTC https://civicdb.org/links/evidence_items/936 https://civicdb.org/links/variants/399 https://civicdb.org/links/genes/5 false KRAS 3845 G12D Pancreatic Carcinoma 4905 Akt Inhibitor MK2206 Predictive Supports C Sensitivity/Response Among 33 patients treated with pan-AKT inhibitor MK-2206 in this phase 1 study, one patient with pancreatic adenocarcinoma and PTEN loss and a KRAS G12D mutation experienced a decrease of approximately 60% in cancer antigen 19-9 levels and 23% shrinkage in tumor measurements. 22025163 PubMed Yap et al., 2011, J. Clin. Oncol. 2 accepted 937 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2016-02-20 23:19:29 UTC https://civicdb.org/links/evidence_items/937 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false PTEN 5728 Loss Pancreatic Carcinoma 4905 Akt Inhibitor MK2206 Predictive Supports C Sensitivity/Response Among 33 patients treated with pan-AKT inhibitor MK-2206 in this phase 1 study, one patient with pancreatic adenocarcinoma and PTEN loss/KRAS G12D mutation experienced a decrease of approximately 60% in cancer antigen 19-9 levels and 23% shrinkage in tumor measurements. 22025163 PubMed Yap et al., 2011, J. Clin. Oncol. 2 accepted 938 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/938 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false HSPB1 3315 EXPRESSION Pancreatic Ductal Adenocarcinoma 3498 Gemcitabine Predictive Supports D Sensitivity/Response HSP27 (HSPB1) expression in pancreatic adenocarcinoma cell lines was associated with sensitivity to treatment with gemcitabine. 22004109 PubMed Schäfer et al., 2012, J. Cell. Mol. Med. 2 accepted 939 400 2784 7 75931861 75933612 ENST00000248553.6 75 GRCh37 N/A 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/939 https://civicdb.org/links/variants/400 https://civicdb.org/links/genes/2784 false NQO1 1728 EXPRESSION Lung Cancer 1324 Amrubicin Predictive Supports D Resistance Higher expression of NQO1 was correlated with decreased cytotoxicity of amrubicin (amrubicinol is the active metabolite) in 27 NSCLC and SCLC cell lines. siRNA knockdown of NQO1 (in two cell lines) increased amrubicinol cytotoxicity. 21964527 PubMed Takakuwa et al., 2011, J Thorac Oncol 2 accepted 940 401 1463 16 69743304 69760854 ENST00000320623.5 75 GRCh37 N/A 2016-02-21 16:33:42 UTC https://civicdb.org/links/evidence_items/940 https://civicdb.org/links/variants/401 https://civicdb.org/links/genes/1463 false NQO1 1728 P187S Lung Cancer 1324 Amrubicin Predictive Supports D Sensitivity/Response The presence of NQO1 C609T SNP (rs1800566) was associated with decreased protein expression and higher amrubicin sensitivity in 29 NSCLC and SCLC cell lines. 15 of these cell lines were genotyped for C609T (only 3 were T/T, and the rest were C/C or C/T). Cell lines with the T/T genotype had lower expression of NQ01 and greater response to amrubicinol. 21964527 PubMed Takakuwa et al., 2011, J Thorac Oncol 2 accepted 941 402 1463 16 69745145 69745145 G A ENST00000320623.5 75 GRCh37 Common Germline 2016-02-22 02:52:19 UTC https://civicdb.org/links/evidence_items/941 https://civicdb.org/links/variants/402 https://civicdb.org/links/genes/1463 false BRCA1 672 Underexpression Ovarian Cancer 2394 Platinum Compound,Taxane Compound Combination Predictive Supports B Sensitivity/Response Absent/low expression of BRCA1 (IHC) was associated with improved response to chemotherapy in 292 patients with sporadic ovarian cancer compared to patients with high expression (odds ratio 2.47: 95%CI 1.10-5.55, p=0.029). 21920589 PubMed Carser et al., 2011, Gynecol. Oncol. 3 accepted 942 403 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 N/A 2020-12-10 20:10:10 UTC https://civicdb.org/links/evidence_items/942 https://civicdb.org/links/variants/403 https://civicdb.org/links/genes/6 false KRAS 3845 Mutation Colorectal Cancer 9256 Immunomodulatory Oligonucleotide,Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Combination Predictive Supports D Sensitivity/Response TLR9 agonist immunomodulatory oligonucleotide (IMO) led to inhibited survival of LS174T colorectal cancer and AsPC1 pancreatic cancer cell lines with KRAS mutations. 21890455 PubMed Rosa et al., 2011, Clin. Cancer Res. 2 accepted 943 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-02-22 20:32:01 UTC https://civicdb.org/links/evidence_items/943 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false ABCB1 5243 Overexpression Lung Non-small Cell Carcinoma 3908 Paclitaxel Predictive Supports D Resistance mRNA expression of ABCB1 in 17 NSCLC cell lines was associated with decreased response to paclitaxel (correlation of mRNA expression and paclitaxel IC50: r=0.5322, P=0.0279). 21883677 PubMed Meng et al., 2011, Respirology 2 accepted 944 2915 4244 N/A 2021-04-16 15:15:33 UTC https://civicdb.org/links/evidence_items/944 https://civicdb.org/links/variants/2915 https://civicdb.org/links/genes/4244 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Pemetrexed Predictive Supports B Sensitivity/Response Among 95 patients with NSCLC in this study, 15 had an ALK translocation. ORR of these patients compared to EGFR mutated or wild-type tumors was superior (46.7 versus 4.7 versus 16.2%, p = 0.001). TYMS expression was lower in ALK-positive cells. 21642865 PubMed Lee et al., 2011, J Thorac Oncol 3 accepted 945 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-08-30 16:14:44 UTC https://civicdb.org/links/evidence_items/945 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false DNMT1 1786 EXPRESSION Gastric Adenocarcinoma 3717 Cisplatin Predictive Supports B Resistance High DNMT1 expression was found in 105/127 (83%) or patients (by qPCR assay). Low DNMT1 expression was associated with improved histopathological and clinical response and OS in patients with gastric cancer (P=0.03/P=0.008, P(log-rank)=0.001, respectively). In one cisplatin resistant cell line, DAC treatment and cisplatin had a synergistic effect. 21458988 PubMed Mutze et al., 2011, Eur. J. Cancer 3 accepted 946 335 1510 19 10244022 10305811 ENST00000340748.4 75 GRCh37 N/A 2016-02-14 00:37:28 UTC https://civicdb.org/links/evidence_items/946 https://civicdb.org/links/variants/335 https://civicdb.org/links/genes/1510 false KRAS 3845 Mutation Colorectal Cancer 9256 Dasatinib,Cetuximab Combination Predictive Supports D Sensitivity/Response Combined treatment with dasatinib and cetuximab, but not either agent in monotherapy, had an antitumor efficacy in-vitro and in xenografts. These results were based on three KRAS mutant cell lines (LS180, LoVo and HCT116) and two KRAS wild-type cell lines (SW48 and CaCo2). 20956938 PubMed Dunn et al., 2011, Oncogene 3 accepted 947 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-02-21 16:23:34 UTC https://civicdb.org/links/evidence_items/947 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false EGFR 1956 Amplification Lung Non-small Cell Carcinoma 3908 Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Predictive Supports B Sensitivity/Response A meta-analysis of EGFR gene copy number as a predictive biomarker for patients receiving tyrosine kinase inhibitor treatment was performed. In total, 20 (1689 patients, 594 with increased gene copy number), 10 (822 patients, 290 with increased gene copy number) and 5 studies (294 patients, 129 with increased gene copy number) were analyzed for overall survival (OS), progression-free survival (PFS) and time-to-progression (TTP) meta-analyses respectively. EGFR amplification was associated with increased OS (HR = 0.77; 95% CI 0.66-0.89; P = 0.001), PFS (HR = 0.60; 95% CI 0.46-0.79; P<0.001) and TTP (HR = 0.50; 95% CI 0.28-0.91; P = 0.02). This effect was shown to influence survival in predominantly white patient populations but not patients of Asian descent. 20826716 PubMed Dahabreh et al., 2011, Ann. Oncol. 4 accepted 948 190 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2016-01-29 03:35:07 UTC https://civicdb.org/links/evidence_items/948 https://civicdb.org/links/variants/190 https://civicdb.org/links/genes/19 false CXCR4 7852 EXPRESSION Gastric Adenocarcinoma 3717 Docetaxel Predictive Supports B Resistance CXCR4 expression as assessed by microarray analysis, was associated with resistance to docetaxel in 11 cancer cell lines (R^2 = 0.23, p = 0.019). Expression levels (by qtPCR) were also higher in resistant tumors among 25 patient samples. 20651371 PubMed Xie et al., 2010, Anticancer Res. 2 accepted 949 405 6329 2 136871919 136873813 ENST00000409817.1 75 GRCh37 N/A 2016-02-20 02:16:03 UTC https://civicdb.org/links/evidence_items/949 https://civicdb.org/links/variants/405 https://civicdb.org/links/genes/6329 false MAGEH1 28986 EXPRESSION Bile Duct Adenocarcinoma 4896 Gemcitabine Predictive Supports D Resistance 10 biliary tract carcinoma cell lines were sorted based on their gemcitabine sensitivity. MAGEH1 protein expression was negatively correlated with sensitivity. In a clinical validation cohort, MAGEH protein expression was found in 4/4 "non-effective" cases and 2/5 effective cases based on RECIST criteria after gemcitabine treatment. 20088962 PubMed Ojima et al., 2010, Cancer Sci. 2 accepted 950 406 11261 X 55478538 55479998 ENST00000342972.1 75 GRCh37 N/A 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/950 https://civicdb.org/links/variants/406 https://civicdb.org/links/genes/11261 false ABCC3 8714 Amplification Breast Cancer 1612 Monomethyl Auristatin E,Paclitaxel Substitutes Predictive Supports D Resistance 44 cell lines and 145 patient samples were utilized in various aspects of this study. 31 breast cancer cell lines for in vitro sensitivity to paclitaxel and Monomethyl Auristatin E (MMAE). Genome wide amplification was assessed by Affymetrix SNP arrays and expression was assessed by Affymetrix gene expression arrays. ABCC3 amplification (and expression) in ERBB2 (HER2) amplified breast cancer cell lines was associated with resistance to paclitaxel and MMAE. Three independently derived EVSA-T cell lines overexpressing ABCC3 were at least 20-fold less sensitive to paclitaxel and MMAE based on EC50 values. 18593940 PubMed O'Brien et al., 2008, Cancer Res. 3 accepted 951 407 6906 17 48712218 48769613 ENST00000285238.8 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/951 https://civicdb.org/links/variants/407 https://civicdb.org/links/genes/6906 false ABCC10 89845 Overexpression Lung Non-small Cell Carcinoma 3908 Paclitaxel Predictive Supports D Resistance Increased expression of ABCC10 in 17 NSCLC cell lines was inversely correlated with paclitaxel sensitivity (r = 0.574; P < 0.05). 18445659 PubMed Oguri et al., 2008, Mol. Cancer Ther. 3 accepted 952 408 16656 6 43395292 43418168 ENST00000372530.4 75 GRCh37 N/A 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/952 https://civicdb.org/links/variants/408 https://civicdb.org/links/genes/16656 false ASNS 440 Amplification Ovarian Cancer 2394 Asparaginase Predictive Supports D Resistance ASNS amplification and expression was associated with resistance to L-asparaginase in ovarian cancer and leukemia cell lines. ASNS silencing increased sensitivity to l-ASP in 2/3 of ovarian cancer cell lines. 17088436 PubMed Lorenzi et al., 2006, Mol. Cancer Ther. 2 accepted 953 409 446 7 97481430 97501854 ENST00000175506.4 75 GRCh37 Somatic 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/953 https://civicdb.org/links/variants/409 https://civicdb.org/links/genes/446 false EGFR 1956 Overexpression Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports B Sensitivity/Response 82 patients treated with gefitinib were retrospectively analyzed for EGFR mRNA expression (rt-PCR in 64 patients). Patients with high EGFR mRNA expression (>5.01) had 43% response probability, whereas patients with low EGFR mRNA expression had 8% response probability (P = 0.006). PFS but not OS was also longer in patients with high EGFR mRNA expression. 16707605 PubMed Dziadziuszko et al., 2006, Clin. Cancer Res. 3 accepted 954 193 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 N/A 2020-10-20 06:03:21 UTC https://civicdb.org/links/evidence_items/954 https://civicdb.org/links/variants/193 https://civicdb.org/links/genes/19 false PTEN 5728 Expression Breast Cancer 1612 Trastuzumab Predictive Supports B Sensitivity/Response Trastuzumab was more effective in cell lines (SKBR3 vs. drug-resistant SKBR3/R) and 17 patient samples that exhibit elevated PTEN expression (by IHC). 16404430 PubMed Fujita et al., 2006, Br. J. Cancer 3 accepted 955 313 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 N/A 2020-10-20 06:02:25 UTC https://civicdb.org/links/evidence_items/955 https://civicdb.org/links/variants/313 https://civicdb.org/links/genes/41 false CDX2 1045 EXPRESSION Colorectal Cancer 9256 Prognostic Supports B Better Outcome Patients with stage II/III colorectal cancer were analyzed for expression of CDX2 (by microarray and IHC). In the discovery (466 patients) and validation sets (314 patients), 5-year DFS was lower among patients with CDX2 negative tumors (discovery set:hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P=0.002; validation set: hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P=0.003). 26789870 PubMed Dalerba et al., 2016, N. Engl. J. Med. 4 accepted 956 410 927 13 28536274 28545276 ENST00000381020.7 75 GRCh37 N/A 2020-10-28 06:59:39 UTC https://civicdb.org/links/evidence_items/956 https://civicdb.org/links/variants/410 https://civicdb.org/links/genes/927 false STAT3 6774 SH2 DOMAIN MUTATION T-cell Large Granular Lymphocyte Leukemia 0050751 Diagnostic Supports B Positive Mutations in the Src homology 2 (SH2) domain (exon 21) of STAT3 were found in 31 of 77 patients (40%) with large granular lymphocytic leukemia. Recurrent mutational hot spots included Y640F, D661V, D661Y, and N647I. Patients with these mutations presented more often with neutropenia and rheumatoid arthritis than did patients without. 22591296 PubMed Koskela et al., 2012, N. Engl. J. Med. 4 accepted 957 411 5516 17 40465342 40475372 ENST00000264657.5 75 GRCh37 Somatic 2016-09-01 23:56:25 UTC https://civicdb.org/links/evidence_items/957 https://civicdb.org/links/variants/411 https://civicdb.org/links/genes/5516 false POU5F1 5460 EXPRESSION Colon Cancer 219 Oxaliplatin Predictive Supports D Resistance OCT4B1 (POU5F1 splice variant) expression reduced sensitivity to oxaliplatin (via P-gp and ABCG2 differential expression) in vitro. 26398480 PubMed Wen et al., 2015, Oncol. Rep. 2 accepted 958 412 4419 6 31132120 31138470 ENST00000259915.8 75 GRCh37 N/A 2016-07-26 14:50:07 UTC https://civicdb.org/links/evidence_items/958 https://civicdb.org/links/variants/412 https://civicdb.org/links/genes/4419 false ERBB2 2064 Kinase Domain Mutation Lung Adenocarcinoma 3910 Afatinib Predictive Supports C Sensitivity/Response A Phase II study for use of Afatinib in non- or light smokers with lung adenocarcinoma. Three patients with metastatic lung adenocarcinomas bearing mutations in the kinase domain of HER2 gene were identified (Y772_A775dup, G776L, and G778_P780dup). Objective response was observed in all three of these patients. 22325357 PubMed De Grève et al., 2012, Lung Cancer NCT00730925 3 accepted 959 413 20 17 37879863 37882870 ENST00000269571.5 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/959 https://civicdb.org/links/variants/413 https://civicdb.org/links/genes/20 false ERBB2 2064 Y772_A775DUP Lung Non-small Cell Carcinoma 3908 Sirolimus,Afatinib Combination Predictive Supports D Sensitivity/Response In preclinical studies of transgenic mice and xenografts, continuous expression of mutant ERBB2 (M774insAYVM or the equivalent A775insYVMA) was found to be essential for tumor maintenance. Furthermore, preclinical in vivo studies assessing erlotinib, trastuzumab, afatinib (aka BIBW2992), and/or sirolimus (aka rapamycin) revealed that the combination of afatinib and sirolimus was most effective in shrinking tumors harboring this insertion. 19122144 PubMed Perera et al., 2009, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 960 414 20 17 37880996 37880997 TACGTGATGGCT ENST00000269571.5 75 GRCh37 Mutations in the HER2 kinase domain occur at a 2-4% frequency in lung adenocarcinomas, the majority of which are in exon 20 as in-frame duplications or insertions in a small 8 codon region (774-781 or 775-782). These are analogous to the exon 20 alterations found in EGFR TK domain. The M774 insertion, M774insAYVM, represents 62.5% of all HER2 kinase domain mutations identified (when combined with the A775insYVMA mutations as they translate to the identical amino acid sequence changes). As demonstrated in mouse models (Perrera et al., PNAS 2009) and subsequent clinical trials in human lung adenocarcinoma with these insertions, HER2 YVMA mutants predict response to several targeted HER2 agonists such as afatinib, trastuzumab, neratinib and TDM-1 (trastuzumab emtansine) as monotherapy or combined with specific chemotherapies. Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/960 https://civicdb.org/links/variants/414 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Afatinib Predictive Supports B Sensitivity/Response A phase II study involving adult female patients, >=18 years, with stage IIIB or IV HER2-positive (by IHC and/or in situ fluorescence) metastatic breast cancer. All patients were previously treated with trastuzumab and a median of three chemotherapy lines. 41 patients received 50 mg afatinib once-daily until disease progression and the primary endpoint was objective response rate. 4 patients (10% of 41 treated; 11% of evaluable patients) had partial response and 15 patients (37% of 41) had stable disease as best response. Thus a total of 19 (46% of 41) achieved clinical benefit. Median progression-free survival was 15.1 weeks. 22418700 PubMed Lin et al., 2012, Breast Cancer Res. Treat. 3 accepted 961 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-02-18 04:14:20 UTC https://civicdb.org/links/evidence_items/961 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Pancreatic Adenocarcinoma 4074 Afatinib Predictive Supports D Sensitivity/Response Afatinib was growth-inhibitory for three pancreatic cancer cell lines but cytotoxic only toward BxPC3 (KRAS wt) and Capan-2 (KRAS mut) cells, both of which express high levels of EGFR, ERBB2, and ERBB3 receptors. Afatinib increased the radiosensitivity of BxPC3 and Capan-2 cells. In comparison, Panc-1 cells (KRAS mut) expressing low levels of EGFR family receptors were resistant to afatinib-induced radiosensitization. 26668065 PubMed Huguet et al., 2016, Target Oncol 2 accepted 962 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. N/A 2016-10-06 18:38:51 UTC https://civicdb.org/links/evidence_items/962 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Osimertinib Predictive Supports D Sensitivity/Response Cell line, xenograft, and transgenic models were used to establish Osimertinib as an inhibitor of both EGFR mutation sensitizing (L858M, del exon 19) and T790M resistance mutants. Preclinically, the drug inhibits signaling pathways and cellular growth in both EGFRm(+) and EGFRm(+)/T790M(+) mutant cell lines in vitro, with lower activity against wild-type EGFR lines. Sustained tumor regression was observed in EGFR-mutant tumor xenograft and transgenic models. Treatment of 2 patients with advanced EGFRm(+) T790M(+) NSCLC was reported as proof of principle. 24893891 PubMed Cross et al., 2014, Cancer Discov 3 accepted 963 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/963 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false EGFR 1956 C797S Lung Non-small Cell Carcinoma 3908 Osimertinib Predictive Supports B Resistance An EGFR resistance mutation, C797S, was discovered by deep sequencing of cell-free plasma DNA (cfDNA) from patients with advanced lung cancer whose tumors had developed resistance to osimertinib. Expression of this mutant EGFR construct in a cell line rendered it resistant to osimertinib. ddPCR on serial cfDNA specimens collected from 15 osimertinib-treated subjects (all positive for T790M before treatment) revealed 6 cases with acquired C797S mutation. 25939061 PubMed Thress et al., 2015, Nat. Med. 3 accepted 964 415 19 7 55249091 55249091 T A ENST00000275493.2 75 GRCh37 Somatic 2016-02-13 05:06:33 UTC https://civicdb.org/links/evidence_items/964 https://civicdb.org/links/variants/415 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Osimertinib Predictive Supports B Sensitivity/Response This phase I/II trial (NCT01802632) involved 253 non-small cell lung cancer patients with activating EGFR mutations, who had progressed on first generation tyrosine kinase inhibitor treatment, and were subsequently treated with Osimertinib (AZD9291). The overall objective tumor response rate was 51%. Among 127 patients with EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without EGFR T790M, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months in EGFR T790M-positive patients and 2.8 months in EGFR T790M-negative patients. 25923549 PubMed Jänne et al., 2015, N. Engl. J. Med. NCT01802632 4 accepted 965 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2017-07-27 15:35:43 UTC https://civicdb.org/links/evidence_items/965 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Osimertinib Predictive Supports B Sensitivity/Response This study summarized 9 EGFR-mutant patients from two clinical trials involving rociletinib (NCT01526928) and subsequent osimertinib (NCT01802632). 8 were T790M-positive prior to treatment with osimertinib. 6 transitioned directly from rociletinib to osimertinib. 3 patients achieved PR and 4 achieved SD. The median PFS was 208 days (95% CI, 41-208 days). Among 6 patients who transitioned directly from rociletinib to osimertinib all derived clinical benefit from osimertinib with either prolonged SD or PR. 26720284 PubMed Sequist et al., 2016, JAMA Oncol 3 accepted 966 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2016-02-11 21:39:47 UTC https://civicdb.org/links/evidence_items/966 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Rociletinib,Osimertinib Substitutes Predictive Supports D Sensitivity/Response For cell harboring EGFR T790M mutation, osimertinib and rociletinib showed potent inhibition compared to erlotinib or afatinib. This study performed drug response assays using five human NSCLC cell lines with various combinations of EGFR mutations. In order to directly compare the sensitivity of multiple EGFR mutations to EGFR-TKIs the authors also generated multiple EGFR transduced Ba/F3 stable cell lines and evaluated sensitivity to EGFR-TKIs by MTS assay. 26515464 PubMed Hirano et al., 2015, Oncotarget 2 accepted 967 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/967 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Afatinib Predictive Supports D Sensitivity/Response Cells harboring L858R were sensitive to afatinib. This study performed drug response assays using five human NSCLC cell lines with various combinations of EGFR mutations. In order to directly compare the sensitivity of multiple EGFR mutations to EGFR-TKIs the authors also generated multiple EGFR transduced Ba/F3 stable cell lines and evaluated sensitivity to EGFR-TKIs by MTS assay. 26515464 PubMed Hirano et al., 2015, Oncotarget 2 accepted 968 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/968 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 Exon 19 Deletion Lung Non-small Cell Carcinoma 3908 Afatinib Predictive Supports D Sensitivity/Response Cells harboring an exon 19 deletion were sensitive to afatinib. This study performed drug response assays using five human NSCLC cell lines with various combinations of EGFR mutations. In order to directly compare the sensitivity of multiple EGFR mutations to EGFR-TKIs the authors also generated multiple EGFR transduced Ba/F3 stable cell lines and evaluated sensitivity to EGFR-TKIs by MTS assay. 26515464 PubMed Hirano et al., 2015, Oncotarget 2 accepted 969 133 19 7 55242415 55242513 ENST00000275493.2 75 GRCh37 Deletions within exon 19 of EGFR are most common in lung cancer. These deletions, in non-small cell lung cancer, have been shown to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib, afatinib, and erlotinib. There is also data to suggest that this event is a good prognostic marker in lung adenocarcinoma. Examples of exon 19 deletions include: p.746_A750delELREA, p.747_753delinsS, p.747_752delLREATS, and p.747_751delLREAT. Somatic 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/969 https://civicdb.org/links/variants/133 https://civicdb.org/links/genes/19 false FGFR1 2260 Expression Head And Neck Squamous Cell Carcinoma 5520 Prognostic Supports B Poor Outcome Expression of bFGF and FGFR1 were evaluated in 61 biopsy specimens of primary OSCC (IHC). Expression was evaluated in both the cancer cells and fibroblasts at the invasive front of each tumor. bFGF and FGFR1 were expressed in all tumor specimens, whereas expression of these proteins in cancer-associated fibroblasts was associated with lymph node metastasis (P < 0.05) and worse patient survival. 16454808 PubMed Hase et al., 2006, J. Oral Pathol. Med. 2 accepted 970 268 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 high expression has been reported in 11.8% (178 patients) of oral squamous cell carcinoma patients, and was enriched in early stages (Freier et. al., 2007). Another study reports FGFR1 expression in 35% of primary HNSSC (353 patients) (Göke et. al., 2015). In both studies, FGFR1 gene amplification and expression do not correlate well with about 35% of samples with FGFR1 amplification overexpressing FGFR1 (Göke et. al., 2015). FGFR1 expression also correlated with sensitivity to FGFR1 inhibitors in preclinical models of lung cancer (Wynes et. al., 2014), HNSSC (Göke et. al., 2015) and urothelial carcinoma (Lamont et. al., 2011). N/A 2016-02-16 15:07:02 UTC https://civicdb.org/links/evidence_items/970 https://civicdb.org/links/variants/268 https://civicdb.org/links/genes/1885 false EGFR 1956 VIII Glioblastoma 3068 Rindopepimut Predictive Supports B Sensitivity/Response In a Phase II clinical trial, patients with Glioblastoma Multiforme (GBM), positive for EGFR VIII deletion mutation (N=65), were treated with the Rindopepimut cancer vaccine, and standard adjuvant temozolomide chemotherapy. Median progression free survival (PFS) was 9.2 months, and median overall survival (OS) was 21.8 months. A pivotal, randomized Phase III trial is currently underway. 25586468 PubMed Schuster et al., 2015, Neuro-oncology 3 accepted 971 312 19 7 55087058 55223523 ENST00000275493.2 75 GRCh37 The EGFRvIII variant is an oncogenic mutation that has been reported in several cancers including glioblastoma multiforme, breast, lung, head and neck, ovarian and prostate. In high-grade gliomas, EGFRvIII has been reported in about 30% of cases with EGFR amplification. The EGFRvIII mutation leads to deletion of the receptor ectodomain exons 2-7. The presence of this variant has been linked with clinical response to EGFR TKI. (Arteaga and Engelmann, 2014) Somatic 2016-02-03 17:18:19 UTC https://civicdb.org/links/evidence_items/971 https://civicdb.org/links/variants/312 https://civicdb.org/links/genes/19 false ERBB2 2064 SERUM LEVELS Breast Cancer 1612 Lapatinib Predictive Supports B Sensitivity/Response Serum and tissue levels of HER2 (ERBB2) were analyzed in 1,902 breast cancer patients treated with lapatinib or control. Serum HER2 (sHER2) levels measured by ELISA were higher in patients with HER2 amplification (median sHER2 levels were 25.1 ng/mL in patients with HER2-positive tumors). Serum HER2 levels were Independent predictors of lapatinib progression free survival benefit (HR per 10-ng/mL increase in serum HER2: lapatinib-containing therapies, 1.009 v nonlapatinib-containing therapies, 1.044; P interaction < .001). Tissue HER2 levels were also predictive, but within this subgroup, serum HER2 still independently predicted lapatinib PFS benefit. 26811533 PubMed Lee et al., 2016, J. Clin. Oncol. 4 accepted 972 416 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 N/A 2016-02-12 23:22:18 UTC https://civicdb.org/links/evidence_items/972 https://civicdb.org/links/variants/416 https://civicdb.org/links/genes/20 false ERBB2 2064 SERUM LEVELS Breast Cancer 1612 Prognostic Supports B Poor Outcome Serum and tissue levels of HER2 (ERBB2) were analyzed in 1,902 breast cancer patients treated with lapatinib or control. In the control group (n = 936), higher serum HER2 (sHER2) was associated with worse prognosis in multivariable analyses (progression free survival hazard ratio per 10 ng/mL: PFS, 1.024; P < .001; and OS, 1.018; P < .001). 26811533 PubMed Lee et al., 2016, J. Clin. Oncol. 3 accepted 973 416 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 N/A 2016-02-12 23:21:32 UTC https://civicdb.org/links/evidence_items/973 https://civicdb.org/links/variants/416 https://civicdb.org/links/genes/20 false THBS2 7058 UNDEREXPRESSION Colorectal Cancer 9256 Prognostic Supports B Poor Outcome 172 patients treated with neoadjuvant concurrent chemoradiotherapy (CCRT) were retrospectively analyzed for expression of thrombospondin 2 (THBS2) using IHC (discovery set with 46 rectal cancer patients, GSE35452). Low expression was associated with advanced pretreatment tumor, nodal status, post-treatment tumor, vascular invasion and inferior regression grade. In multivariate analysis, low expression served as negative prognostic factor for disease-free survival (Hazard ratio=3.057, P=0.002). 26807188 PubMed Lin et al., 2015, Am J Transl Res 3 accepted 974 417 5761 6 169615875 169654139 ENST00000366787.3 75 GRCh37 N/A 2016-02-18 18:34:36 UTC https://civicdb.org/links/evidence_items/974 https://civicdb.org/links/variants/417 https://civicdb.org/links/genes/5761 false CD274 29126 Expression Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome 74 patients with stage III NSCLC treated with concurrent chemoradiotherapy were retrospectively analyzed for PD-L1 expression and CD8+ tumour-infiltrating lymphocytes (TILs) density (IHC). CD8+ TIL density was an independent predictor of progression free survival (PFS) and overall survival (OS). Only when both TIL density and PD-L1 expression were both considered, was PD-L1 expression associated with survival. The subgroup, PD-L1+/CD8 low tumors had the shortest PFS (8.6 months, p = 0.02) and shortest, but not significantly different, OS (13.9 months, p = 0.11). 26771872 PubMed Tokito et al., 2016, Eur. J. Cancer 2 accepted 975 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2016-02-17 17:17:15 UTC https://civicdb.org/links/evidence_items/975 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false TERT 7015 Promoter Mutation Brain Glioma 0060108 Diagnostic Supports B Positive In this meta-analysis of 16 Trials, TERT mutations were more common in glioblastomas (69%), oligodendrogliomas (72%) in comparison to astrocytomas (24%) and oligoastrocytomas (38%). 26765760 PubMed Yuan et al., 2016, J Clin Neurosci 3 accepted 976 220 79 5 1295161 1295373 ENST00000310581.5 75 GRCh37 TERT promoter mutations are activating and commonly found at two hotspots within the TERT promoter region which occur 124 and 146 base pairs (hg19) upstream of the translation start site. These hotspots, termed C228T and C250T are observed in many cancer types and have a particularly high prevalence in glioblastoma (83%), melanoma (71%), bladder cancer (66%) and hepatocelluar carcinoma (HCC) (47%). The two mutations are usually heterozygous and mutually exclusive and result in an increased similarity to an ETS binding domain and may act as a binding site to an ETS transcription factor. These mutations are thought to be early events in tumorgenesis and aid in cellular immortality. Decreased overall survival in patients with these mutations have been observed in medulloblastoma, thyroid cancer, urogenital cancer, melanoma, and laryngeal tumors. The presence of these mutations has also been shown to be predictive of malignant/premalignant nodules in HCC and meningiomas. Somatic 2016-02-07 01:34:08 UTC https://civicdb.org/links/evidence_items/976 https://civicdb.org/links/variants/220 https://civicdb.org/links/genes/79 false EGFR 1956 Amplification Lung Non-small Cell Carcinoma 3908 Gefitinib,Erlotinib Substitutes Predictive Does Not Support B Sensitivity/Response In 290 patients with advanced NSCLC, 177 of which were treated with EGFR TKI (erlotinib or gefitinib). EGFR amplification (Multiplex ligation-dependent probe amplification; MLPA) and Mutation (PCR) were analzed. EGFR amplification was associated with EGFR mutation but not independently with patient benefit from EGFR TKI (overall and progression-free survival). 26722081 PubMed Fiala et al., 2016, Anticancer Res. 2 accepted 977 190 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2016-02-13 05:10:02 UTC https://civicdb.org/links/evidence_items/977 https://civicdb.org/links/variants/190 https://civicdb.org/links/genes/19 false NTRK1 4914 Fusion Colorectal Cancer 9256 Larotrectinib Predictive Supports D Sensitivity/Response NTRK1 fusions (one LMNA-NTRK1 and two TPM3-NTRK1) were identified in 2% of Korean colorectal cancer patients (147 patients). TrkA (NTRK1) protein expression was associated with presence of NTRK1 gene fusion. These fusions were mutually exclusive with other oncogenic drivers and showed in-vitro sensitivity to TrkA Inhibitor ARRY470 (Larotrectinib) (one cell line with fusion (KM12), one control cell line). 26716414 PubMed Park et al., 2016, Oncotarget 2 accepted 978 419 3983 1 156844175 156851434 ENST00000524377.1 75 GRCh37 Somatic 2018-08-21 19:02:58 UTC https://civicdb.org/links/evidence_items/978 https://civicdb.org/links/variants/419 https://civicdb.org/links/genes/3983 false IDH1 3417 R132H Oligodendroglioma 3181 AGI-5198 Predictive Supports D Sensitivity/Response In pre-clinical studies, an IDH1 inhibitor (AG-5198) impaired growth of glioma / anaplastic oligodendroglioma cell lines with IDH1 R132H mutations. A phase I clinical trial of the AG-120 IDH1 inhibitor in IDH1 mutant positive solid tumors, including glioma is currently underway. 23558169 PubMed Rohle et al., 2013, Science 4 accepted 979 420 26 2 209113112 209113112 C T ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes and acute myeloid leukemia (AML), IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/979 https://civicdb.org/links/variants/420 https://civicdb.org/links/genes/26 false TERT 7015 RS2736100 Brain Glioma 0060108 Predisposing Supports B Positive Meta-analysis of 10 studies (9,411 patients, 13,708 controls) showed that TERT polymorphisms (rs2736100) were associated with an increased glioma risk (RR=1.28, 95% CI 1.23-1.33). 26765760 PubMed Yuan et al., 2016, J Clin Neurosci 2 accepted 980 421 79 5 1286516 1286516 C A ENST00000310581.5 75 GRCh37 Common Germline 2017-01-23 15:49:27 UTC https://civicdb.org/links/evidence_items/980 https://civicdb.org/links/variants/421 https://civicdb.org/links/genes/79 false EGFR 1956 Exon 19 Deletion Lung Adenocarcinoma 3910 Afatinib Predictive Supports B Sensitivity/Response Afatinib is an irreversible covalent inhibitor of EGFR (second generation). This Phase III clinical trial (LUX-Lung 6; NCT01121393) was performed in Asian patients with EGFR mutant advanced NSCLC. 364 eligible patients with EGFR mutations were assigned to afatinib (n=242) or gemcitabine and cisplatin (n=122) treatment. The trial observed significantly longer median progression-free survival with afatinib vs. gemcitabine and cisplatin treatment (11.0 vs. 5.6 months). Afatinib/Chemotherapy group compositions: 51.2/50.8 % del 19; 38/37.7 % Leu858Arg; 10.8/11.5 % Uncommon. 24439929 PubMed Wu et al., 2014, Lancet Oncol. NCT01121393 4 accepted 981 133 19 7 55242415 55242513 ENST00000275493.2 75 GRCh37 Deletions within exon 19 of EGFR are most common in lung cancer. These deletions, in non-small cell lung cancer, have been shown to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib, afatinib, and erlotinib. There is also data to suggest that this event is a good prognostic marker in lung adenocarcinoma. Examples of exon 19 deletions include: p.746_A750delELREA, p.747_753delinsS, p.747_752delLREATS, and p.747_751delLREAT. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/981 https://civicdb.org/links/variants/133 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Adenocarcinoma 3910 Afatinib Predictive Supports B Sensitivity/Response Afatinib is an irreversible covalent inhibitor of EGFR (second generation). This Phase III clinical trial (LUX-Lung 6; NCT01121393) was performed in Asian patients with EGFR mutant advanced NSCLC. 364 eligible patients with EGFR mutations were assigned to afatinib (n=242) or gemcitabine and cisplatin (n=122) treatment. The trial observed significantly longer median progression-free survival with afatinib vs. gemcitabine and cisplatin treatment (11.0 vs. 5.6 months). Afatinib/Chemotherapy group compositions: 51.2/50.8 % del 19; 38/37.7 % Leu858Arg; 10.8/11.5 % Uncommon. 24439929 PubMed Wu et al., 2014, Lancet Oncol. NCT01121393 4 accepted 982 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/982 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 Exon 19 Deletion Lung Adenocarcinoma 3910 Afatinib Predictive Supports B Sensitivity/Response In analysis of LUX-Lung 3 and LUX-Lung 6 trials (NCT00949650 and NCT01121393), of EGFR mutant NSCLC, median overall survival with afatinib treatment was seen to be significantly improved over chemotherapy (33.3 vs 21.1 and 31.4 vs 18.4 months in LUX-Lung 3 and LUX-Lung 6 respectively). This effect was observed in the EGFR exon 19 deletion subgroup, but not in the L858R mutant subgroup. 25589191 PubMed Yang et al., 2015, Lancet Oncol. NCT00949650,NCT01121393 4 accepted 983 133 19 7 55242415 55242513 ENST00000275493.2 75 GRCh37 Deletions within exon 19 of EGFR are most common in lung cancer. These deletions, in non-small cell lung cancer, have been shown to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib, afatinib, and erlotinib. There is also data to suggest that this event is a good prognostic marker in lung adenocarcinoma. Examples of exon 19 deletions include: p.746_A750delELREA, p.747_753delinsS, p.747_752delLREATS, and p.747_751delLREAT. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/983 https://civicdb.org/links/variants/133 https://civicdb.org/links/genes/19 false STAG2 10735 Underexpression Bladder Carcinoma 4007 Prognostic Supports B Better Outcome Tumor samples from 125 patients with bladder cancer were assessed by IHC for STAG2 expression. STAG2-negativity was associated with lower histological grade (p = 0.009). Complete loss of STAG2 expression was associated with a lower risk of recurrence (P = 0.023) and diminished risk of death (P = 0.034) in log-rank analysis and was a beneficial factor in uni- and multivariate analysis. 26838030 PubMed Qiao et al., 2016, Tumour Biol. 2 accepted 984 422 8553 X 123095568 123236506 ENST00000371157.3 75 GRCh37 N/A 2016-02-12 23:30:30 UTC https://civicdb.org/links/evidence_items/984 https://civicdb.org/links/variants/422 https://civicdb.org/links/genes/8553 false HLA-DRA 3122 EXPRESSION Skin Melanoma 8923 Atezolizumab,Pembrolizumab,Nivolumab Substitutes Predictive Supports B Sensitivity/Response Melanoma patients treated with Anti-PD1 or anti-PD-L1(nivolumab, pembrolizumab, MPDL3280A) therapy were analyzed for expression of HLA-DRA (the primary antigen-presenting molecule of the MHC-II pathway). In a discovery cohort, 30 patients underwent IHC for HLA-DRA. 11/14 (79%) patients with positive HLA-DR staining, had complete (n=3) or partial (n=8) response. 6/16 (38%) HLA-DR non-expressing melanomas responded to therapy (overall response rate 79 versus 38%, Fisher’s exact test P=0.033). This finding was confirmed in a second independent data set of 23 melanoma patients with 6/8 (75%) of HLA-DR(+) tumours in comparison to 4/15 (27%) HLA-DR(−) responding (Fisher’s exact test P=0.025). Preclinical models confirmed the result. 26822383 PubMed Johnson et al., 2016, Nat Commun 3 accepted 985 423 2622 6 32407619 32412823 ENST00000395388.2 75 GRCh37 N/A 2016-02-12 23:28:37 UTC https://civicdb.org/links/evidence_items/985 https://civicdb.org/links/variants/423 https://civicdb.org/links/genes/2622 false MYD88 4615 L265P Waldenstroem's Macroglobulinemia 0060901 Ibrutinib Predictive Supports B Sensitivity/Response A prospective study of ibrutinib in 63 symptomatic patients with Waldenström's macroglobulinemia who had received at least one previous treatment. The response rates were highest among patients with MYD88(L265P) and CXCR4(WT). The MYD88 L265P mutation was present in 56 patients (89%). 25853747 PubMed Treon et al., 2015, N. Engl. J. Med. NCT01614821 4 accepted 986 424 3742 3 38182641 38182641 T C ENST00000396334.3 75 GRCh37 Somatic 2016-02-13 05:50:58 UTC https://civicdb.org/links/evidence_items/986 https://civicdb.org/links/variants/424 https://civicdb.org/links/genes/3742 false KRAS 3845 G12V Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome Retrospective analysis of data from 841 patients who underwent surgery and molecular testing for NSCLC. Mutant KRAS was observed in 265 (31.5%) cases and 90 of these were G12V. Patients with KRAS G12V exhibited worse OS and TTR compared with the entire cohort. These results were confirmed using multivariate analyses (non-G12V status, hazard ratio (HR): 0.43 (confidence interval: 0.28–0.65), P<0.0001 for OS. Risk of recurrence was significantly lower for non-KRAS G12V (HR: 0.01, (0.001–0.08), P<0.0001). 26372703 PubMed Renaud et al., 2015, Br. J. Cancer 3 accepted 987 425 30 12 25398284 25398284 C A ENST00000256078.4 75 GRCh37 KRAS mutations are the most common mutations in pancreatic cancer occurring in > 90% of cases. Of these the G12D activating mutation is the most prevalent and results in a loss of GTPase activity which in turn leads to a constitutively active form of KRAS. This is enough to cause pre-cancerous pancreatic intraepithelial lesions Somatic 2016-02-13 05:56:06 UTC https://civicdb.org/links/evidence_items/987 https://civicdb.org/links/variants/425 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Colorectal Cancer 9256 B-Raf/VEGFR-2 Inhibitor RAF265,Selumetinib Combination Predictive Supports D Sensitivity/Response SiRNA Screening in 37 KRAS Mutant colorectal cancer cell lines identified RAF1 and MEK Inhibition as synergistic, whereas MEK Inhibition alone led to quick resistance via upregulation of RAF-signalling. This finding could be reproduced in colorectal and lung cancer cell lines in a second, independent screen. 25199829 PubMed Lamba et al., 2014, Cell Rep 4 accepted 988 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/988 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 B-Raf/VEGFR-2 Inhibitor RAF265,Selumetinib Combination Predictive Supports D Sensitivity/Response SiRNA Screening in 37 KRAS Mutant colorectal cancer cell lines identified RAF1 and MEK Inhibition as synergistic, whereas MEK Inhibition alone led to quick resistance via upregulation of RAF-signalling. This finding was reproduced two NSCLC cell lines in a second, independent shRNA screen. 25199829 PubMed Lamba et al., 2014, Cell Rep 2 accepted 989 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/989 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 G12/G13 Pancreatic Adenocarcinoma 4074 Trametinib Predictive Does Not Support B Sensitivity/Response KRAS G12/G13 status was evaluated in cell-free DNA (cfDNA) of patients with untreated metastatic adenocarcinoma of the pancreas that were randomised (1:1) to receive gemcitabine plus trametinib or placebo. KRAS mutations were identified in 103 patients using cfDNA. There was no difference betweeen overall survival of KRAS Mutation-positive and -negative patients. Of note, evaluation of KRAS mutations from archival tissue from 71/143 patients identified 8 patients with mutant KRAS (wildtype by cfDNA) and 3 patients with wildtype KRAS (mutant by cfDNA). 24915778 PubMed Infante et al., 2014, Eur. J. Cancer NCT01231581 3 accepted 990 77 30 12 25398280 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2016-02-11 23:19:06 UTC https://civicdb.org/links/evidence_items/990 https://civicdb.org/links/variants/77 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Colorectal Cancer 9256 Trametinib,Afatinib Combination Predictive Supports D Sensitivity/Response An shDNA Screen identified synergy betwenn ERBB3 Inhibition and MEK Inhibition in KRAS mutated cell lines. Dual EGFR/ERBB2 Inhibitors afatinib and dacomitinib and MEK Inhibition was synergistic in colorectal and lung cancer cell lines. Induction of ERBB3 signalling was also identified in a patient with KRAS mutation after MEK inhibition with trametinib. 24685132 PubMed Sun et al., 2014, Cell Rep 4 accepted 991 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/991 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Trametinib,Afatinib Combination Predictive Supports D Sensitivity/Response An shDNA screen identified synergy between ERBB3 Inhibition and MEK Inhibition in KRAS mutated cell lines. Dual EGFR/ERBB2 Inhibitors afatinib and dacomitinib and MEK Inhibition was synergistic in colorectal and lung cancer cell lines. Induction of ERBB3 signalling was also identified in a patient with KRAS mutation after MEK inhibition with trametinib. 24685132 PubMed Sun et al., 2014, Cell Rep 2 accepted 992 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-02-17 19:50:05 UTC https://civicdb.org/links/evidence_items/992 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Exon 2 Mutation Colorectal Cancer 9256 Cetuximab Predictive Supports A Resistance KRAS mutation status was assessed in 394 tumor samples from colorectal cancer patients who were randomly assigned to receive cetuximab plus best supportive care or best supportive care alone. 42% of the tumors evaluated had at least one mutation in exon 2. Patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab, whereas patients with a tumor bearing wild-type K-ras did benefit from cetuximab. The effectiveness of cetuximab was significantly associated with K-ras mutation status (P=0.01 for overall survival and P<0.001 for progression-free survival). In patients with wild-type K-ras tumors, treatment with cetuximab as compared with supportive care alone significantly improved overall survival. The related clinical trial ID is NCT00079066. 18946061 PubMed Karapetis et al., 2008, N. Engl. J. Med. NCT00079066 5 accepted 993 75 30 12 25398208 25398329 ENST00000256078.4 75 GRCh37 Exon 2 mutations have been associated with reduced response rates or resistance to EGFR inhibitors in non-small cell lung and colorectal cancer. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. Somatic 2016-02-10 20:24:53 UTC https://civicdb.org/links/evidence_items/993 https://civicdb.org/links/variants/75 https://civicdb.org/links/genes/30 false BRAF 673 V600E Melanoma 1909 MEK Inhibitor RO4987655 Predictive Does Not Support B Resistance This was a phase I expansion and pharmacodynamic study of oral MEK inhibitor RO4987655 on advanced cancer. Of 17 patients with BRAF V600E melanoma, 4 achieved partial response, 5 experienced stable disease lasting longer than 16 weeks, and 8 experienced disease progression (including 2 with prior vemurafenib treatment). One of the partial responders had a concomitant EGFR mutation, and two of the stable disease patients had other concomitant mutations (in RET or MET). The median days on treatment was 113 (18-366) for BRAF V600E melanoma patients and 107 (17-323) for BRAF V600 wildtype patients (n=23). Patients with BRAF V600E mutant melanoma experienced similar response rates (24% vs 20%) and rates of metabolic response measured by decrease in FDG uptake assessed by FDG-PET (86% vs 75%) compared to non-BRAF mutant patients. Patients with melanoma, either BRAF wt or V600E, experienced significant decreases in Ki67 expression by day 15 of MEK inhibitor treatment (P<0.02). The authors conclude that RO4987655 has clinical activity in BRAF V600E and BRAF wt melanoma. 24947927 PubMed Zimmer et al., 2014, Clin. Cancer Res. 2 accepted 994 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-09-25 00:05:15 UTC https://civicdb.org/links/evidence_items/994 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 WILD TYPE Melanoma 1909 MEK Inhibitor RO4987655 Predictive Does Not Support B Resistance Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655. Among 12 patients with melanoma BRAF wild type and non-NRAS or NRAS unknown status, seven patients experienced partial response (n=3) or stable disease (n=4). Authors conclude that RO4987655 has clinical activity in BRAF V600-wt (and BRAF V600E) melanoma. They suggest that other drugs such as immune check point inhibitors are preferred in BRAF wt melanoma, so the role of RO4987655 as a single agent is limited for BRAF WT patients with the possible exception of a small window of opportunity for combinations with MEK inhibitors after immunotherapy progression. 24947927 PubMed Zimmer et al., 2014, Clin. Cancer Res. 2 accepted 995 426 5 7 140434279 140624564 ENST00000288602.6 75 GRCh37 N/A 2020-09-25 00:05:32 UTC https://civicdb.org/links/evidence_items/995 https://civicdb.org/links/variants/426 https://civicdb.org/links/genes/5 false NRAS 4893 Mutation Melanoma 1909 MEK Inhibitor RO4987655 Predictive Does Not Support C Resistance Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655). Among 8 patients with NRAS mutated melanoma, 3 experienced clinical benefit: 2 stable disease and 1 partial response (1 Patient received study treatment for 323 days). Of 10 NRAS wt patients, 4 experienced clinical benefit. Authors note that RO4987655 demonstrates clinical efficacy in BRAF wildtype melanomas with NRAS mutations. 24947927 PubMed Zimmer et al., 2014, Clin. Cancer Res. 2 accepted 996 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2020-09-17 23:14:54 UTC https://civicdb.org/links/evidence_items/996 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 MEK Inhibitor RO4987655 Predictive Does Not Support B Resistance This was a phase I expansion and pharmacodynamic study of oral MEK inhibitor RO4987655 on advanced cancer. Of 18 patients with KRAS mutant non-small cell lung cancer (NSCLC), 10 experienced clinical benefit: 2 partial responses and 8 patients experiencing stable disease for longer than 8 weeks. The median days on treatment was 58.5 (13-394) with one patient ongoing treatment at the end of the study period (56 weeks). The response rate of patients with KRAS mutant NSCLC was 11%, and 71% showed decrease in metabolic response (less FDG uptake in FDG-PET analysis). All responders showed decreases in FDG-uptake. There was not a significant decrease in Ki67 expression between day 1 and day 15 of treatment. Authors conclude that RO4987655 has some clinical activity in KRAS mutated NSCLC, though patients with KRAS wild-type NSCLC were excluded from this expansion study, so it is not possible to determine whether activity of RO4987655 in NSCLC is related to KRAS mutation status. 24947927 PubMed Zimmer et al., 2014, Clin. Cancer Res. 3 accepted 997 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2020-09-17 23:34:57 UTC https://civicdb.org/links/evidence_items/997 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Colorectal Cancer 9256 MEK Inhibitor RO4987655 Predictive Does Not Support B Sensitivity/Response Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655). All 25 patients with KRAS mutant colorectal cancer experienced PD. Median days on treatment was 57 (5-269). Among the patients with KRAS mutant cancer, 52% showed decrease in metabolic response (less FDG uptake in FDG-PET analysis). There was not a significant decrease in Ki67 expression between day 1 and day 15 of treatment. The authors concluded that RO4987655 does not have clinical activity in patients with KRAS mutant advanced colorectal cancer. 24947927 PubMed Zimmer et al., 2014, Clin. Cancer Res. 2 accepted 998 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2020-09-17 23:54:27 UTC https://civicdb.org/links/evidence_items/998 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Selumetinib,Docetaxel Combination Predictive Supports B Sensitivity/Response 87 patients with KRAS mutant stage IIB-IV NSCLC after first line therapy were randomly assigned (1:1) to oral selumetunib and docetaxel or docetaxel and Placebo. Median OS was 9·4 months (6·8-13·6) in selumetinib group and 5·2 months (95% CI 3·8-non-calculable) in placebo group (hazard ratio [HR] for death 0·80, 80% CI 0·56-1·14; one-sided p=0·21). Median PFS was 5·3 months (4·6-6·4) in selumetinib group and 2·1 months (95% CI 1·4-3·7) in placebo group (HR for progression 0·58, 80% CI 0·42-0·79; one-sided p=0·014). An objective response was observed in 16 (37%) patients in the selumetinib group and none in the placebo group(p<0·0001). 23200175 PubMed Jänne et al., 2013, Lancet Oncol. NCT00890825 4 accepted 999 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-02-12 19:32:29 UTC https://civicdb.org/links/evidence_items/999 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false BRAF 673 V600 Melanoma 1909 Refametinib Predictive Supports C Resistance Phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766. 2 of 2 patients with BRAF mutant melanoma had moderate progressive disease (despite receiving the highest doses administered in the study). 23434733 PubMed Weekes et al., 2013, Clin. Cancer Res. 2 accepted 1000 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/1000 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false KRAS 3845 Mutation Colorectal Cancer 9256 Refametinib Predictive Does Not Support C Sensitivity/Response Phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766. 4 patients with KRAS +/- PIK3CA mutant colorectal cancer. 3 with SD, 1 with PD. 23434733 PubMed Weekes et al., 2013, Clin. Cancer Res. 2 accepted 1001 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-02-17 19:49:55 UTC https://civicdb.org/links/evidence_items/1001 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false NRAS 4893 Q61K Neuroblastoma 769 Everolimus,Binimetinib Combination Predictive Supports D Sensitivity/Response In-vitro study in 5 neuroblastoma cell lines (2 with NRAS Q61K mutation). The combination of mTOR and MEK Inhibitors synergistically blocked cell growth in NRAS mutant but not wild type cell lines. Single agent MEK inhibition (AZD6244/selumetinib, MEK162 or PD0325901) and single agent mTOR inhibition (Everolimus or AZD8055) also blocked cell growth in NRAS mutant cell lines, whereas single agent PI3K inhibitors or MEK Inhibitors in combination with PIK3CA/AKT inhibitors did not show synergistic effects. 26821351 PubMed Kiessling et al., 2016, PLoS ONE 3 accepted 1002 427 36 1 115256530 115256530 G T ENST00000369535.4 75 GRCh37 Somatic 2016-07-13 23:52:01 UTC https://civicdb.org/links/evidence_items/1002 https://civicdb.org/links/variants/427 https://civicdb.org/links/genes/36 false KRAS 3845 Mutation Pancreatic Adenocarcinoma 4074 PI3Kbeta Inhibitor AZD8186,SCH772984 Combination Predictive Supports D Sensitivity/Response Inhibition of ERK in 11 KRAS mutant pancreatic cancer cell lines with SCH772984 was more effective than MEK Inhibition. Combined Treatment with PI3K Inhibitor AZD8186 was more effective than either agent alone. Chemical library screen in two cell lines also identified mTOR, AKT Family Inhibitors (Temsirolimus, Everolimus) to act synergistically with ERK Inhibition. 26725216 PubMed Hayes et al., 2016, Cancer Cell 4 accepted 1003 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/1003 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Colorectal Cancer 9256 Selumetinib,Teprotumumab Combination Predictive Supports D Sensitivity/Response Preclinial data from KRAS mutant colorectal cancer cell lines show syngergistic effect on cell viability and apoptosis in vitro and in vivo when MEK and IGF-IR are inhibited concomitantly. In other cell lines, activation of other RTKs (such as MET) were observed upon MEK Inhibition and combination of RTKi and METi also showed synergistic activity. A total of 16 cell lines were used in this study. 6 were KRAS wild type, and 10 harbored various KRAS mutations (G12C, G12D, G12V, G13D, and Q61L). Additional data was obtained from xenografts. 21985784 PubMed Ebi et al., 2011, J. Clin. Invest. 3 accepted 1004 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/1004 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false BRAF 673 V600E Melanoma 1909 Dactolisib,Selumetinib Combination Predictive Supports D Sensitivity/Response 49 BRAF-mutant melanoma cell lines from patients not previously treated with BRAF inhibition were analyzed. 21 exhibited primary resistance to BRAF inhibition using PLX4720. Inhibition of MEK1/2 (AZD6244 [selumetinib]) and PI3K/mTOR (BEZ235 [dactolisib]) was the most effective approach to counteract resistance in comparison to inhibition with the PLX4720 (progenitor of vemurafenib)-BEZ235 (where response was assessed by apoptosis, viability, p-ERK, p-Akt inhibition). 26678033 PubMed Penna et al., 2016, Oncotarget 2 accepted 1005 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2019-10-01 05:41:11 UTC https://civicdb.org/links/evidence_items/1005 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false ERBB2 2064 Amplification Breast Cancer 1612 Lapatinib,Trastuzumab Combination Predictive Supports D Sensitivity/Response In-vitro studies using ERBB2 over-expressing breast cancer cell lines BT474 and SKBR3 (with ERBB2 amplification) showed apoptosis under either labatinib or trastuzumab treatment. A marked synergistic apoptotic effect under lapatinib and trastuzumab co-treatment was observed in BT474 cells, and a milder synergistic effect was observed in SKBR3 cells. 16091755 PubMed Xia et al., 2005, Oncogene 3 accepted 1006 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-02-22 02:57:20 UTC https://civicdb.org/links/evidence_items/1006 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Trastuzumab,Lapatinib Combination Predictive Supports B Sensitivity/Response In light of results showing increased PFS using mAB plus TKI in heavily pretreated patients, the efficacy of trastuzumab plus lapatinib in a neoadjuvant setting with untreated stage II or IIIA HER2 positive breast cancer was assessed. In this randomized 3 arm phase II study (CHER-LOB), patients received (A) chemotherapy plus trastuzumab, (B) chemotherapy plus lapatinib, or (C) chemotherapy plus trastuzumab and lapatinib, with pathologic complete response (pCR) as endpoint. From 121 patients, pCR rates were 25% in arm A, 26.3% in arm B, and 46.7% in arm C. The authors conclude these results support the superiority of dual-HER2 inhibition in the neoadjuvant context of HER2 positive BC. 22493419 PubMed Guarneri et al., 2012, J. Clin. Oncol. 4 accepted 1007 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-02-18 03:58:19 UTC https://civicdb.org/links/evidence_items/1007 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Lapatinib,Trastuzumab Combination Predictive Does Not Support B Sensitivity/Response This Phase III trial compared the activity of lapatinib vs. trastuzumab vs. sequential trastuzumab followed by lapatinib vs. lapatinib plus trastuzumab in an adjuvant treatment setting. 8381 women were randomized to one of four treatment arms. Patients had HER2 positive non-metastatic operable BC. The primary endpoint was disease free survival. First results report that after median 4.5 year follow up, a non significant 16% improvement in DFS was seen in trastuzumab + lapatinib vs. trastuzumab alone. The results are interpreted as showing no added benefit for labatinib addition to trastuzumab in the adjuvant treatment context. This trial is ongoing but not recruiting patients (NCT00490139). 26255196 PubMed Zardavas et al., 2015, Breast 4 accepted 1008 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-02-18 03:56:43 UTC https://civicdb.org/links/evidence_items/1008 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Trastuzumab,Lapatinib Combination Predictive Supports B Sensitivity/Response This Phase III study (EGF104900) was motivated by preclinical and other data demonstrating synergistic activity between lapatinib and trastuzumab against HER2 positive breast cancer (BC) cells. In this study of HER2 positive metastatic BC which had progressed on trastuzumab, two arms were compared: lapatinib vs. lapatinib + trastuzumab. Progression free survival (PFS) was the primary endpoint. For 296 patients, 148 in each arm, median PFS of 8.1 weeks for lapatinib and 12.0 for combination therapy was observed (P=0.008). The authors conclude that in the context of metastatic trastuzumab-progressed HER2 positive BC, trastuzumab with lapatinib TKI addition is a favorable treatment. 20124187 PubMed Blackwell et al., 2010, J. Clin. Oncol. 4 accepted 1009 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-02-18 04:00:40 UTC https://civicdb.org/links/evidence_items/1009 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Afatinib Predictive Supports B Sensitivity/Response With multiple mechanisms of HER reprogramming thought to be behind trastuzumab resistance, including increased expression of ErbB members, afatinib, which broadly and irreversibly targets ErbB receptors was tested in a single arm phase II trial on advanced stage HER2 positive metastatic breast cancer. From 41 treated patients, 10% had partial response, 37% had stable disease as best response and 46% achieved clinical benefit. Median progression free survival (PFS) was 15.1 weeks and median overall survival (OS) was 61.0 weeks. The authors conclude that Afatinib monotherapy shows promise in treatment of metastatic HER2 positive breast cancer that has progressed under trastuzumab. 22418700 PubMed Lin et al., 2012, Breast Cancer Res. Treat. 3 accepted 1010 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-02-18 04:14:52 UTC https://civicdb.org/links/evidence_items/1010 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Afatinib Predictive Supports B Sensitivity/Response This Phase II trial (LUX-Breast 3 - NCT01441596) compared afatinib, afatinib plus vinorelbine, or investigator's choice of treatment. 121 patients with HER2 overexpressing breast cancer with CNS recurrence or regression who had previously progressed on trastuzumab or lapatinib were assigned to 3 arms, with endpoint in the intention-to-treat population being patient benefit at 12 weeks defined as absence of CNS or extra CNS progression, no tumor related worsening of neurological symptoms and no increase in corticosteroid dose. Benefit was seen in 30% of 40 patients assigned to afatinib alone, 34.2% of 38 assigned to afatinib plus vinorelbine, and 41.9% of 43 assigned to investigator's treatment choice. Differences were not statistically significant, and afatanib patients experienced more adverse effects. While Afatanib did show response in HER2 breast cancer patients, it was not better than investigator's treatment choice and the investigators state that no further development of afatinib for HER2 breast cancer will be planned. 26596672 PubMed Cortés et al., 2015, Lancet Oncol. NCT01441596 3 accepted 1011 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-02-18 04:15:11 UTC https://civicdb.org/links/evidence_items/1011 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Afatinib Predictive Does Not Support B Sensitivity/Response LUX-Breast 1 is a phase 3 trial (NCT01125566) which enrolled 508 patients with metastatic HER2 positive BC who had progressed after adjuvant or first-line trastuzumab. It was thought that the wider range of ErbB family blocking and irreversible properties of afatinib could be beneficial in trastuzumab resistant cancer cells, since ErbB family members are thought to play a role in trastuzumab resistance. Primary endpoint was intention-to-treat group PFS. 339 patients were assigned to afatanib + vinorelbine and 169 to trastuzumab + vinorelbine. Recruitment was stopped prematurely when it was deemed unlikely that the increased PFS would be seen in the afatinib group. Median PFS was 5.5 months in the afatinib group and 5.6 months in the trastuzumab group. Afatanib plus vinorelbine was less well tolerated than trastuzumab plus vinorelbine, and the authors conclude that trastuzumab remains the best choice for treatment of trastuzumab-progressed HER2 positive metastatic BC. 26822398 PubMed Harbeck et al., 2016, Lancet Oncol. NCT01125566 4 accepted 1012 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-02-18 04:01:02 UTC https://civicdb.org/links/evidence_items/1012 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Trastuzumab,Afatinib Combination Predictive Supports B Sensitivity/Response Trastuzumab resistance is thought to consist of multiple compensatory mechanisms involving ErbB family members such as increased signaling through ErbB family heterodimers. The irreversible TKI afatinib blocks EGFR, HER2, ErbB3 and ErbB4. Thus afatinib was studied in this Phase I trial of trastuzumab-progressed HER2 positive metastatic BC (MBC) in combination with continued trastuzumab treatment, where trastuzumab is still the perferred treatment for trastuzumab-progressed MBC. Objective response and disease control rates were 11% and 39%. The authors conclude that the clinical activity observed in this trial warrants further work with afatinib and trastuzumab combination therapy. 25370464 PubMed Ring et al., 2015, Clin. Cancer Res. 3 accepted 1013 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-02-18 04:15:24 UTC https://civicdb.org/links/evidence_items/1013 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false NOTCH1 4851 P2514FS Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome NOTCH1 mutations were found to be associated with worse overall survival (3.77-fold increase in the hazard of death, P < .001) in a series of 309 newly diagnosed CLL and confirmed in an additional set of 230 patients. NOTCH1 mutations were mostly represented (26/34, 76.5%) by a recurrent 2-bp frameshift deletion (c.7544_7545delCT), with the remaining being other frameshift deletions or insertions. 22077063 PubMed Rossi et al., 2012, Blood 4 accepted 1014 207 50 9 139390649 139390650 ENST00000277541.6 75 GRCh37 This mutation disrupts the C-terminal PEST domain that in normal conditions promotes degradation, resulting in accumulation of an active NOTCH1 isoform sustaining deregulated signaling. Somatic 2016-02-11 20:52:28 UTC https://civicdb.org/links/evidence_items/1014 https://civicdb.org/links/variants/207 https://civicdb.org/links/genes/50 false EZH2 2146 Mutation Follicular Lymphoma 0050873 Prognostic Supports B Better Outcome In advanced stage follicular lymphoma patients receiving rituximab + chemotherapy (R-CHOP or R-CVP), EZH2 mutations were associated with better failure free survival in patients with high-risk FLIPI scores compared to patients that were EZH2 wildtype with high-risk FLIPI scores. 26256760 PubMed Pastore et al., 2015, Lancet Oncol. 4 accepted 1015 163 63 7 148504477 148581370 ENST00000320356.2 75 GRCh37 Somatic 2016-02-12 16:54:03 UTC https://civicdb.org/links/evidence_items/1015 https://civicdb.org/links/variants/163 https://civicdb.org/links/genes/63 false MRE11 4361 Frameshift Prostate Cancer 10283 Olaparib Predictive Supports B Sensitivity/Response One patient in a cohort of 50 patients with metastatic prostate cancer had a frameshift mutation in the MRE11, ATM, MLH3 and NBN genes and showed clinical response to PARP inhibitor olaparib (16 weeks on Treatment). 26510020 PubMed Mateo et al., 2015, N. Engl. J. Med. NCT01682772 2 accepted 1016 428 3586 11 94152895 94227074 ENST00000323929.3 75 GRCh37 Somatic 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/1016 https://civicdb.org/links/variants/428 https://civicdb.org/links/genes/3586 false EGFR 1956 VIII Brain Glioma 0060108 Nimotuzumab Predictive Supports D Sensitivity/Response Two human glioma cell lines (U87MG or LNZ308) overexpressing either wild-type (wt) EGFR or EGFRvIII were treated with nimotuzumab, temozolomide, or both in vitro. Anti-tumor effects of nimotuzumab were greater in EGFRvIII in comparison to EGFRwt (as measured by antitumor effects, growth suppression, survival elongation and EGFR and Akt phosphorylation). Combination of nimotuzumab and temozolomide further increased efficacy. 26778701 PubMed Nitta et al., 2016, Cancer Med 1 accepted 1017 312 19 7 55087058 55223523 ENST00000275493.2 75 GRCh37 The EGFRvIII variant is an oncogenic mutation that has been reported in several cancers including glioblastoma multiforme, breast, lung, head and neck, ovarian and prostate. In high-grade gliomas, EGFRvIII has been reported in about 30% of cases with EGFR amplification. The EGFRvIII mutation leads to deletion of the receptor ectodomain exons 2-7. The presence of this variant has been linked with clinical response to EGFR TKI. (Arteaga and Engelmann, 2014) Somatic 2016-02-17 19:50:04 UTC https://civicdb.org/links/evidence_items/1017 https://civicdb.org/links/variants/312 https://civicdb.org/links/genes/19 false TP53 7157 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In a study of 97 patients with AML treated with HSCT, 40 had TP53 mutations comprising a total of 44 mutations. Patients with a TP53 mutation had a reduced three year probability of overall survival and event-free survival compared to patients with the wild-type TP53. 26771088 PubMed Middeke et al., 2016, Br. J. Haematol. 4 accepted 1018 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2016-02-12 19:20:50 UTC https://civicdb.org/links/evidence_items/1018 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false NTRK1 4914 Fusion Lung Adenocarcinoma 3910 Lestaurtinib,Crizotinib,Larotrectinib Substitutes Predictive Supports D Sensitivity/Response Two patients were found to harbor gene fusions maintaining the kinase domain of NTRK1 (3' partner), specifically: MPRIP-NTRK1 and CD74-NTRK1. Both of these fusions lead to constitutive kinase activity and were found to be oncogenic. Treatment of cells expressing NTRK1 fusions with inhibitors of TRKA kinase activity (ARRY-470, CEP-701 and, to a lesser extent, crizotinib) inhibited autophosphorylation of TRKA and cell growth. 24162815 PubMed Vaishnavi et al., 2013, Nat. Med. 3 accepted 1019 419 3983 1 156844175 156851434 ENST00000524377.1 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1019 https://civicdb.org/links/variants/419 https://civicdb.org/links/genes/3983 false AREG 374 Expression Colorectal Cancer 9256 Panitumumab Predictive Supports B Sensitivity/Response Prospectively planned retrospective biomarker study in archived tumor tissue from 323 patients from the PICCOLO trial (panitumumab plus irinotecan in CRC patients with KRAS wt). Tumors were classified as "high expressor" (either EREG or AREG mRNA level) or "low expressor" (neither EREG nor AREG in top tertile). For RAS wild-type patients with high ligand expression, median PFS was 8.3 [4.0-11.0] months (irinotecan with panitumumab) vs 4.4 [2.8-6.7] months (irinotecan alone); HR, 0.38 [95% CI, 0.24-0.61]; P < .001. In RAS wild-type patients with low ligand expression, median PFS was 3.2 [2.7-8.1] months (irinotecan with panitumumab) vs 4.0 [2.7-7.5] months (irinotecan); HR, 0.93 [95% CI, 0.64-1.37]; P = .73; interaction test results were significant [P = .01]). Results were less clear for response rate (interaction P = .17) and OS (interaction P = .11). 26867820 PubMed Seligmann et al., 2016, JAMA Oncol 4 accepted 1020 315 389 4 75310851 75320726 ENST00000395748.3 75 GRCh37 N/A 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1020 https://civicdb.org/links/variants/315 https://civicdb.org/links/genes/389 false EREG 2069 EXPRESSION Colorectal Cancer 9256 Panitumumab Predictive Supports B Sensitivity/Response Prospectively planned retrospective biomarker study in archived tumor tissue from 323 patients from the PICCOLO trial (panitumumab plus irinotecan in CRC patients with KRAS wt). Tumors were classified as "high expressor" (either EREG or AREG mRNA level) or "low expressor" (neither EREG nor AREG in top tertile). For RAS wild-type patients with high ligand expression, median PFS was 8.3 [4.0-11.0] months (irinotecan with panitumumab) vs 4.4 [2.8-6.7] months (irinotecan alone); HR, 0.38 [95% CI, 0.24-0.61]; P < .001. In RAS wild-type patients with low ligand expression, median PFS was 3.2 [2.7-8.1] months (irinotecan with panitumumab) vs 4.0 [2.7-7.5] months (irinotecan); HR, 0.93 [95% CI, 0.64-1.37]; P = .73; interaction test results were significant [P = .01]). Results were less clear for response rate (interaction P = .17) and OS (interaction P = .11). 26867820 PubMed Seligmann et al., 2016, JAMA Oncol 4 accepted 1021 318 1737 4 75230860 75254468 ENST00000244869.2 75 GRCh37 N/A 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1021 https://civicdb.org/links/variants/318 https://civicdb.org/links/genes/1737 false ERBB2 2064 Amplification Gastric Adenocarcinoma 3717 Trastuzumab Predictive Supports B Sensitivity/Response ToGA, a Phase III study (NCT01041404) addressed use of trastuzumab in HER2 positive advanced gastric cancer, where chemotherapy using fluoropyrimidine-based and platinum-based combinations had been common practice. Patients were given a chemotherapy regime containing capecitabine, flourouracil and cisplatin with (n=298) or without (n=296) trastuzumab, and had not been previously treated for metastatic cancer. Study endpoint was overall survival, which was significantly different in the two populations (13.8 months with chemotherapy + trastuzumab and 11.1 months for chemotherapy alone). The authors conclude that trastuzumab should be a standard option for HER2 positive advanced gastric cancer. 20728210 PubMed Bang et al., 2010, Lancet NCT01041404 4 accepted 1022 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-02-15 23:09:31 UTC https://civicdb.org/links/evidence_items/1022 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Gastric Adenocarcinoma 3717 Lapatinib Predictive Supports B Sensitivity/Response TyTAN, a Phase III study in Asian patients, looked at addition of tyrosine kinase inhibitor lapatinib to chemptherapy in advanced HER2 positive gastric cancer. Primary endpoint was Overall Survival (OS). Participants had progressed under previous treatment and only a small percentage had seen first line trastuzumab. Patients were a mix of those having undergone gastrectomy and not. OS was not significantly different in the ITT population, but certain subpopulations showed significant differences. In the subset of patients showing a stronger immunohistochemistry result for HER2 (IHC3+), progression free survival was significantly different at 5.6 months for lapatinib + pacitaxel vs. 4.2 months for pacitaxel alone. The authors conclude that proof of concept for lapatanib addition to chemotherapy for certain subgroups is provided in this study. 24868024 PubMed Satoh et al., 2014, J. Clin. Oncol. 3 accepted 1023 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-02-15 23:08:05 UTC https://civicdb.org/links/evidence_items/1023 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false KIT 3815 EXPRESSION Endometrial Cancer 1380 Imatinib Predictive Supports C Sensitivity/Response Case Report of a 42-year old patient with low-grade endometrial stromal sarcoma. IHC was focally positive for CD117. Imatinib mesylate led to complete metabolic response (PET-CT). 18607592 PubMed Kalender et al., 2009, Cancer Chemother. Pharmacol. 2 accepted 1024 429 29 4 55524085 55606881 ENST00000288135.5 75 GRCh37 N/A 2016-03-16 22:09:26 UTC https://civicdb.org/links/evidence_items/1024 https://civicdb.org/links/variants/429 https://civicdb.org/links/genes/29 false KIT 3815 EXPRESSION Endometrial Cancer 1380 Imatinib Predictive Supports C Sensitivity/Response Case Report of a 41-year old patient with high-grade stromal endometrial sarcoma and a large abdominal and retroperitoneal mass progressing after chemotherapy. IHC for c-Kit was positive and treatment with imatinib led to an objective Response. Surgery was performed and the patient was free of disease two years later. 16487996 PubMed Salvatierra et al., 2006, Gynecol. Oncol. 2 accepted 1025 429 29 4 55524085 55606881 ENST00000288135.5 75 GRCh37 N/A 2016-02-17 19:49:54 UTC https://civicdb.org/links/evidence_items/1025 https://civicdb.org/links/variants/429 https://civicdb.org/links/genes/29 false CBFB 865 CBFB::MYH11 Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome The CBFB-MYH11 fusion has been shown to be associated with favorable prognosis in acute myeloid leukemia. 22180162 PubMed Estey, 2012, Am. J. Hematol. 4 accepted 1027 431 776 16 67063148 67116211 ENST00000412916.2 16 15797029 15820911 ENST00000396324.3 75 GRCh37 CBFB-MYH11 is the result of inv(16)(p13q22) or t(16;16)(p13;q22) and is sufficient for the diagnosis of acute myeloid leukemia (in the correct setting) according to WHO criteria, even when blast counts are <20% (Vardiman et al, Blood 2008). This fusion is typically associated with favorable prognosis relative to other AML subtypes (including cytogenetically normal); however, the impact of additional mutations in the context of this fusion is incompletely understood. AMLs with this fusion are often grouped with other rearrangements affecting genes encoding core binding factor subunits, referred to as CBF AMLs. Somatic 2016-02-18 14:35:22 UTC https://civicdb.org/links/evidence_items/1027 https://civicdb.org/links/variants/431 https://civicdb.org/links/genes/776 false TP53 7157 Mutation Adrenocortical Carcinoma 3948 Prognostic Supports B Poor Outcome TP53 mutation was shown to be associated with shorter overall survival in patients with adrenocortical tumors (log-rank test; P=0.098). Of 20 patients studied, 5 had coding mutation in TP53. Four of the 5 patients with a TP53 mutation had metastases at diagnosis or detected soon thereafter, and 3 of 4 died of disease within 12 months of surgical resection. 15922892 PubMed Sidhu et al., 2005, Eur J Surg Oncol 2 accepted 1028 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2016-02-22 02:50:28 UTC https://civicdb.org/links/evidence_items/1028 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false KMT2A 4297 KMT2A::MLLT3 Acute Myeloid Leukemia 9119 Diagnostic Supports A Positive The MLL-MLLT3 translocation, along with other MLL translocations, are so common in acute myeloid leukemia that the World Health Organization has developed a sub-type of "AML with t(9;11)(p22;q23); MLLT3-MLL" under the AML with recurrent genetic abnormalities diagnosis. 19357394 PubMed Vardiman et al., 2009, Blood 4 accepted 1029 432 3537 Somatic 2016-02-18 14:33:11 UTC https://civicdb.org/links/evidence_items/1029 https://civicdb.org/links/variants/432 https://civicdb.org/links/genes/3537 false ROS1 6098 Rearrangement Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports B Sensitivity/Response In a retrospective study, 30 patients were evaluated after crizotinib treatment for stage IV NSCLC confirmed for ROS1 rearrangement. On crizotinib, 24 of the patients achieved objective responses including 5 complete responses. Median progression free survival was 9.1 months and all patients had been pretreated with 1 or more lines of chemotherapy. 25667280 PubMed Mazières et al., 2015, J. Clin. Oncol. 3 accepted 1030 269 4941 6 117609463 117747018 ENST00000368508.3 75 GRCh37 ROS1 is a receptor tyrosine kinase that frequently forms gene fusions in several cancer types. Approximately 2% of NSCLC patients harbor a ROS1 gene fusion. Several fusion partners have been described with a constant ROS1-breakpoint, maintaining the kinase domain (Solomon B, 2015). Following case-studies and retrospective analyses, an expansion cohort of a phase-1 study showed clinical benefit of crizotinib in ROS1 rearranged NSCLC. The benefit was independent of the type of ROS1-rearrangement (Shaw et. al.,2014). Somatic 2016-02-18 17:13:47 UTC https://civicdb.org/links/evidence_items/1030 https://civicdb.org/links/variants/269 https://civicdb.org/links/genes/4941 false HIF1A 3091 3' UTR Polymorphism Pancreatic Adenocarcinoma 4074 Prognostic Supports B Poor Outcome The HIF1A rs2057482 SNP was genotyped in 410 pancreatic ductal adenocarcinoma cases and 490 healthy controls. The CC genotype was significantly correlated with PDAC risk (OR = 1.719, 95% CI: 1.293-2.286) and shorter overall survival (OS, P<0.0001), compared with the CT/TT alleles Group. After multivariate Analysis, CC-HIF1A and HIF-1α expression were still significantly associated with OS (P<0.0001). This SNP is expected to reduce MiR-199a induced repression of HIF-1α Expression. 26872370 PubMed Wang et al., 2016, Oncotarget 2 accepted 1031 433 2596 14 62213848 62213848 T C ENST00000394997.1 75 GRCh37 Common Germline 2016-02-22 20:57:15 UTC https://civicdb.org/links/evidence_items/1031 https://civicdb.org/links/variants/433 https://civicdb.org/links/genes/2596 false HIF1A 3091 OVEREXPRESSION Colorectal Cancer 9256 Prognostic Supports B Poor Outcome HIF1A overexpression was assessed by IHC in 731 colorectal cancers from two prospective cohort studies. 142 (19%) tumors showed HIF1A overexpression. Overexpression of HIF1A was associated with higher colorectal cancer-specific mortality in Kaplan-Meier analysis (log-rank test, P < 0.0001), univariate Cox regression (hazard ratio = 1.84; 95% confidence interval, 1.37 to 2.47; P < 0.0001) and multivariate analysis (adjusted hazard ratio = 1.72; 95% confidence interval, 1.26 to 2.36; P = 0.0007, adjusted for clinical and tumoral features: microsatellite instability, TP53 (p53), PTGS2 (cyclooxygenase-2), CpG island methylator phenotype, and KRAS, BRAF, PIK3CA, and LINE-1 methylation). 20363910 PubMed Baba et al., 2010, Am. J. Pathol. 3 accepted 1032 434 2596 14 62162258 62214976 ENST00000394997.1 75 GRCh37 N/A 2016-02-18 17:29:45 UTC https://civicdb.org/links/evidence_items/1032 https://civicdb.org/links/variants/434 https://civicdb.org/links/genes/2596 false EPAS1 2034 Overexpression Colorectal Cancer 9256 Prognostic Does Not Support B Poor Outcome Expression of EPAS1 (HIF-2alpha) was assessed in 731 colorectal cancers from two prospective cohort studies. EPAS1 overexpression was found in 322 (46%) cancers by immunohistochemistry and not significantly associated with patient survival. 20363910 PubMed Baba et al., 2010, Am. J. Pathol. 3 accepted 1033 435 1705 2 46524541 46613836 ENST00000263734.3 75 GRCh37 N/A 2016-02-18 17:30:31 UTC https://civicdb.org/links/evidence_items/1033 https://civicdb.org/links/variants/435 https://civicdb.org/links/genes/1705 false HIF1A 3091 OVEREXPRESSION Sarcoma 1115 Prognostic Supports B Poor Outcome Expression of HIF1A was analyzed by IHC in 49 soft-tissue sarcomas (29 malignant fibrous histiocytomas, 12 synovial sarcomas, 4 leiomyosarcomas and 4 malignant peripheral nerve sheath tumors). High (18.4%) or moderate (35.4%) expression of HIF-1alpha was significatnly associated with shorter overall survival rate in comparison with those with a weak or negative expression in univariate analysis (P = 0.029; log-rank test) and multivariate analysis (P = 0.018). 17103226 PubMed Shintani et al., 2006, Virchows Arch. 2 accepted 1034 434 2596 14 62162258 62214976 ENST00000394997.1 75 GRCh37 N/A 2016-02-18 17:29:55 UTC https://civicdb.org/links/evidence_items/1034 https://civicdb.org/links/variants/434 https://civicdb.org/links/genes/2596 false VHL 7428 Loss Renal Carcinoma 4451 Temsirolimus Predictive Supports D Sensitivity/Response Preclinical studies linking the efficacy of mTOR inhibitor CCI-779 to VHL loss in vitro and in mouse models of kidney cancer. VHL-deficient tumors were more sensitive to mTOR inhibition than VHL-proficient tumors. Growth arrest caused by CCI-779 correlated with a block in translation of HIF1A mRNA. Expression of a VHL-resistant HIF1A cDNA lacking the 5' untranslated region rescued tumor growth. 16341243 PubMed Thomas et al., 2006, Nat. Med. 3 accepted 1035 436 58 3 10182692 10193904 ENST00000256474.2 75 GRCh37 Somatic 2016-02-22 20:32:45 UTC https://civicdb.org/links/evidence_items/1035 https://civicdb.org/links/variants/436 https://civicdb.org/links/genes/58 false FLT3 2322 D835 Acute Myeloid Leukemia 9119 Ponatinib,Quizartinib Substitutes Predictive Supports D Resistance An in-vitro saturation mutagenesis screen of 50 independently derived FLT3-ITD clones was performed to identify mutations that confer resistance to ponatinib. Mutations at 3 AL residues (D835 [n = 31], D839 [n = 3], and Y842 [n = 16]), with varying degrees of resistance to ponatinib were identified. FLT3 D835 mutations were shown to confer resistance to the tyrosine kinase inhibitor AC220 and ponatinib. This was especially found for D835Y and D835V mutations, whereas D835H mutations were found to confer moderate resistance to ponatinib but relatively minimal resistance to AC220. 23430109 PubMed Smith et al., 2013, Blood 3 accepted 1036 437 24 13 28592642 28592642 C A ENST00000241453.7 75 GRCh37 Somatic 2016-02-21 22:23:23 UTC https://civicdb.org/links/evidence_items/1036 https://civicdb.org/links/variants/437 https://civicdb.org/links/genes/24 false FLT3 2322 D835 Acute Myeloid Leukemia 9119 SU5614 Predictive Supports D Resistance An in-vitro cell-based screening approach generated FLT3-ITD-expressing cell lines resistant to the FLT3 inhibitors SU5614, PKC412, and sorafenib. SU5614 resistance mutations were limited to exchanges in the second part of the kinase domain (TK2), with exchanges of D835 predominating (D835E were most common). In clones that emerged at 1,500 nmol/L SU5614 after ENU (mutagen) treatment, 127 of 179 clones (71%) displayed mutations, generating 9 different exchanges affecting 6 positions in the activation loop of FLT3. 19318574 PubMed von Bubnoff et al., 2009, Cancer Res. 3 accepted 1037 437 24 13 28592642 28592642 C A ENST00000241453.7 75 GRCh37 Somatic 2016-02-22 02:47:15 UTC https://civicdb.org/links/evidence_items/1037 https://civicdb.org/links/variants/437 https://civicdb.org/links/genes/24 false FLT3 2322 D835 Acute Myeloid Leukemia 9119 Sorafenib,Quizartinib Substitutes Predictive Supports B Resistance In an in-vitro study using an in vitro saturation mutagenesis assay, 4 residues with AC220 (quizartinib) resistance-conferring mutations in the kinase domain of FLT3-ITD were identified. Mutations at three of these amino acid positions conferred high degrees of in vitro AC220 resistance (based on proliferation and cell-based biochemical assays). Among these residues, two within the activation loop were found (D835, Y842). Pre-treatment and relapse samples of 8 patients (treated with AC220) with FLT3-ITD+ acute myeloid leukemia were analyzed. The activation loop mutation D835Y was detected in three cases, D835V in two, and D835F was identified in a single patient. Cross-resistance to sorafenib was identified in-vitro. 22504184 PubMed Smith et al., 2012, Nature 4 accepted 1038 437 24 13 28592642 28592642 C A ENST00000241453.7 75 GRCh37 Somatic 2016-07-13 23:40:36 UTC https://civicdb.org/links/evidence_items/1038 https://civicdb.org/links/variants/437 https://civicdb.org/links/genes/24 false FLT3 2322 D835 Acute Myeloid Leukemia 9119 Sorafenib Predictive Supports B Resistance 13 patients with relapsed or chemo-refractory FLT3-ITD+ AML were treated with sorafenib (200-400 mg twice daily). 12 patients responded, but sorafenib response was lost in most patients after 72 (range 54-287) days. Leukemia initiating cells bearing the D835 mutation expanded during sorafenib treatment and dominated during the subsequent clinical resistance. Results were recapitulated in-vivo. 22368270 PubMed Man et al., 2012, Blood 4 accepted 1039 437 24 13 28592642 28592642 C A ENST00000241453.7 75 GRCh37 Somatic 2016-02-19 23:15:01 UTC https://civicdb.org/links/evidence_items/1039 https://civicdb.org/links/variants/437 https://civicdb.org/links/genes/24 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Sorafenib Predictive Supports B Sensitivity/Response 13 patients with relapsed or chemo-refractory FLT3-ITD+ AML were treated with sorafenib (200-400 mg twice daily). 12 patients showed clearance or near clearance of bone marrow myeloblasts after 27 (range 21-84) days with evidence of differentiation of leukemia cells. Sorafenib response was lost in most patients after 72 (range 54-287) days. 22368270 PubMed Man et al., 2012, Blood 2 accepted 1040 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-02-19 23:30:17 UTC https://civicdb.org/links/evidence_items/1040 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false ERBB2 2064 Amplification Lung Non-small Cell Carcinoma 3908 Trastuzumab Predictive Does Not Support B Sensitivity/Response In this phase II trial with 2 arms, 103 patients with untreated stage IIIB/IV HER2 positive NSCLC were given gemcitabine-cisplatin with or without trastuzumab. HER2 positivity was broadly defined as IHC2+/3+, positive by FISH, or increased circulating HER2 extracellular domain. Significant differences between the treatment arms were not observed, but in a small subset of IHC3+/FISH positive patients, 5 of 6 responded to trastuzumab and had increased PFS of 8.5 months in comparison to 6.1 months in the IHC2+ group. Although from 2004, this study remains cited in 2016 literature when discussing the unclear efficacy of trastuzumab in wild-type HER2 overexpressing NSCLC. The authors conclude that future studies of trastuzumab in HER2 positive NSCLC should focus on high expressing subjects. 14679114 PubMed Gatzemeier et al., 2004, Ann. Oncol. 2 accepted 1041 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-10-06 18:38:51 UTC https://civicdb.org/links/evidence_items/1041 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Lung Non-small Cell Carcinoma 3908 Trastuzumab Predictive Does Not Support B Sensitivity/Response In this phase II trial a small group of patients with IHC2+ or IHC3+ HER2 NSCLC, in which primary platinum-based therapy had failed, were given either docetaxel or trastuzumab after which both groups were given docetaxel and trastuzumab together. there was one partial response in the docetaxel group and none in the trastuzumab group. The authors report that due to the limited clinical activity of trastuzumab-based therapy in this cohort, as well as similar results in other trastuzumab studies, that targets other than HER2 in NSCLC should be considered for future study. This 2004 study remains cited in 2016 literature in discussing the unclear efficacy of trastuzumab in wild-type HER2 overexpressing NSCLC, but mutant HER2 in NSCLC has been further studied and a picture of different HER2 mutations being potentially responsive to specific targeted therapies is emerging. 14967075 PubMed Lara et al., 2004, Clin Lung Cancer 3 accepted 1042 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-10-06 18:38:51 UTC https://civicdb.org/links/evidence_items/1042 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Kinase Domain Mutation Lung Adenocarcinoma 3910 Trastuzumab Predictive Supports C Sensitivity/Response This was a retrospective study of patients with advanced HER2-mutant NSCLC who had undergone varied courses of treatment. All tumors were adenocarcinoma with in-frame HER2 exon 20 insertions. In patients (n=57) that had been treated with trastuzumab plus chemotherapy, an overall response rate of 75% and progression free survival of 5.1 months were observed. No standard of care currently exists for HER2-mutant NSCLC. While trastuzumab has not shown clear benefit yet in wild-type HER2 overexpressed NSCLC, the authors conclude that further prospective studies should be done with trastuzumab plus chemotherapy in advanced HER2 mutant NSCLC, and that trastuzumab plus chemotherapy should be considered in current treatment courses of this cancer type. 26598547 PubMed Mazières et al., 2016, Ann. Oncol. 4 accepted 1043 413 20 17 37879863 37882870 ENST00000269571.5 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1043 https://civicdb.org/links/variants/413 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Lung Small Cell Carcinoma 5409 Trastuzumab,Irinotecan Combination Predictive Supports C Sensitivity/Response This report details 2 case studies in relapsed HER2 positive SCLC. In the first case, a 50 pack-year patient showed intense non-mutant HER2 expression by IHC without DNA amplification, and had undergone multiple prior lines of treatment. With induction of trastuzumab and irinotecan treatment, tumor regression was observed with progression free survival of 4.5 months. Case 2 involved a 68 year old never-smoker with relapsed SCLC. Tumor showed HER2 positive SCLC cells with no amplification or mutation. Third line trastuzumab plus irinotecan brought about some symptom improvement and PFS of 3.5 months. While the efficacy of trastuzumab against NSCLC with elevated levels of wild-type HER2 expression remains unclear, the authors conclude that trastuzumab based therapy is a promising strategy for chemo-resistant SCLC. 25601188 PubMed Kinehara et al., 2015, Lung Cancer 4 accepted 1044 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-10-06 18:38:51 UTC https://civicdb.org/links/evidence_items/1044 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Y772_A775DUP Lung Adenocarcinoma 3910 Afatinib Predictive Supports C Sensitivity/Response A 55 year old heavily pretreated patient with equivocal HER2 overexpression (IHC2+ and no amplification in FISH) was found to have the HER2 YMVA kinase domain insertion. Afatinib monotherapy resulted in resolution of symptoms and 10 months before progressive disease. The patient was subsequently given trastuzumab with no response. The observed efficacy of afatinib against M774insAYVM, and studies reporting afatinib activity against other variants in the HER2 kinase domain, are cited by the authors as motivation for the arm of NCI-MATCH focusing on afatinib and activating HER2 mutations. 26559459 PubMed Li et al., 2015, Lung Cancer 4 accepted 1045 414 20 17 37880996 37880997 TACGTGATGGCT ENST00000269571.5 75 GRCh37 Mutations in the HER2 kinase domain occur at a 2-4% frequency in lung adenocarcinomas, the majority of which are in exon 20 as in-frame duplications or insertions in a small 8 codon region (774-781 or 775-782). These are analogous to the exon 20 alterations found in EGFR TK domain. The M774 insertion, M774insAYVM, represents 62.5% of all HER2 kinase domain mutations identified (when combined with the A775insYVMA mutations as they translate to the identical amino acid sequence changes). As demonstrated in mouse models (Perrera et al., PNAS 2009) and subsequent clinical trials in human lung adenocarcinoma with these insertions, HER2 YVMA mutants predict response to several targeted HER2 agonists such as afatinib, trastuzumab, neratinib and TDM-1 (trastuzumab emtansine) as monotherapy or combined with specific chemotherapies. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1045 https://civicdb.org/links/variants/414 https://civicdb.org/links/genes/20 false ERBB2 2064 Y772_A775DUP Lung Carcinoma 3905 Afatinib Predictive Supports D Sensitivity/Response Human HER2 with YVMA insertion was put under a clara cell specific, rtTA promoter system inducible via doxycycline. Induction of mutant HER2 in these mice drove rapid development of adenosquamous lung tumors, where tumor maintenance was dependent on continued YMVA HER2 induction by doxycycline. Administration of afatinib had a stronger effect than erlotinib or trastuzumab, as measured by histology and tumor volume regression. Authors state that in the case of afatinib vs. trastuzumab, intracellular HER2 signaling may be blocked by afatanib but remain unaltered by trastuzumab. 19122144 PubMed Perera et al., 2009, Proc. Natl. Acad. Sci. U.S.A. 4 accepted 1047 414 20 17 37880996 37880997 TACGTGATGGCT ENST00000269571.5 75 GRCh37 Mutations in the HER2 kinase domain occur at a 2-4% frequency in lung adenocarcinomas, the majority of which are in exon 20 as in-frame duplications or insertions in a small 8 codon region (774-781 or 775-782). These are analogous to the exon 20 alterations found in EGFR TK domain. The M774 insertion, M774insAYVM, represents 62.5% of all HER2 kinase domain mutations identified (when combined with the A775insYVMA mutations as they translate to the identical amino acid sequence changes). As demonstrated in mouse models (Perrera et al., PNAS 2009) and subsequent clinical trials in human lung adenocarcinoma with these insertions, HER2 YVMA mutants predict response to several targeted HER2 agonists such as afatinib, trastuzumab, neratinib and TDM-1 (trastuzumab emtansine) as monotherapy or combined with specific chemotherapies. Somatic 2016-02-22 18:20:48 UTC https://civicdb.org/links/evidence_items/1047 https://civicdb.org/links/variants/414 https://civicdb.org/links/genes/20 false ERBB2 2064 P780INS Lung Adenocarcinoma 3910 Dacomitinib Predictive Supports C Sensitivity/Response In this phase II study (NCT00818441) of dacomitinib in HER2 amplified or mutant NSCLC tumors, three of 26 patients with HER2 p.P780_Y781insGSP or p.M774delinsWLV showed partial responses of duration between 3 and 14 months, while 13 patients with the more common HER2 p. A775_G776insYVMA showed no partial responses. The authors conclude that in the set of activating HER2 mutations, benefits of an individual agent may be specific to certain mutations, and that "HER2-positive lung cancers" is not an adequate term to describe this group of distinguishable illnesses. 25899785 PubMed Kris et al., 2015, Ann. Oncol. NCT00818441 3 accepted 1048 41 20 17 37881011 37881012 GGCTCCCCA ENST00000269571.5 75 GRCh37 ERBB2 P780 insertion was one of the first ERBB2 variants to be functionally classified (Bose et al. 2013). This mutation was shown to be an activating mutation in an in vitro assay. In the same paper, this mutation (along with other ERBB2 activating mutations) in MCF10A breast cancer cell lines have been shown to be sensitive to the kinase inhibitor neratinib. More recent evidence may show that HER2 activating mutations confer sensitivity to a host of tyrosine kinase inhibitors, which is the topic of current clinical trials and research. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1048 https://civicdb.org/links/variants/41 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Lung Non-small Cell Carcinoma 3908 Trastuzumab Emtansine Predictive Supports D Sensitivity/Response Efficacy of trastuzumab in HER2 overexpressing NSCLC remains unclear. In this study using a panel of NSCLC HER2 overexpressing cell lines, antiproliferative effects of trastuzumab emtansine (T-DM1) were observed in a HER2-expression dependant manner, with strongest effects in Calu-3 (high expressing) and no effects in Calu-6 (low expressing). Trastuzumab did not show notable effects on cell growth in any tested cells. HER2 positivity in NSCLC is fairly common at 2-20%. A clinical trial (NCT02289833) is currently underway to asses TDM-1 in HER2 overexpressing lung cancer. 24898067 PubMed Cretella et al., 2014, Mol. Cancer 4 accepted 1050 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-10-06 18:38:51 UTC https://civicdb.org/links/evidence_items/1050 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false PSMB8 5696 NUCLEAR EXPRESSION Gastric Adenocarcinoma 3717 Prognostic Supports B Poor Outcome Microarray expression data from 48 patients with gastric adenocarcinoma were analyzed for genes differentially expressed with regard to overall survival. Expression of 294 and 116 genes was enriched in good and poor prognosis subtypes, respectively. Of these genes, upregulation of proteasome subunit beta type 8 PSMB8 and PDZ binding kinase PBK was confirmed by real-time reverse transcription-PCR Analysis. IHC in 385 gastric cancer patients showed that increased nuclear expression of PSMB8 and PBK was correlated with depth of invasion, lymph node metastasis, and lower survival rates (survival durations of the (-), (+), and (++) groups, classified according to nuclear PSMB8 expression, were 77.2, 70.6, and 62.2 months, respectively; P = 0.004). Cytoplasmic staining of PSMB8 and PBK were not statistically significant. In multivariate Analysis, nuclear expression of PSMB8 and PBK were not significant predictors of overall survival (P = 0.085, P = 0.083, respectively). 26894977 PubMed Kwon et al., 2016, Oncotarget 2 accepted 1051 438 4616 6 32808494 32812480 ENST00000374881.2 75 GRCh37 N/A 2016-02-23 00:04:24 UTC https://civicdb.org/links/evidence_items/1051 https://civicdb.org/links/variants/438 https://civicdb.org/links/genes/4616 false PBK 55872 NUCLEAR EXPRESSION Gastric Adenocarcinoma 3717 Prognostic Supports B Poor Outcome Microarray expression data from 48 patients with gastric adenocarcinoma were analyzed for genes differentially expressed with regard to overall survival. Upregulation of proteasome subunit beta type 8 (PSMB8) and PDZ binding kinase (PBK) was confirmed by real-time reverse transcription-PCR Analysis. IHC in 385 gastric cancer patients showed that increased nuclear expression of PSMB8 and PBK was correlated with depth of invasion, lymph node metastasis, and lower survival rates (survival duration, months according to nuclear PBK Expression: -, 72.3 ± 1.2; +, 66.2 ± 3.4; ++, 53.1 ± 9.2; P = 0.002). Cytoplasmic staining of PSMB8 and PBK were not statistically significant. In multivariate analysis, nuclear expression of PSMB8 and PBK were not significant predictors of overall survival (P = 0.085, P = 0.083, respectively). 26894977 PubMed Kwon et al., 2016, Oncotarget 2 accepted 1052 439 13276 8 27667137 27695612 ENST00000301905.4 75 GRCh37 N/A 2016-07-26 14:51:23 UTC https://civicdb.org/links/evidence_items/1052 https://civicdb.org/links/variants/439 https://civicdb.org/links/genes/13276 false PTTG1 9232 OVEREXPRESSION Meningioma 3565 Prognostic Supports B Poor Outcome 144 cases (discovery set: N=62 discovery; independent validation set: N = 82) of meningiomas were analyzed for transcriptional features defining aggressive clinical course (recurrent, malignantly progressing, or WHO grade III). Meningiomas were categorized into non-recurrent (NR), recurrent (R), and tumors undergoing malignant progression (M). Unsupervised transcriptomic analysis in 62 meningiomas revealed a large set of differentially expressed genes in aggressive subgroups (R+M tumors and WHO grade III, n=332; p<0.01, FC>1.25). Multivariate analysis identified PTTG1 and LEPR mRNA expression independent of gender, WHO grade and extent of resection. The patient group with the longest progression free survival was characterized by co-occurrence of low PTTG1 and high LEPR mRNA expression. IHC in 36 tumors validated these results at the protein level. 26894859 PubMed Schmidt et al., 2016, Oncotarget 2 accepted 1053 440 7297 5 159848829 159855748 ENST00000352433.5 75 GRCh37 N/A 2016-02-23 02:29:41 UTC https://civicdb.org/links/evidence_items/1053 https://civicdb.org/links/variants/440 https://civicdb.org/links/genes/7297 false LEPR 3953 UNDEREXPRESSION Meningioma 3565 Prognostic Supports B Poor Outcome 144 cases (discovery set: N=62 discovery; Independent validation set: N = 82) of meningiomas were analyzed for transcriptional features defining aggressive clinical course (recurrent, malignantly progressing or WHO grade III). Meningiomas were categorized into non-recurrent (NR), recurrent (R), and tumors undergoing malignant progression (M). Unsupervised transcriptomic analysis in 62 meningiomas revealed a large set of differentially expressed genes in aggressive subgroups (R+M tumors and WHO grade III, n=332; p<0.01, FC>1.25). Multivariate analysis identified PTTG1 and LEPR mRNA expression independent of gender, WHO grade and extent of resection. The patient group with the longest PFS was characterized by co-occurrence of low PTTG1 and high LEPR mRNA expression. IHC in 36 tumors validated these results on protein level. 26894859 PubMed Schmidt et al., 2016, Oncotarget 2 accepted 1054 441 3274 1 65886335 66107242 ENST00000349533.6 75 GRCh37 N/A 2016-02-23 19:21:09 UTC https://civicdb.org/links/evidence_items/1054 https://civicdb.org/links/variants/441 https://civicdb.org/links/genes/3274 false EREG 2069 EXPRESSION Lung Adenocarcinoma 3910 Prognostic Supports E Poor Outcome Study reporting an in-vivo two-stage initiation/promotion model, testing the hypothesis that Ereg deficiency would reduce lung tumor promotion in mice. Cancerogenesis with chemical initiators/promoters (3-methylcholanthrene or control, butylated hydroxytoluene) was assessed in mice lacking Ereg (Ereg-/-) and wildtype controls (BALB/ByJ; Ereg+/+) at multiple time points and endpoints (bronchoalveolar lavage analysis, tumor analysis, mRNA expression, ELISA, wound assay). Initially a significantly reduced amount of inflammation (macrophages, PMNs) was observed in the Ereg-/- mice. At 20 wk, tumor multiplicity was also significantly decreased in the Ereg-/- mice. 26894620 PubMed Bauer et al., 2016, Mol. Carcinog. 2 accepted 1055 318 1737 4 75230860 75254468 ENST00000244869.2 75 GRCh37 N/A 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1055 https://civicdb.org/links/variants/318 https://civicdb.org/links/genes/1737 false EGFR 1956 G465R Colorectal Cancer 9256 Futuximab/Modotuximab Mixture Predictive Supports C Sensitivity/Response An EGFR G465R mutation (22% of mutant alleles) was detected in a biopsy from one patient which had been previously treated with cetuximab in the analysis of 15 patients with refractory, metastatic CRC after cetuximab/panitumumab, prior to Sym004 (Futuximab/Modotuximab mixture) treatment. Subsequent treatment of this patient with Sym004 yielded disease stabilization lasting 15 weeks. In vitro analysis in colorectal cancer cell line NIH3T3 with EGFR mutations S492R, R451C, K467T, and G465R showed that antibody mixture Sym004 effectively bound to all mutants, whereas cetuximab and panitumumab did not effectively bind to all mutants. In-vitro, Sym004 inhibited growth of S492R and G465R EGFR mutant cell lines. In-vivo analysis of S492R and G465R mutant cell lines showed regression of S492R and tumor growth delay of G465R mutant cell lines. 26888827 PubMed Sánchez-Martín et al., 2016, Clin. Cancer Res. 4 accepted 1057 443 19 7 55227926 55227926 G A ENST00000275493.2 75 GRCh37 Somatic 2021-04-27 04:01:17 UTC https://civicdb.org/links/evidence_items/1057 https://civicdb.org/links/variants/443 https://civicdb.org/links/genes/19 false EGFR 1956 G465R Colorectal Cancer 9256 Cetuximab,Panitumumab Substitutes Predictive Supports C Resistance An EGFR G465R mutation (22% of mutant alleles) was detected in a biopsy from one patient which had been previously treated with cetuximab in the analysis of 15 patients with refractory, metastatic CRC after cetuximab/panitumumab, prior to Sym004 treatment. Treatment of this patient with Sym004 yielded disease stabilization lasting 15 weeks. Sym004 is a 1:1 mixture of two non-overlapping anti-EGFR monoclonal antibodies. In vitro analysis in the murine fibroblast cell line NIH3T3 with ectopic expression of EGFR mutations S492R, R451C, K467T, and G465R showed that Sym004 effectively bound to all mutants, whereas cetuximab and panitumumab did not effectively bind to all mutants. In-vitro, Sym004 inhibited growth of S492R and G465R EGFR mutant cell lines. In-vivo analysis of S492R and G465R mutant cell lines showed regression of S492R and tumor growth delay of G465R mutant cell lines. G465R mutant cell lines were resistant to treatment with panitumumab or cetuximab in-vitro. 26888827 PubMed Sánchez-Martín et al., 2016, Clin. Cancer Res. 4 accepted 1058 443 19 7 55227926 55227926 G A ENST00000275493.2 75 GRCh37 Somatic 2016-02-24 17:44:07 UTC https://civicdb.org/links/evidence_items/1058 https://civicdb.org/links/variants/443 https://civicdb.org/links/genes/19 false NEDD9 4739 EXPRESSION Hepatocellular Carcinoma 684 Prognostic Supports B Poor Outcome IHC was performed in 123 hepatocellular carcinoma tissues and their adjacent normal liver tissues for protein expression of HEF1 (NEDD9). Overexpression of HEF1 protein was observed in HCC tissue when compared with their adjacent non-malignant liver tissue. High expression of HEF1 correlated with higher advanced tumor, node, metastasis (TNM) stage and vascular invasion (P<0.05). In univariate and multivariate analysis, the expression of HEF1 was identified as an independent prognostic factor (Spearman's rank correlation, Kaplan-Meier plots and Cox regression model). In subgroup analysis, high expression of HEF1 correlated with a poorer prognosis in advanced (TNM III+IV) stages (P<0.05). 26893853 PubMed Li et al., 2016, Mol Clin Oncol 3 accepted 1059 444 3852 6 11185051 11382581 ENST00000504387.1 75 GRCh37 N/A 2016-02-22 17:33:12 UTC https://civicdb.org/links/evidence_items/1059 https://civicdb.org/links/variants/444 https://civicdb.org/links/genes/3852 false ETS2 2114 RS461155 Lung Non-small Cell Carcinoma 3908 Cisplatin,Paclitaxel Combination Predictive Supports B Sensitivity/Response Eighty SNPs in miRNA binding sites of cancer related genes selected from 18,500 miRNA:target bindings in crosslinking, ligation, and sequencing of hybrids (CLASH) data were investigated in 379 advanced NSCLC patients using a sequenom mass spectrometry-based genotype assay. 16 SNPs were significantly associated with the clinical outcomes after chemotherapy with paclitaxel-cisplatin: ETS2 SNP: OR = 1.34, 95% CI = 1.00–1.81, P = 0.05; aHR = 0.80, 95% CI = 0.69–0.94, P = 0.006, under additive model. ETS2 rs461155A>G was significantly associated with decreased ETS2 mRNA expression in both tumor and paired normal lung tissues (Ptrend = 4 × 10-7, and 3 × 10-4, respectively). 26893365 PubMed Hong et al., 2016, Oncotarget 2 accepted 1060 445 1763 21 40191638 40191638 A G ENST00000360214.3 75 GRCh37 Common Germline 2016-02-23 21:51:43 UTC https://civicdb.org/links/evidence_items/1060 https://civicdb.org/links/variants/445 https://civicdb.org/links/genes/1763 false KRT18 3875 UNDEREXPRESSION Prostate Cancer 10283 Prognostic Supports D Poor Outcome Comparison of nuclear matrix protein (NMP) patterns of paclitaxel-resistant PCa cells (DU145-TxR), with that of parental cell (DU145) using two-dimensional electrophoresis, identified cytokeratin 18 (CK18) as downregulated in DU145-TxR cells (validated at mRNA, NMP and total cellular protein levels). An in-vivo assay of xenograft transplantation showed higher tumorigenicity of DU145-TxR cells. Immunohistochemistry showed that CK18 expression in PCa tissues was statistically significant inversely correlated with tumor grade. 26892177 PubMed Yin et al., 2016, Int. J. Oncol. 2 accepted 1061 446 3215 12 53342655 53346684 ENST00000388837.2 75 GRCh37 N/A 2016-02-23 02:23:58 UTC https://civicdb.org/links/evidence_items/1061 https://civicdb.org/links/variants/446 https://civicdb.org/links/genes/3215 false FGF13 2258 CYTOPLASMIC EXPRESSION Prostate Cancer 10283 Prognostic Supports B Poor Outcome 243 primary PCa, 37 metastatic PCa, and 20 castration-resistant PCa (CRPC) specimens underwent IHC and microarray analysis. Immunohistochemistry (IHC) showed that FGF13 was detectable in the majority of human PCa samples, and FGF13 IHC scores were higher in high-grade prostatic intraepithelial neoplasia, in primary PCa, and in metastatic PCa than in benign prostatic tissue. There was a significant association between high cytoplasmic FGF13 staining and a risk of biochemical recurrence (BCR) after radical prostatectomy. Multivariate regression analysis indicated that high cytoplasmic FGF13 staining was associated with BCR. Results were recapitulated in cell lines and public databases. 26891277 PubMed Yu et al., 2016, Int. J. Cancer 3 accepted 1062 447 1883 X 137715011 138286269 ENST00000370603.3 75 GRCh37 N/A 2016-02-22 23:27:53 UTC https://civicdb.org/links/evidence_items/1062 https://civicdb.org/links/variants/447 https://civicdb.org/links/genes/1883 false SSX1 6756 SS18::SSX1 Synovial Sarcoma 5485 Diagnostic Supports A Positive A t(X;18) translocation resulting in the fusion SYT-SSX (SS18-SSX1 or SS18-SSX2) is detected cytogenetically in over 90% of synovial sarcomas, regardless of histologic subtype. The prevalence of this fusion in synovial sarcoma approaches 100% when there is adequate tumor RNA for RT-PCR. Its specificity for synovial sarcoma, has been confirmed by molecular screening of other morphologically similar sarcomas. 11607825 PubMed Ladanyi, 2001, Oncogene 4 accepted 1063 448 5500 Somatic 2016-02-24 17:23:19 UTC https://civicdb.org/links/evidence_items/1063 https://civicdb.org/links/variants/448 https://civicdb.org/links/genes/5500 false SSX2 6757 SS18::SSX2 Synovial Sarcoma 5485 Diagnostic Supports A Positive A t(X;18) is detected cytogenetically in over 90% of synovial sarcomas, regardless of histologic subtype. This translocation results primarily in two fusions. SYT-SSX1 (aka SS18-SSX1) and SYT-SSX2 (aka SS18-SSX2). The ratio of SYT-SSX1 to SYT-SSX2 cases is close to 2:1. 11607825 PubMed Ladanyi, 2001, Oncogene 4 accepted 1064 449 5501 Somatic 2016-02-24 17:23:19 UTC https://civicdb.org/links/evidence_items/1064 https://civicdb.org/links/variants/449 https://civicdb.org/links/genes/5501 false SSX1 6756 SS18::SSX1 Synovial Sarcoma 5485 Diagnostic Supports B Positive A characteristic SYT-SSX fusion gene resulting from the chromosomal translocation t(X;18)(p11;q11) is detectable in almost all synovial sarcomas. SYT (aka SS18) pairs with various 3' partners know as SSX (especially SSX1, and SSX2). In this study, 45 synovial sarcomas were assayed for SYT-SSX by RT-PCR using tumor cDNA as template. 29 (64%) had a SYT–SSX1 (SS18-SSX1) fusion transcript. 9428816 PubMed Kawai et al., 1998, N. Engl. J. Med. 3 accepted 1065 448 5500 Somatic 2016-02-24 17:23:19 UTC https://civicdb.org/links/evidence_items/1065 https://civicdb.org/links/variants/448 https://civicdb.org/links/genes/5500 false SSX2 6757 SS18::SSX2 Synovial Sarcoma 5485 Diagnostic Supports B Positive A characteristic SYT-SSX fusion gene resulting from the chromosomal translocation t(X;18)(p11;q11) is detectable in almost all synovial sarcomas. SYT (aka SS18) pairs with various 3' partners know as SSX (especially SSX1, and SSX2). In this study, 45 synovial sarcomas were assayed for SYT-SSX by RT-PCR using tumor cDNA as template. 16 (36%) contained a SYT–SSX2 (SS18-SSX2) fusion transcript. 9428816 PubMed Kawai et al., 1998, N. Engl. J. Med. 3 accepted 1066 449 5501 Somatic 2016-02-24 17:23:19 UTC https://civicdb.org/links/evidence_items/1066 https://civicdb.org/links/variants/449 https://civicdb.org/links/genes/5501 false SSX2 6757 SS18::SSX2 Synovial Sarcoma 5485 Prognostic Supports B Better Outcome In this study, SYT-SSX fusion transcripts (SS18-SSX1 and SS18-SSX2) were detected in 29 (64%) and 16 (36%) of the tumors, respectively. There was a significant relationship (P=0.003) between histologic subtype (monophasic vs. biphasic) and SSX1 or SSX2 involvement in the fusion transcript: all 12 biphasic synovial sarcomas had a SYT-SSX1 fusion transcript, and all 16 tumors that were positive for SYT-SSX2 were monophasic. Kaplan-Meier analysis of 39 patients with localized tumors showed that the 15 patients with SYT-SSX2 had significantly better metastasis-free survival than the 24 patients with SYT-SSX1 (P=0.03 by multivariate analysis; relative risk, 3.0). 9428816 PubMed Kawai et al., 1998, N. Engl. J. Med. 3 accepted 1067 449 5501 Somatic 2016-02-24 17:23:19 UTC https://civicdb.org/links/evidence_items/1067 https://civicdb.org/links/variants/449 https://civicdb.org/links/genes/5501 false SSX1 6756 SS18::SSX1 Synovial Sarcoma 5485 Prognostic Supports B Poor Outcome In this study, SYT-SSX fusion transcripts (SS18-SSX1 and SS18-SSX2) were detected in 29 (64%) and 16 (36%) of the tumors, respectively. There was a significant relationship (P=0.003) between histologic subtype (monophasic vs. biphasic) and SSX1 or SSX2 involvement in the fusion transcript: all 12 biphasic synovial sarcomas had a SYT-SSX1 fusion transcript, and all 16 tumors that were positive for SYT-SSX2 were monophasic. Kaplan-Meier analysis of 39 patients with localized tumors showed that the 15 patients with SYT-SSX2 had significantly better metastasis-free survival than the 24 patients with SYT-SSX1 (P=0.03 by multivariate analysis; relative risk, 3.0). 9428816 PubMed Kawai et al., 1998, N. Engl. J. Med. 3 accepted 1068 448 5500 Somatic 2016-02-24 17:23:19 UTC https://civicdb.org/links/evidence_items/1068 https://civicdb.org/links/variants/448 https://civicdb.org/links/genes/5500 false SSX1 6756 SS18::SSX1 Synovial Sarcoma 5485 Diagnostic Supports B Positive In this review, the author summarize the role of this fusion in diagnosis of synovial sarcomas. Cytogenetic studies have repeatedly demonstrated the t(X;18)(p11;q11) translocation in approximately 90% of both monophasic and biphasic synovial sarcomas. The fusion has clear diagnostic value, though the authors caution that it is not perfectly specific to synovial sarcomas, and suggest that demonstration of t(X;18) in a spindle cell neoplasm should be integrated with the morphology, immunoprofile, and clinical setting of the tumour. 11122430 PubMed Pfeifer et al., 2000, Histopathology 4 accepted 1069 448 5500 Somatic 2016-02-24 17:23:19 UTC https://civicdb.org/links/evidence_items/1069 https://civicdb.org/links/variants/448 https://civicdb.org/links/genes/5500 false SSX1 6756 SS18::SSX1 Synovial Sarcoma 5485 Diagnostic Supports B Positive In this study, 141 spindle cell sarcomas were evaluated for the presence of t(X;18) by RT-PCR. 85% of the synovial sarcomas were positive for this event. The study did not indicate the specific fusion detected but from related studies we know that the majority of these fusions are SYT-SSX1 (aka SS18-SSX1). 11144931 PubMed O'Sullivan et al., 2000, Mod. Pathol. 4 accepted 1070 448 5500 Somatic 2016-02-24 17:23:19 UTC https://civicdb.org/links/evidence_items/1070 https://civicdb.org/links/variants/448 https://civicdb.org/links/genes/5500 false SSX1 6756 SS18::SSX1 Malignant Peripheral Nerve Sheath Tumor 5940 Diagnostic Supports B Positive In this study, 141 spindle cell sarcomas were evaluated for the presence of t(X;18) by RT-PCR. 75% of the malignant peripheral nerve sheath tumors (MPNSTs) were positive for this event. The study did not indicate the specific fusion detected but from related studies we know that the majority of these fusions are SYT-SSX1 (aka SS18-SSX1). 11144931 PubMed O'Sullivan et al., 2000, Mod. Pathol. 3 accepted 1071 448 5500 Somatic 2016-02-23 18:15:24 UTC https://civicdb.org/links/evidence_items/1071 https://civicdb.org/links/variants/448 https://civicdb.org/links/genes/5500 false SSX1 6756 SS18::SSX1 Synovial Sarcoma 5485 Prognostic Supports B Poor Outcome This study collected data on SYT-SSX fusion type, pathology, and clinical course in a retrospective multi-institutional study of 243 patients (age range, 6-82) with synovial sarcoma. SYT-SSX1 and SYT-SSX2 fusions were detected in 147 tumors (61%) and 91 tumors (37%), respectively. Histologically, 61 (25%) were classified as biphasic type and 180 (74%) as monophasic type based on the presence or absence of areas of glandular epithelial differentiation, respectively. Median and 5-year overall survivals for the SYT-SSX1 and SYT-SSX2 groups were 6.1 years and 53%, and 13.7 years and 73%, respectively. 11782370 PubMed Ladanyi et al., 2002, Cancer Res. 4 accepted 1072 448 5500 Somatic 2016-02-24 17:23:19 UTC https://civicdb.org/links/evidence_items/1072 https://civicdb.org/links/variants/448 https://civicdb.org/links/genes/5500 false SSX2 6757 SS18::SSX2 Synovial Sarcoma 5485 Prognostic Supports B Better Outcome This study collected data on SYT-SSX fusion type, pathology, and clinical course in a retrospective multi-institutional study of 243 patients (age range, 6-82) with synovial sarcoma. SYT-SSX1 and SYT-SSX2 fusions were detected in 147 tumors (61%) and 91 tumors (37%), respectively. Histologically, 61 (25%) were classified as biphasic type and 180 (74%) as monophasic type based on the presence or absence of areas of glandular epithelial differentiation, respectively. Median and 5-year overall survivals for the SYT-SSX1 and SYT-SSX2 groups were 6.1 years and 53%, and 13.7 years and 73%, respectively. 11782370 PubMed Ladanyi et al., 2002, Cancer Res. 3 accepted 1073 449 5501 Somatic 2016-02-24 17:23:19 UTC https://civicdb.org/links/evidence_items/1073 https://civicdb.org/links/variants/449 https://civicdb.org/links/genes/5501 false SSX4 6759 SS18::SSX4 Synovial Sarcoma 5485 Diagnostic Supports C Positive Three synovial sarcomas were assayed for SYT-SSX fusion messenger RNA by nested RT-PCR. In a single case an SYT-SSX4 (SS18-SSX4) fusion was detected. The majority of synovial sarcomas are characterized by SS18-SSX1 or SS18-SSX2, but other rare events such as this SS18-SSX4 may explain some or all of the synovial sarcomas that are negative for the most common fusions. 10359553 PubMed Skytting et al., 1999, J. Natl. Cancer Inst. 2 accepted 1074 450 5503 18 23612363 23670589 ENST00000415083.2 X 48261524 48265521 ENST00000376884.2 75 GRCh37 Somatic 2016-02-24 17:23:19 UTC https://civicdb.org/links/evidence_items/1074 https://civicdb.org/links/variants/450 https://civicdb.org/links/genes/5503 false ABCB1 5243 S893A/T Breast Cancer 1612 Prognostic Supports B Better Outcome A total of 57 women with HER2-positive metastatic breast cancer were analyzed after taxane plus trastuzumab chemotherapy. ABCB1 G2677T carriers had a longer progression-free survival (p = 0.037) along with a tendency toward a longer overall survival (p = 0.057). 22906996 PubMed Kim et al., 2012, Oncology 3 accepted 1075 451 4244 7 87160618 87160618 A C ENST00000265724.3 75 GRCh37 Refer to https://www.pharmgkb.org/rsid/rs2032582 for more information. Common Germline 2016-02-23 20:21:49 UTC https://civicdb.org/links/evidence_items/1075 https://civicdb.org/links/variants/451 https://civicdb.org/links/genes/4244 false ABCB1 5243 I1145I Breast Cancer 1612 Prognostic Supports B Better Outcome A total of 57 women with HER2-positive metastatic breast cancer were analyzed after taxane plus trastuzumab chemotherapy. ABCB1 C3435T carriers had a longer progression-free survival (p = 0.039) along with a tendency toward a longer overall survival (p = 0.093). 22906996 PubMed Kim et al., 2012, Oncology 3 accepted 1076 263 4244 7 87138645 87138645 A G ENST00000265724.3 75 GRCh37 ABCB1 I1145I is a germline polymorphism that has improved responses in cancer. Specifically, it can indicate sensitivity to platinum-based chemotherapies for patients with NSCLC or better outcome for HER2-positive metastatic breast cancer patients. Common Germline 2016-02-23 19:08:25 UTC https://civicdb.org/links/evidence_items/1076 https://civicdb.org/links/variants/263 https://civicdb.org/links/genes/4244 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Trastuzumab,Pertuzumab,Docetaxel Combination Predictive Supports B Sensitivity/Response CLEOPATRA (NCT00567190) was a Phase III, randomized and double-blind, placebo-controlled study of 808 patients with HER2-positive metastatic breast cancer. Patients were HER2-positive by IHC3+ or FISH, and patients who had received prior hormonal treatment or adjuvant/neo-adjuvant therapy with or without trastuzumab for longer than 12 months before randomization were also eligible. The two arms of the study were trastuzumab and docetaxel with either placebo or pertuzumab. Median PFS in the placebo arm was 12.4 months while in the petuzumab arm 18.5 months was achieved. Median OS in the control arm was 40.8 months and 56.5 months with pertuzumab. These strong results make a case for dual antibody blockade in first line treatments of HER2-positive metastatic breast cancer. 25693012 PubMed Swain et al., 2015, N. Engl. J. Med. NCT00567190 5 accepted 1077 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-02-18 03:58:48 UTC https://civicdb.org/links/evidence_items/1077 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false EGFR 1956 S492R Colorectal Cancer 9256 Panitumumab Predictive Supports C Sensitivity/Response Tumor sequencing in pre- and post-therapy specimens from ten individuals with mCRC who experienced disease progression after a prior response to cetuximab with chemotherapy was performed. The S492R mutation was identified in two persons. One of them had already died, the other received treatment with panitumumab and had a partial response (50% tumor reduction in all liver lesions) for 5 months. 22270724 PubMed Montagut et al., 2012, Nat. Med. 2 accepted 1078 453 19 7 55228009 55228009 C A ENST00000275493.2 75 GRCh37 Somatic 2016-02-23 19:38:18 UTC https://civicdb.org/links/evidence_items/1078 https://civicdb.org/links/variants/453 https://civicdb.org/links/genes/19 false EGFR 1956 S492R Colorectal Cancer 9256 Panitumumab,Futuximab/Modotuximab Mixture Substitutes Predictive Supports D Sensitivity/Response In this preclinical study of cetuximab, panitumumab or sym004 on various EGFR mutations in colorectal cancer. The S492R mutation was sensitive to Sym004 and panitumumab treatment but resistant to cetuximab. Experiments include flow cytometry binding assay, kinase phosphorylation, cell viability, downstream signalling. 26888827 PubMed Sánchez-Martín et al., 2016, Clin. Cancer Res. 4 accepted 1079 453 19 7 55228009 55228009 C A ENST00000275493.2 75 GRCh37 Somatic 2016-02-23 19:46:39 UTC https://civicdb.org/links/evidence_items/1079 https://civicdb.org/links/variants/453 https://civicdb.org/links/genes/19 false EGFR 1956 S492R Colorectal Cancer 9256 Cetuximab Predictive Supports D Resistance In this preclinical study of the effects of cetuximab, panitumumab or sym004 on various EGFR mutations in colorectal cancer. The S492R mutation was sensitive to Sym004 and panitumumab treatment but resistant to cetuximab. Experiments include flow cytometry binding assay, kinase phosphorylation, cell viability, downstream signalling. 26888827 PubMed Sánchez-Martín et al., 2016, Clin. Cancer Res. 4 accepted 1080 453 19 7 55228009 55228009 C A ENST00000275493.2 75 GRCh37 Somatic 2016-03-16 22:09:25 UTC https://civicdb.org/links/evidence_items/1080 https://civicdb.org/links/variants/453 https://civicdb.org/links/genes/19 false EGFR 1956 R451C Colorectal Cancer 9256 Futuximab/Modotuximab Mixture,Panitumumab,Cetuximab Substitutes Predictive Supports D Sensitivity/Response In this preclinical study on the effects of cetuximab, panitumumab or sym004 on various EGFR mutations in colorectal cancer. The R451C mutation showed moderate drug-receptor binding with sym004, cetuximab and panitumumab treatment and inhibition of EGFR phosphorylation. 26888827 PubMed Sánchez-Martín et al., 2016, Clin. Cancer Res. 2 accepted 1081 454 19 7 55227884 55227884 C T ENST00000275493.2 75 GRCh37 Somatic 2016-02-23 18:43:15 UTC https://civicdb.org/links/evidence_items/1081 https://civicdb.org/links/variants/454 https://civicdb.org/links/genes/19 false EGFR 1956 K467T Colorectal Cancer 9256 Futuximab/Modotuximab Mixture,Panitumumab Substitutes Predictive Supports D Sensitivity/Response In this preclinical study on the effects of cetuximab, panitumumab or sym004 on various EGFR mutations in colorectal cancer. In NIH3T3 cells expressing EGFR with a K467T mutation, Sym004 and panitumumab bound the mutated receptor and inhibited EGFR phosphorylation in the presence of ligand while cetuximab neither bound to nor inhibited EGFR phosphorylation of the mutated receptor. 26888827 PubMed Sánchez-Martín et al., 2016, Clin. Cancer Res. 3 accepted 1082 455 19 7 55227933 55227933 A C ENST00000275493.2 75 GRCh37 Somatic 2016-10-10 22:39:47 UTC https://civicdb.org/links/evidence_items/1082 https://civicdb.org/links/variants/455 https://civicdb.org/links/genes/19 false EGFR 1956 K467T Colorectal Cancer 9256 Cetuximab Predictive Supports D Resistance In this preclinical study on the effects of cetuximab, panitumumab or sym004 on various EGFR mutations in colorectal cancer. In NIH3T3 cells expressing EGFR with a K467T mutation, Sym004 and panitumumab bound the mutated receptor and inhibited EGFR phosphorylation in the presence of ligand while cetuximab neither bound to nor inhibited EGFR phosphorylation of the mutated receptor. 26888827 PubMed Sánchez-Martín et al., 2016, Clin. Cancer Res. 3 accepted 1083 455 19 7 55227933 55227933 A C ENST00000275493.2 75 GRCh37 Somatic 2016-10-10 22:40:26 UTC https://civicdb.org/links/evidence_items/1083 https://civicdb.org/links/variants/455 https://civicdb.org/links/genes/19 false FCGR2A 2212 H167R Breast Cancer 1612 Prognostic Does Not Support B N/A A total of 57 women with HER2-positive metastatic breast cancer were analyzed after taxane plus trastuzumab chemotherapy. FCGR2A H131R carriers did not have a significantly different response rate, progression-free survival, or overall survival. 22906996 PubMed Kim et al., 2012, Oncology 3 accepted 1084 456 1842 1 161479745 161479745 A G ENST00000271450.6 75 GRCh37 Common Germline 2016-02-23 20:21:29 UTC https://civicdb.org/links/evidence_items/1084 https://civicdb.org/links/variants/456 https://civicdb.org/links/genes/1842 false FCGR3A 2214 F212V Breast Cancer 1612 Prognostic Does Not Support B N/A A total of 57 women with HER2-positive metastatic breast cancer were analyzed after taxane plus trastuzumab chemotherapy. FCGR3A V158F carriers did not have a significantly different response rate, progression-free survival, or overall survival. 22906996 PubMed Kim et al., 2012, Oncology 3 accepted 1085 457 1844 1 161514542 161514542 A C ENST00000367969.3 75 GRCh37 Common Germline 2016-02-23 20:20:48 UTC https://civicdb.org/links/evidence_items/1085 https://civicdb.org/links/variants/457 https://civicdb.org/links/genes/1844 false FCGR2B 2213 I232T Breast Cancer 1612 Prognostic Supports B Poor Outcome 1325 HER2-positive breast cancer patients treated with trastuzumab and chemotherapy from the N9831 clinical trial were analyzed. There was a difference in disease-free survival for FCGR2B I232T, with I/I patients deriving benefit from trastuzumab (p<0.001) compared to the T carriers who did not (p=0.81). The interaction between FCGR2B genotype and treatment was statistically significant (p=0.03). 24989892 PubMed Norton et al., 2014, Cancer Immunol Res 4 accepted 1086 458 1843 1 161643798 161643798 T C ENST00000358671.5 75 GRCh37 Common Germline 2016-02-23 19:07:58 UTC https://civicdb.org/links/evidence_items/1086 https://civicdb.org/links/variants/458 https://civicdb.org/links/genes/1843 false FCGR3A 2214 F212V Breast Cancer 1612 Trastuzumab Predictive Does Not Support B Sensitivity/Response 1325 HER2-positive breast cancer patients treated with trastuzumab and chemotherapy from the N9831 clinical trial were analyzed. There was no statistically significant difference in disease-free survival between trastuzumab-treated patients who had the FCGR3A 158 V/V high-affinity genotype and patients without that genotype (V/F and F/F). 24989892 PubMed Norton et al., 2014, Cancer Immunol Res 4 accepted 1087 457 1844 1 161514542 161514542 A C ENST00000367969.3 75 GRCh37 Common Germline 2020-12-17 19:27:11 UTC https://civicdb.org/links/evidence_items/1087 https://civicdb.org/links/variants/457 https://civicdb.org/links/genes/1844 false FCGR2A 2212 H167R Breast Cancer 1612 Trastuzumab Predictive Does Not Support B Sensitivity/Response 1325 HER2-positive breast cancer patients treated with trastuzumab and chemotherapy from the N9831 clinical trial were analyzed. There was no statistical difference in disease-free survival between trastuzumab-treated patients who had the FCGR2A 131 H/H high-affinity genotype and patients without that genotype. 24989892 PubMed Norton et al., 2014, Cancer Immunol Res 4 accepted 1088 456 1842 1 161479745 161479745 A G ENST00000271450.6 75 GRCh37 Common Germline 2020-12-17 19:28:12 UTC https://civicdb.org/links/evidence_items/1088 https://civicdb.org/links/variants/456 https://civicdb.org/links/genes/1842 false EGFR 1956 P753S Skin Squamous Cell Carcinoma 3151 Cetuximab,Sirolimus Combination Predictive Supports C Sensitivity/Response 72-year old male patient presents with SCC with a mutation profile consistent with UV exposure. Sequencing revealed a number of abnormalities including P753S mutation in EGFR. Patient began therapy with cetuximab and sirolimus and continued for 9 months. Disease burden was not measurable by Response Evaluation Criteria in Solid Tumors. 24934779 PubMed Ganesan et al., 2016, J. Clin. Oncol. 3 accepted 1089 460 19 7 55242487 55242487 C T ENST00000275493.2 75 GRCh37 Somatic 2016-02-24 00:19:48 UTC https://civicdb.org/links/evidence_items/1089 https://civicdb.org/links/variants/460 https://civicdb.org/links/genes/19 false PML 5371 PML::RARA Acute Promyelocytic Leukemia 0060318 Diagnostic Supports A Positive The presence of the PML-RARa fusion protein is a diagnostic marker of Acute Promyelocytic Leukemia, or M3 AML. 7628753 PubMed Diverio et al., Haematologica 5 accepted 1090 108 39 15 74287058 74325755 ENST00000268058.3 17 38504568 38513048 ENST00000254066.5 75 GRCh37 The PML-RARA fusion is seen as a diagnostic event in acute promyelocytic leukemia (APL). Both in vitro and in vivo studies have shown sensitivity to ATRA in APL patients harboring the PML-RARa fusion. Recent interest has been shown in combining ATRA and arsenic trioxide for treating these patients, and early results seem promising. Somatic 2016-02-25 18:43:57 UTC https://civicdb.org/links/evidence_items/1090 https://civicdb.org/links/variants/108 https://civicdb.org/links/genes/39 false PML 5371 PML::RARA Acute Promyelocytic Leukemia 0060318 Tretinoin,Arsenic Trioxide Combination Predictive Supports A Sensitivity/Response ATRA/Arsenic combined with standard chemotherapy has been shown to induce a complete remission rate of greater than 75% of patients with acute promyelocytic leukemia harboring the PML-RARa fusion. 11704842 PubMed Degos et al., 2001, Oncogene 5 accepted 1091 108 39 15 74287058 74325755 ENST00000268058.3 17 38504568 38513048 ENST00000254066.5 75 GRCh37 The PML-RARA fusion is seen as a diagnostic event in acute promyelocytic leukemia (APL). Both in vitro and in vivo studies have shown sensitivity to ATRA in APL patients harboring the PML-RARa fusion. Recent interest has been shown in combining ATRA and arsenic trioxide for treating these patients, and early results seem promising. Somatic 2016-02-25 18:43:33 UTC https://civicdb.org/links/evidence_items/1091 https://civicdb.org/links/variants/108 https://civicdb.org/links/genes/39 false PML 5371 B2 DOMAIN MUTATION Acute Promyelocytic Leukemia 0060318 Tretinoin Predictive Supports B Resistance Mutations in the B2 domain of PML in the PML-RARa fusion have been shown to be associated with resistance to standard ATRA treatment in patients with acute promyelocytic leukemia. 23670176 PubMed Tomita et al., 2013, Int. J. Hematol. 4 accepted 1092 461 39 15 74315213 74315219 ENST00000268058.3 75 GRCh37 The B2 domain in PML is the binding site for ATRA. Point mutations in this region have been associated with ATRA resistance in patients with APL. Somatic 2016-02-25 18:45:13 UTC https://civicdb.org/links/evidence_items/1092 https://civicdb.org/links/variants/461 https://civicdb.org/links/genes/39 false PML 5371 PML::RARA A216V Acute Promyelocytic Leukemia 0060318 Tretinoin Predictive Supports C Resistance The mutation A216V in the B2 domain of PML in the PML-RARa fusion was seen in a patient with ATRA-resistant acute promyelocytic leukemia. 21613260 PubMed Goto et al., 2011, Blood 4 accepted 1093 462 39 15 74315213 74315213 C T ENST00000268058.3 75 GRCh37 A216V in the B2 domain of PML is one of the variants found in a patient with ATRA-resistant APL. Somatic 2016-02-25 18:44:57 UTC https://civicdb.org/links/evidence_items/1093 https://civicdb.org/links/variants/462 https://civicdb.org/links/genes/39 false PML 5371 PML::RARA L218P Acute Promyelocytic Leukemia 0060318 Tretinoin Predictive Supports C Resistance The PML L218P mutation in the PML-RARa fusion was observed in a patient with previously ATRA-treated, relapsed acute promyelocytic leukemia refractory to arsenic trioxide. 21613260 PubMed Goto et al., 2011, Blood 3 accepted 1094 463 39 15 74315219 74315219 T C ENST00000268058.3 75 GRCh37 L218P in the B2 domain of PML is one of the variants found in a patient with ATRA-resistant APL. Somatic 2016-08-15 20:03:33 UTC https://civicdb.org/links/evidence_items/1094 https://civicdb.org/links/variants/463 https://civicdb.org/links/genes/39 false MET 4233 EXON 14 MUTATION and AMPLIFICATION Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Sensitivity/Response 64-year old female (non-smoker) was diagnosed with NSCLC. A c.3028 G->A mutation was identified in exon 14 resulting in exon 14 skipping. Further, amplification of the MET gene was observed. The patient was given crizotinib and CT scans showed a positive response after 8 weeks of treatment. 26729443 PubMed Awad et al., 2016, J. Clin. Oncol. 3 accepted 1095 464 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 Somatic 2016-02-24 17:44:45 UTC https://civicdb.org/links/evidence_items/1095 https://civicdb.org/links/variants/464 https://civicdb.org/links/genes/52 false ERBB2 2064 Amplification Endometrial Serous Adenocarcinoma 5750 Prognostic Supports B Poor Outcome In a study of 27 African American and caucasian patients, endometrial adenocarcinoma samples were assessed for HER2 via IHC staining, and association studies were performed using corresponding patient information. Earlier deaths were seen with heavier HER2 expression. Multivariate Cox regression indicated that shorter survival was associated with higher HER2 expression, and not with age or ethnicity, and that observed differences in survival rates between ethnicities can be ascribed to higher rates of HER2 overexpression in African American patients. The authors conclude that high HER2 expression in USPC is associated with poor outcome and explains observed differences in outcome between ethnicities. 15746676 PubMed Santin et al., 2005, Am. J. Obstet. Gynecol. 4 accepted 1096 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-03-10 17:28:59 UTC https://civicdb.org/links/evidence_items/1096 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Endometrial Serous Adenocarcinoma 5750 Trastuzumab Predictive Supports C Sensitivity/Response HER2 expression in uterine serous papillary carcinoma (USPC) is thought to be associated with poor prognosis and may act as a targetable driver mutation in this cancer. HER2 overexpression in USPC is more common in African American women. This report covered 2 African American patients, the first of which presented high-grade endometrial adenocarcinoma with IHC3+ HER2-positivity as well as positivity by FISH. Prior treatment involved surgery and chemotherapy. Treatment with pacitaxel/carboplatin with trastuzumab showed clear clinical improvement assessed by CT scan and drop in CA-125 levels from 988 to 7.9 U/mL. The second patient had USPC, and was treated with surgery and radiation. Trastuzumab monotheraby was then administered. After 7 months of treatment, the patient showed no sign of disease progression and CA-125 had dropped from 144 to 41 U/mL. The investigators conclude there is promise in trastuzumab-based therapies in advanced endometrial cancers, including USPC. 18555254 PubMed Santin et al., 2008, Int J Gynaecol Obstet 4 accepted 1097 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-10-06 18:38:51 UTC https://civicdb.org/links/evidence_items/1097 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Endometrial Cancer 1380 Trastuzumab Predictive Does Not Support B Sensitivity/Response This phase II single arm study assessed trastuzumab monotherapy in HER2 positive endometrial cancers with tumor response as primary endpoint. Participants had stage III, IV or recurrent HER2 positive endometrial cancer. During the trial's initial phase, 23 of 132 patients screened met the criteria of IHC2+ or 3+ or FISH positivity for HER2 status. In the absence of results, the trial entered phase B, where only patients with HER2 amplification by FISH were admitted. The trial ended early due to poor accrual with 11 of 154 screened meeting the phase B criteria. No major objective tumor responses were observed in the study. 28% of the cancers were of the serous type that had shown trastuzumab response in case studies. The investigators note that in other HER2 cancers, such as breast and gastrointestinal, trastuzumab in combination with chemotherapy has been found most effective, and could warrant more study. Currently a clinical trial (NCT01367002) is evaluating carboplatin/paclitaxel with or without trastuzumab in uterine serous cancer. 19840887 PubMed Fleming et al., 2010, Gynecol. Oncol. 2 accepted 1098 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-02-24 21:06:11 UTC https://civicdb.org/links/evidence_items/1098 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false SMO 6608 D473H Medulloblastoma 0050902 Patidegib Predictive Supports D Sensitivity/Response Saridegib treatment induced tumor reduction and significantly prolonged survival in a Shh-driven mouse medulloblastoma model, and was found to be active in cells with the D473H point mutation. 22550175 PubMed Lee et al., 2012, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 1099 299 5365 7 128849189 128849189 G C ENST00000249373.3 75 GRCh37 Somatic 2020-11-20 16:16:34 UTC https://civicdb.org/links/evidence_items/1099 https://civicdb.org/links/variants/299 https://civicdb.org/links/genes/5365 false ROS1 6098 CD74::ROS1 G2032R Lung Adenocarcinoma 3910 Crizotinib Predictive Supports C Resistance Resistance to crizotinib developed in a patient with metastatic lung adenocarcinoma harboring a CD74-ROS1 rearrangement who had initially shown a dramatic response to treatment. An acquired G2032R mutation in the ROS1 kinase domain was observed in the resistant tumor, and was found to confer resistance to ROS1 kinase inhibition through steric interference with drug binding. 23724914 PubMed Awad et al., 2013, N. Engl. J. Med. NCT00585195 4 accepted 1100 465 4941 6 117638347 117638347 C T ENST00000368508.3 75 GRCh37 The G2032R missense mutation has been observed in patients with crizotinib-resistant non-small cell lung cancer harboring CD74-ROS1 rearrangement. Independent in vitro studies have confirmed that this mutation confers marked resistance to crizotinib cells over CD74-ROS1 alone. Multiple groups have indicated CD74-ROS1 G2032R expressing cell lines are sensitive to both cabozantinib and foretinib individually administered in vitro. One group additionally showed this mutation conferred relative resistance to alectinib, brigatinib, ceritinib, and AZD3463 in vitro. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1100 https://civicdb.org/links/variants/465 https://civicdb.org/links/genes/4941 false ROS1 6098 CD74::ROS1 G2032R Lung Non-small Cell Carcinoma 3908 Cabozantinib Predictive Supports D Sensitivity/Response Cabozantinib was assessed in the CD74-ROS1-mutant Ba/F3 cells and crizotinib-resistant patient-derived cancer cells (MGH047) harboring G2032R-mutated CD74-ROS1. It effectively inhibited the survival of CD74-ROS1 wild-type (WT) and resistant mutants harboring Ba/F3 and MGH047 cells. Furthermore, cabozantinib could overcome all the resistance by all newly identified secondary mutations. 25351743 PubMed Katayama et al., 2015, Clin. Cancer Res. 3 accepted 1101 465 4941 6 117638347 117638347 C T ENST00000368508.3 75 GRCh37 The G2032R missense mutation has been observed in patients with crizotinib-resistant non-small cell lung cancer harboring CD74-ROS1 rearrangement. Independent in vitro studies have confirmed that this mutation confers marked resistance to crizotinib cells over CD74-ROS1 alone. Multiple groups have indicated CD74-ROS1 G2032R expressing cell lines are sensitive to both cabozantinib and foretinib individually administered in vitro. One group additionally showed this mutation conferred relative resistance to alectinib, brigatinib, ceritinib, and AZD3463 in vitro. Somatic 2016-02-24 18:08:59 UTC https://civicdb.org/links/evidence_items/1101 https://civicdb.org/links/variants/465 https://civicdb.org/links/genes/4941 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Peripheral blood from NPM1 mutated AMLs was assessed for NPM1 mutation status at multiple time points using RT-qPCR with primers designed to amplify different mutant NPM1 transcripts. The test development cohort consisted of 194 cases and an independent validation cohort consisted of 91 cases. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle. This persistence was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P<0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI, 2.57 to 9.15; P<0.001). On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. 26789727 PubMed Ivey et al., 2016, N. Engl. J. Med. 4 accepted 1102 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-02-24 18:02:02 UTC https://civicdb.org/links/evidence_items/1102 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false CEBPA 1050 N-TERMINAL FRAME SHIFT Acute Myeloid Leukemia 9119 OICR-9429 Predictive Supports D Sensitivity/Response This preclinical study establishes that the p30 isoform of CEBPA expressed as a result of N-terminal truncating mutations preferentially interacts with WRD5, a component of the SET/MLL complex. Knockdown of WRD5 in 32D cells (mouse hematopoietic cell line) or transplanted primary mouse bone marrow expressing the p30 isoform restored myeloid differentiation in these cells. OICR-9429, a small molecule inhibitor of WRD5, and anti-WRD5 siRNAs selectively inhibited colony formation of mouse fetal liver cells homozygous for N-terminal CEBPA mutations but not wildtype colony formation. Finally, OICR-9429 reduced viability of primary human AML blasts harboring N-terminal domain CEBPA mutations in culture but not AML blasts with other mutations. Taken together, WRD5 inhibition is a potential therapeutic method for patients harboring N-terminal CEBPA mutations. 26167872 PubMed Grebien et al., 2015, Nat. Chem. Biol. 3 accepted 1103 28 15 19 33792961 33793470 ENST00000498907.2 75 GRCh37 CEBPA N-terminal frame shift mutations that result in a premature stop codon are associated with cytogenetically normal acute myeloid leukemia (CN-AML). CEBPA mutations are associated with a favorable prognosis; however, NPM1 and FLT3 mutations should also be assessed in CN-AML patients as concurrent mutations may have prognostic implications. N-terminal frame shift mutations within amino acids 1-120 have been shown to disrupt expression of the full-length 42kDa isoform while maintaining expression of a 30kDa isoform (translated from the AUG at full-length protein isoform amino acid M120). This 30kDa isoform exhibits dominant negative activity. Somatic 2016-02-24 21:16:02 UTC https://civicdb.org/links/evidence_items/1103 https://civicdb.org/links/variants/28 https://civicdb.org/links/genes/15 false FGFR1 2260 ZNF198::FGFR1 Myeloproliferative Neoplasm 2226 Midostaurin Predictive Supports C Sensitivity/Response A t(8;13)(p11;q12) patient with ZNF198-FGFR1-induced progressive myeloproliferative disorder was treated with PKC412. Radiographic studies performed 3 months after initiation of therapy revealed marked improvement of her cervical, mediastinal, and retroperitoneal lymphadenopathy, and marked regression of splenomegaly to normal size. 15448205 PubMed Chen et al., 2004, Proc. Natl. Acad. Sci. U.S.A. 4 accepted 1104 466 1885 Somatic 2016-02-25 19:34:52 UTC https://civicdb.org/links/evidence_items/1104 https://civicdb.org/links/variants/466 https://civicdb.org/links/genes/1885 false FGFR1 2260 Amplification Breast Cancer 1612 Afimoxifene Predictive Supports D Resistance FGFR1-amplified breast cancer cell lines show resistance to 4-hydroxytamoxifen, which is reversed by small interfering RNA silencing of FGFR1. 20179196 PubMed Turner et al., 2010, Cancer Res. 3 accepted 1105 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). Somatic 2016-02-25 19:23:59 UTC https://civicdb.org/links/evidence_items/1105 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false KDR 3791 A1065T Angiosarcoma 0001816 Sorafenib,Sunitinib Substitutes Predictive Supports D Sensitivity/Response COS-7 cells were transiently transfected with expression constructs encoding cDNAs for wild-type or A1065T-mutant KDR. Autophosphorylation was observed on tyrosine of mutant cells, but not wild-type cells, which were starved from serum for 6 hours without rhVEGF stimulation. Decreased phosphorylation in mutant cells was noted after treatment with either sunitinib or sorafenib. 19723655 PubMed Antonescu et al., 2009, Cancer Res. 3 accepted 1106 467 3153 4 55955969 55955969 C T ENST00000263923.4 75 GRCh37 Somatic 2016-02-25 19:38:24 UTC https://civicdb.org/links/evidence_items/1106 https://civicdb.org/links/variants/467 https://civicdb.org/links/genes/3153 false KDR 3791 D717V Angiosarcoma 0001816 Sorafenib,Sunitinib Substitutes Predictive Supports D Sensitivity/Response COS-7 cells were transiently transfected with expression constructs encoding cDNAs for wild-type or D717V-mutant KDR. Autophosphorylation was observed on tyrosine of mutant cells, but not wild-type cells, which were starved from serum for 6 hours without rhVEGF stimulation. Decreased phosphorylation in mutant cells was noted after treatment with either sunitinib or sorafenib. 19723655 PubMed Antonescu et al., 2009, Cancer Res. 3 accepted 1107 468 3153 4 55968180 55968180 T A ENST00000263923.4 75 GRCh37 Somatic 2016-02-25 19:38:50 UTC https://civicdb.org/links/evidence_items/1107 https://civicdb.org/links/variants/468 https://civicdb.org/links/genes/3153 false TSC2 7249 Q1178* Thyroid Gland Carcinoma 3963 Everolimus Predictive Supports C Sensitivity/Response The pretreatment tumor contained a somatic nonsense mutation (Q1178*) in the tumor-suppressor gene TSC2 that inactivates the gene, allowing for activation of the mTOR pathway and resulting in sensitivity to mTOR inhibition by everolimus. The patient received a sustained response to everolimus for 18 months. 25295501 PubMed Wagle et al., 2014, N. Engl. J. Med. 5 accepted 1108 469 47 16 2130300 2130300 C T ENST00000219476.3 75 GRCh37 Somatic 2016-02-25 19:17:13 UTC https://civicdb.org/links/evidence_items/1108 https://civicdb.org/links/variants/469 https://civicdb.org/links/genes/47 false FLT3 2322 ITD Acute Promyelocytic Leukemia 0060318 Prognostic Supports B Poor Outcome In a study of 53 APL patients treated with combination ATRA/anthracycline chemotherapy, patients with the FLT3 ITD mutation (n=10) had higher rates of relapse (30% vs. 2.5%), lower rates of remission (70% vs 87.5%), and lower 3-year Leukemia-Free Survival (44.4% vs. 84.4%). 21461300 PubMed Hong et al., 2011, Korean J Hematol 3 accepted 1109 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-02-28 18:06:43 UTC https://civicdb.org/links/evidence_items/1109 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false MTOR 2475 F2108L Thyroid Gland Carcinoma 3963 Everolimus Predictive Supports C Resistance The pretreatment tumor contained a somatic nonsense mutation (Q1178*) in the tumor-suppressor gene TSC2 that inactivates the gene, allowing for activation of the mTOR pathway and resulting in sensitivity to mTOR inhibition by everolimus. The patient received a sustained response to everolimus for 18 months, after which time resistance developed. The resistant tumor had a somatic mutation in MTOR (F2108L), that was not detected in the pretreatment tumor. 25295501 PubMed Wagle et al., 2014, N. Engl. J. Med. 5 accepted 1110 470 2073 1 11187094 11187094 G T ENST00000361445.4 75 GRCh37 Somatic 2016-02-25 19:25:03 UTC https://civicdb.org/links/evidence_items/1110 https://civicdb.org/links/variants/470 https://civicdb.org/links/genes/2073 false RAD51D 5892 R186* Breast Cancer 1612 Predisposing N/A C N/A A healthy, 36-year-old woman presented with a palpable right breast mass upon biopsy determined to be high-grade, triple negative invasive ductal carcinoma. Her family history was notable for multiple relatives on her maternal side with breast cancer, including a distant male relative with breast cancer. Multigene panel testing with an 18-gene panel revealed a germline truncating pathogenic mutation in RAD51D (p.R186X; c. 556C>T). 25445424 PubMed Baker et al., 2015, Clin. Breast Cancer 2 accepted 1111 471 4765 17 33433425 33433425 G A ENST00000345365.6 75 GRCh37 Rare Germline 2020-10-20 21:31:50 UTC https://civicdb.org/links/evidence_items/1111 https://civicdb.org/links/variants/471 https://civicdb.org/links/genes/4765 false FLT3 2322 ITD Acute Promyelocytic Leukemia 0060318 Anthracycline Antineoplastic Antibiotic,Tretinoin Combination Predictive Supports B Resistance In a study of 171 APL patients treated with combination ATRA/anthracycline chemotherapy, FLT3 ITD mutations (n=35) were associated with lower 3-year OS compared to the FLT3 ITD-negative group (62% vs. 82%), as well as higher CR achievement failure and early death. 24981688 PubMed Lucena-Araujo et al., 2014, Ann. Hematol. 4 accepted 1112 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-02-25 18:37:09 UTC https://civicdb.org/links/evidence_items/1112 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Trastuzumab,Neratinib Sequential Predictive Supports A Sensitivity/Response In this two arm, Phase III study (NCT00878709) of the efficacy of a 12 month course of the TKI neratinib after trastuzumab-based adjuvant therapy of early stage HER2-positive breast cancer was assessed using invasive disease-free survival as primary endpoint. HER2 positivity was assessed via FISH. At 2 year follow-up, 70 vs. 109 disease-free survival events had occurred and disease-free survival rates were 93.9% vs. 91.6% (significant) in neratinib vs. placebo groups respectively. Distant disease-free survival and time to distant recurrence were similar in both groups. These results are an interesting contrast to results of long-term adjuvant therapy with trastuzumab (HERA) which did not show significant benefit. 26874901 PubMed Chan et al., 2016, Lancet Oncol. NCT00878709 4 accepted 1113 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2020-04-14 16:58:34 UTC https://civicdb.org/links/evidence_items/1113 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ALDH1A2 8854 Overexpression Head And Neck Squamous Cell Carcinoma 5520 Prognostic Supports B Better Outcome IHC for expression of ALDH1A2 and CRABP2 was performed in 89 patients with squamous cell carcinoma of the head and neck. High expression of both, ALDH1A2 and CRABP2 (in comparison to ALDH1A2 low or ALDH1A2 high and CRABP2 low) was significantly associated with OS and PFS in multivariate Cox analysis (OS, HR: 0.303, 95%CI 0.14–0.63, p-value 0.002 PFS, HR: 0.395, 95%CI 0.20–0.77, p-value 0.007). 26634247 PubMed Seidensaal et al., 2015, Mol. Cancer 3 accepted 1114 472 7024 15 58245622 58358616 ENST00000249750.4 75 GRCh37 N/A 2016-02-25 20:29:13 UTC https://civicdb.org/links/evidence_items/1114 https://civicdb.org/links/variants/472 https://civicdb.org/links/genes/7024 false ALDH1A2 8854 Underexpression Head And Neck Squamous Cell Carcinoma 5520 Tretinoin Predictive Supports D Sensitivity/Response FaDu (a high ALDH1A2 expression cell line) and Cal27 (a low expression cell line) were treated with all-trans retinoic acid (ATRA), Adapalene or Fenretinide. This led to concentration dependent decrease in the survival fraction in both cell lines with higher efficacy in Cal27 (ED50 ≈ 1 μM) as compared to FaDu cells (ED ≈ 44 μM). Treatment with 3 μM ATRA sensitized Cal27 cells to irradiation at a dose of 2 Gy, but had no or only a minor effect on ALDH1A2-postitive cells. 26634247 PubMed Seidensaal et al., 2015, Mol. Cancer 2 accepted 1115 473 7024 15 58245622 58358616 ENST00000249750.4 75 GRCh37 N/A 2016-02-25 20:20:42 UTC https://civicdb.org/links/evidence_items/1115 https://civicdb.org/links/variants/473 https://civicdb.org/links/genes/7024 false ALDH1A2 8854 Overexpression Head And Neck Squamous Cell Carcinoma 5520 Prognostic Supports B Better Outcome ALDH1A2 protein levels were determined (IHC) in 115 patients with oropharyngeal squamous cell carcinoma with known HPV status (n = 89 non–HPV-driven; n = 26 HPV-driven). Low to moderate ALDH1A2 protein levels (combined as ALDH1A2low) were identified in keratinocytes of healthy mucosa as well as 73 (63.5%) primary tumors, and high ALDH1A2 protein levels in 42 (36.5%) primary tumors. Significantly higher ALDH1A2 protein levels were identified in HPV-driven than non-HPV-driven tumors. Moreover, PFS and OS strongly correlated with the ALDH1A2 protein expression level (OS, P < 0.001; PFS, P = 0.001; log-rank/Mantel-Cox test. Previous analyses in the same study identify hypermethylation of ALDH1A2 as the underlying mechanism of differential protein expression. 23635773 PubMed Kostareli et al., 2013, J. Clin. Invest. 3 accepted 1116 472 7024 15 58245622 58358616 ENST00000249750.4 75 GRCh37 N/A 2016-02-25 20:25:06 UTC https://civicdb.org/links/evidence_items/1116 https://civicdb.org/links/variants/472 https://civicdb.org/links/genes/7024 false CIP2A 57650 EXPRESSION Pancreatic Ductal Adenocarcinoma 3498 Prognostic Supports B Poor Outcome Expression of the protein CIP2A was investigated in 72 cases of pancreatic ductal adenocarcinoma and 27 cases of adjacent tissues. Immunohistochemistry revealed a significant difference in expression between tumor and adjacent normal samples. Furthermore, a statistically significant decrease in overall survival was discovered between positive and negative CIP2A expression. 26894380 PubMed Xu et al., 2016, Oncotarget 3 accepted 1117 474 13948 3 108268716 108308299 ENST00000295746.8 75 GRCh37 Somatic 2016-05-18 14:23:08 UTC https://civicdb.org/links/evidence_items/1117 https://civicdb.org/links/variants/474 https://civicdb.org/links/genes/13948 false CIP2A 57650 Underexpression Pancreatic Ductal Adenocarcinoma 3498 Gemcitabine Predictive Supports D Sensitivity/Response Researchers studied the effect of CIP2A expression in relation to gemcitabine sensitivity via SW1990 cell lines. SW1990 cells with CIP2A expression knocked-down displayed lower IC50 (p=.024), indicating a sensitivity to gemcitabine. 26894380 PubMed Xu et al., 2016, Oncotarget 3 accepted 1118 475 13948 3 108268716 108308299 ENST00000295746.8 75 GRCh37 Somatic 2016-02-25 21:45:17 UTC https://civicdb.org/links/evidence_items/1118 https://civicdb.org/links/variants/475 https://civicdb.org/links/genes/13948 false MIR218-1 407000 EXPRESSION Colorectal Cancer 9256 Prognostic Supports B Better Outcome Researchers examined the prognostic role of miR-218 expression in CRC tumor samples when receiving 5-FU based treatment. CRC samples from patients who received first-line 5-FU-based adjuvant chemotherapy were stratified into two groups (complete/partial response and stable/progressive disease) based on RECIST criteria. miR-218 expression levels were found to be significantly higher in the complete/partial response group. Further Kaplan-Meier survival analysis revealed that in groups with higher miR-218 expression, overall survival was significantly greater. 26442524 PubMed Li et al., 2015, Carcinogenesis 3 accepted 1119 476 24938 4 20529898 20530007 ENST00000384999.1 75 GRCh37 N/A 2016-03-23 22:10:38 UTC https://civicdb.org/links/evidence_items/1119 https://civicdb.org/links/variants/476 https://civicdb.org/links/genes/24938 false MIR218-1 407000 EXPRESSION Colorectal Cancer 9256 Prognostic Supports B Better Outcome Researchers examined the overall and progression free survival of CRC patients receiving first line 5-Fluorouracil therapy. Samples were stratified into two groups (low/high expressing miR-218). Kaplan-Meier survival analysis revealed that in groups with higher miR-218 expression, overall survival was significantly greater. 26442524 PubMed Li et al., 2015, Carcinogenesis 3 accepted 1120 476 24938 4 20529898 20530007 ENST00000384999.1 75 GRCh37 N/A 2016-03-23 15:04:58 UTC https://civicdb.org/links/evidence_items/1120 https://civicdb.org/links/variants/476 https://civicdb.org/links/genes/24938 false ALK 238 EML4::ALK Lung Acinar Adenocarcinoma 6482 Erlotinib Predictive Supports C Resistance A 39-year-old man presented was observed to have lung acinar adenocarcinoma. Treatment with chemotherapy produced no remarkable response. A EGFR L858R point mutation was observed; the patient was therefore treated with erlotinib, but the disease progressed after 30 days. A second biopsy identified a EML4-ALK fusion, which may explain the therapeutic resistance. 23181703 PubMed Tanaka et al., 2012, BMC Cancer 2 accepted 1121 5 1 2 42396490 42522656 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The EML4-ALK fusion variant 1 consisting of ALK kinase domain (exons 20-29) fused to EML4 exons 1-13 is the most common EML4-ALK variant, and was discovered in non-small cell lung cancer. Multiple EML4 breakpoint shave been described with differential sensitivity to inhibitors with variant 1 showing greater sensitivity than 3a in cell lines. EML4-ALK is crizotinib sensitive; however, several mutations that confer resistance mutations have been described in case studies. In the only clinical trial for crizotinib that included determination of EML4-ALK variant type in a subset of its participants, a very high response rate was observed, although the numbers were insufficient to validate correlation of variant type to outcome. Preclinical studies with this variant have indicated sensitivity to Hsp90 inhibitors. Somatic 2016-02-26 14:58:09 UTC https://civicdb.org/links/evidence_items/1121 https://civicdb.org/links/variants/5 https://civicdb.org/links/genes/1 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Supports A Sensitivity/Response HERA was a Phase III trial assessing application of trastuzumab in an extended adjuvant setting. Patients were HER2 positive with completely excised invasive BC, node positive or negative, and having undergone prior adjuvant or neo-adjuvant chemotherapy. In the 3 arm study patients were given trastuzumab courses of 1 year, 2 years, or untreated. At the first planned interim analysis, trastuzumab treatment for one year was compared with observation alone. A significant difference in disease-free survival was seen with 220 DFS events out of 1693 in the observation arm versus 127 DFS events out of 1694 in the 1 year trastuzumab arm. 1 year adjuvant trastuzumab is currently the standard of care. 16236737 PubMed Piccart-Gebhart et al., 2005, N. Engl. J. Med. NCT00045032 4 accepted 1122 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2017-12-04 15:42:23 UTC https://civicdb.org/links/evidence_items/1122 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false BRCA1 672 P968FS Breast Cancer 1612 Predisposing Supports C Likely Pathogenic A 55-year-old non-Ashkenazi Spanish female diagnosed with breast cancer (at 51 years old) and ovarian cancer. Sequencing of BRCA1 and BRCA2 revealed a 2-base frameshift insertion in BRCA1 (labeled 3020insCT/c.2901insCT in this paper, with the data shown corresponding to a GA insertion, reading left to right in the reference genome, between chr17:43092628-43092629 in GRCh38). This mutation ultimately causes a downstream premature stop codon and truncated BRCA1. 24137399 PubMed Salgado et al., 2013, Oncol Lett 4 accepted 1123 477 6 17 41244645 41244646 GA ENST00000471181.2 75 GRCh37 Rare Germline 2017-07-25 20:48:12 UTC https://civicdb.org/links/evidence_items/1123 https://civicdb.org/links/variants/477 https://civicdb.org/links/genes/6 false BRCA1 672 P968FS Ovarian Cancer 2394 Predisposing Supports C Pathogenic A 55-year-old non-Ashkenazi Spanish female diagnosed with breast cancer (at 51 years old) and ovarian cancer. Sequencing of BRCA1 and BRCA2 revealed a 2-base frameshift insertion in BRCA1 (labeled 3020insCT/c.2901insCT in this paper, with the data shown corresponding to a GA insertion, reading left to right in the reference genome, between chr17:43092628-43092629 in GRCh38). This mutation ultimately causes a downstream premature stop codon and truncated BRCA1. 24137399 PubMed Salgado et al., 2013, Oncol Lett 4 accepted 1124 477 6 17 41244645 41244646 GA ENST00000471181.2 75 GRCh37 Rare Germline 2017-07-25 20:48:25 UTC https://civicdb.org/links/evidence_items/1124 https://civicdb.org/links/variants/477 https://civicdb.org/links/genes/6 false ERBB2 2064 Y772_A775DUP Lung Adenocarcinoma 3910 Trastuzumab Emtansine Predictive Supports C Sensitivity/Response A 51-year old female never smoker with stage IV lung adenocarcinoma carrying a HER2 insertion in exon 20 (p.A775_G776insYVMA) by sequencing archived material, HER2 overexpression by IHC (2+) and HER2 amplification by in situ hybridization was treated with T-DM1 (trastuzumab emtansine). Patient received two cycles off-label at 3.6mg/kg and was found to have morphologic response of lung and bone lesions by PET and CT. TDM-1 therapy was ongoing as of publication April 2015. 25789838 PubMed Weiler et al., 2015, J Thorac Oncol 3 accepted 1125 414 20 17 37880996 37880997 TACGTGATGGCT ENST00000269571.5 75 GRCh37 Mutations in the HER2 kinase domain occur at a 2-4% frequency in lung adenocarcinomas, the majority of which are in exon 20 as in-frame duplications or insertions in a small 8 codon region (774-781 or 775-782). These are analogous to the exon 20 alterations found in EGFR TK domain. The M774 insertion, M774insAYVM, represents 62.5% of all HER2 kinase domain mutations identified (when combined with the A775insYVMA mutations as they translate to the identical amino acid sequence changes). As demonstrated in mouse models (Perrera et al., PNAS 2009) and subsequent clinical trials in human lung adenocarcinoma with these insertions, HER2 YVMA mutants predict response to several targeted HER2 agonists such as afatinib, trastuzumab, neratinib and TDM-1 (trastuzumab emtansine) as monotherapy or combined with specific chemotherapies. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1125 https://civicdb.org/links/variants/414 https://civicdb.org/links/genes/20 false BRAF 673 V600E Hairy Cell Leukemia 285 Diagnostic Supports B Positive In 47 patients with Hairy Cell Leukemia, sequencing discovered a V600E mutation in all 47 of the sequenced patients. 21663470 PubMed Tiacci et al., 2011, N. Engl. J. Med. 4 accepted 1127 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-03-22 16:40:00 UTC https://civicdb.org/links/evidence_items/1127 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false EGFR 1956 VIII Glioblastoma 3068 Erlotinib,Gefitinib Substitutes Predictive Supports B Sensitivity/Response Expression of EGFRvIII and PTEN was evaluated in 26 patients with glioblastomas treated with erlotinib or gefitinib and no EGFR or Her2/neu kinase domain mutations. 7 patients responded to treatment while 19 progressed rapidly. Coexpression of EGFRvIII and PTEN was associated with clinical response (defined as 25% tumor shrinkage). These results were confirmed using IHC in an independent cohort of 33 patients (8 responders) treated with erlotinib at another institution. 16282176 PubMed Mellinghoff et al., 2005, N. Engl. J. Med. 3 accepted 1128 312 19 7 55087058 55223523 ENST00000275493.2 75 GRCh37 The EGFRvIII variant is an oncogenic mutation that has been reported in several cancers including glioblastoma multiforme, breast, lung, head and neck, ovarian and prostate. In high-grade gliomas, EGFRvIII has been reported in about 30% of cases with EGFR amplification. The EGFRvIII mutation leads to deletion of the receptor ectodomain exons 2-7. The presence of this variant has been linked with clinical response to EGFR TKI. (Arteaga and Engelmann, 2014) Somatic 2016-04-06 16:53:52 UTC https://civicdb.org/links/evidence_items/1128 https://civicdb.org/links/variants/312 https://civicdb.org/links/genes/19 false PTEN 5728 Expression Glioblastoma 3068 Gefitinib,Erlotinib Substitutes Predictive Supports B Sensitivity/Response Expression of EGFRvIII and PTEN was evaluated in 26 patients with glioblastomas treated with erlotinib or gefitinib and no EGFR or Her2/neu kinase domain mutations. 7 patients responded to treatment while 19 progressed rapidly. Coexpression of EGFRvIII and PTEN was associated with clinical response (defined as 25% tumor shrinkage). These results were confirmed using IHC in an independent cohort of 33 patients (8 responders) treated with erlotinib at another institution. 16282176 PubMed Mellinghoff et al., 2005, N. Engl. J. Med. 3 accepted 1129 313 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 N/A 2016-04-06 16:54:26 UTC https://civicdb.org/links/evidence_items/1129 https://civicdb.org/links/variants/313 https://civicdb.org/links/genes/41 false KRAS 3845 Q22* Colon Mucinous Adenocarcinoma 3029 Panitumumab Predictive Supports C Resistance A 43-year-old female was diagnosed with an adenocarcinoma of the ascending colon and received 6-months of adjuvant chemotherapy. After 5 years of completion of adjuvant chemotherapy, the disease relapsed. EGFR was assessed by immunohistochemistry, and the patient was subsequently treated with the anti-EGFR monoclonal antibody panitumumab. However, there was a rapid clinical worsening, which may possibly be attributed to a somatic mutation in KRAS (Q22*). 19661358 PubMed Palmirotta et al., 2009, Anticancer Res. 2 accepted 1131 479 30 12 25398255 25398255 G A ENST00000256078.4 75 GRCh37 Somatic 2016-03-08 17:48:40 UTC https://civicdb.org/links/evidence_items/1131 https://civicdb.org/links/variants/479 https://civicdb.org/links/genes/30 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Capecitabine,Lapatinib Combination Predictive Supports B Sensitivity/Response This Phase III trial took patients with locally advanced or metastatic HER2 (ERBB2) positive breast cancer that had progressed on prior trastuzumab treatment. Patients were given capecitabine (n=161) or lapatinib plus capecitabine (n=163). The primary endpoint of the study was time to progression. Median time to progression was 4.4 months in the capecitabine group and 8.4 months in capecitabine plus lapatinib group (hazard ratio was 0.49 ; 95% confidence interval, 0.34 to 0.71; P<0.001). The results indicated that lapatinib may be useful in addressing the problem of trastuzumab progression in HER2 breast cancer. 17192538 PubMed Geyer et al., 2006, N. Engl. J. Med. NCT00078572 4 accepted 1132 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-02-18 04:00:14 UTC https://civicdb.org/links/evidence_items/1132 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Capecitabine,Trastuzumab Combination Predictive Supports B Sensitivity/Response In this Phase III trial, trastuzumab-based treatment was assessed in women with locally advanced or metastatic HER2 positive breast cancer who had progressed on trastuzumab. Patients had 12 weeks or greater previous trastuzumab treatment with time since end of last cycle less than 6 weeks. Primary endpoint was time to progression. 78 patients were assigned to each group, with median time to progression of 5.6 months in capecitabine group and 8.2 months in trastuzumab plus capecitabine group. The results are in contrast to the principle of change of treatment on disease progression, and authors suggest that chemotherapy-sensitizing mechanisms of trastuzumab remain intact in HER2 breast cancer cells with trastuzumab progression. 19289619 PubMed von Minckwitz et al., 2009, J. Clin. Oncol. 4 accepted 1133 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-02-18 04:12:16 UTC https://civicdb.org/links/evidence_items/1133 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false DDX43 55510 Overexpression Uveal Melanoma 6039 Mirdametinib,Trametinib,Selumetinib Substitutes Predictive Supports D Resistance MEK inhibitor-resistant (selumetinib, PD0325901, GSK1129212) uveal melanoma cell lines were created from two GNAQ Q209L mutant cell lines. Overexpression of DDX43 mediated RAS-induced selumetinib resistance as demonstrated by depletion of DDX43 decreasing RAS proteins and ectopic expression of DDX43 induced RAS protein levels. These results were confirmed using biopsies from liver metastases in 14 patients with uveal melanoma harboring GNAQ or GNA11 mutations who were treated on a phase II study of selumetinib. 6 patients with partial response or stable disease for ≥16 weeks, were defined as “responders” (R), 8 patients who had disease progression before 16 weeks were defined as “nonresponders” (NR). DDX43 Expression (qPCR) was higher in nonresponders (P = 0.045). Liver metastasis biopsy samples (3 R and 3 NR) were immunoblotted for DDX43, pERK and RAS proteins with consistent results. 24899684 PubMed Ambrosini et al., 2014, Mol. Cancer Ther. 4 accepted 1135 481 13005 6 74104471 74127292 ENST00000370336.4 75 GRCh37 Somatic 2016-10-10 22:50:09 UTC https://civicdb.org/links/evidence_items/1135 https://civicdb.org/links/variants/481 https://civicdb.org/links/genes/13005 false KIT 3815 RS3733542 Acute Myeloid Leukemia 9119 Selumetinib Predictive Supports B Sensitivity/Response Patients with relapsed/refractory AML or 60 years old or more with untreated AML were enrolled on a phase II study of selumetinib and analyzed for mutations in KIT, NRAS, KRAS and FLT3. KIT mutation analysis (N=41) revealed the presence of a synonymous SNP rs3733542 (known population frequency of 20%) in exon 18 of the KIT gene in six of ten (60%) patients assessed as having a response or disease stabilization to selumetinib. In contrast, this SNP was detected in only seven of 31 (23%) patients without a response or disease stabilization (P = 0.027, Chi-squared test). 24178622 PubMed Jain et al., 2014, Clin. Cancer Res. 1 accepted 1136 482 29 4 55602765 55602765 G C ENST00000288135.5 75 GRCh37 Common Germline 2016-06-29 20:21:06 UTC https://civicdb.org/links/evidence_items/1136 https://civicdb.org/links/variants/482 https://civicdb.org/links/genes/29 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Selumetinib Predictive Supports B Resistance Forty-seven patients with relapsed/refractory AML or 60+ years old with untreated AML were enrolled on a phase II study. In FLT3 wild-type patients, six out of 36 (17%) had a response (1 PR, 3 MR, 2 uMR) that lasted a median of 58 days (range, 33–273 days). No patient with FLT3-ITD (n = 10) responded. One patient with unknown FLT3 status also had no response. Of note, this study did not meet its primary endpoint of 6 responses (CR, CRi, PR or MR) in the first 35 patients enrolled. 24178622 PubMed Jain et al., 2014, Clin. Cancer Res. 2 accepted 1137 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-03-14 14:16:37 UTC https://civicdb.org/links/evidence_items/1137 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false TBK1 29110 Overexpression Melanoma 1909 AZ909,Selumetinib Combination Predictive Supports D Sensitivity/Response Preclinical study in melanoma cell lines. TBK1 depletion (siRNA) inhibited migration and invasion, whereas its constitutive overexpression led to an increase in invasion. In MEK-resistant NRAS mutant melanoma cell lines, TBK1 depletion or inhibition (AZ909) in combination with MEK inhibitors (selumetinib) promoted apoptosis in 3D culture. 24962318 PubMed Vu et al., 2014, Mol. Cancer Res. 2 accepted 1138 483 11322 12 64845660 64895888 ENST00000331710.5 75 GRCh37 N/A 2016-05-12 22:03:10 UTC https://civicdb.org/links/evidence_items/1138 https://civicdb.org/links/variants/483 https://civicdb.org/links/genes/11322 false KRAS 3845 Mutation Colorectal Cancer 9256 Chemotherapy,Bevacizumab Combination Predictive Supports B Resistance Meta-Analysis of 12 studies with 2,266 patients (54 % were KRAS wt). The pooled response rates (RR) for KRAS wild-type (wt) versus mutated (mut) patients were 54.8 and 48.3 %, respectively (OR 1.42, P = 0.02). Median PFS in KRAS wild-type patients was significantly longer than in KRAS mut patients (HR = 0.85; 95 % confidence interval (CI) 0.74-0.98; P = 0.02). Median OS in wild-type KRAS patients compared was significantly better than in KRAS mut patients (HR = 0.65; 95 % CI 0.46-0.92; P = 0.01). 23828442 PubMed Petrelli et al., 2013, Med. Oncol. 4 accepted 1139 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1139 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Cancer 162 MEK Inhibitor GDC-0623,G-573 Substitutes Predictive Supports D Sensitivity/Response Preclinical study analyzing the differential response to MEK Inhibitors in KRAS and BRAF mutant cancer cell lines and mouse xenografts. Efficacy of MEK inhibitors (GDC-0623 and G-573) in KRAS-driven tumours is mediated by a hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF. This mechanism was distinct from GDC-0973 which is less potent in KRAS mutant tumors. Overall, this work indicates that MEK inhibitors with this mechanism of action will be most effective in patients with both BRAF and KRAS mutations. 23934108 PubMed Hatzivassiliou et al., 2013, Nature 3 accepted 1140 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-06-22 19:00:05 UTC https://civicdb.org/links/evidence_items/1140 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false BRAF 673 V600E Cancer 162 Cobimetinib Predictive Supports D Sensitivity/Response Preclinical study analyzing the differential response to MEK inhibitors in KRAS and BRAF mutant cancer cell lines and mouse xenografts. Inhibition of active, phosphorylated MEK by GDC-0973 (cobimetinib) is required for strong inhibition of the MAPK pathway in BRAF-mutant tumours. This study provides mechanistic rationale for improved efficacy of cobimetinib in BRAF-mutant models compared to MEK inhibitors acting through an alternative mechanism (GDC-0623 and G-573). 23934108 PubMed Hatzivassiliou et al., 2013, Nature 3 accepted 1141 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-06-29 21:04:10 UTC https://civicdb.org/links/evidence_items/1141 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false KRAS 3845 G12C Lung Non-small Cell Carcinoma 3908 Docetaxel,Selumetinib Combination Predictive Supports B Sensitivity/Response 83 patients from a phase II trial (docetaxel + placebo or MEK1/2 inhibitor selumetinib) with KRAS mutant tumors were retrospectively assessed for differences in OS, PFS, ORR and change in tumor size at week 6 according to type of KRAS mutation. G12C, G12D and G12V were the most common mutations (46%, 22%, 11%, respectively). Patients with G12C or G12V mutations receiving selumetinib and docetaxel combined treatment had a trend towards longer OS, PFS and ORR compared to other KRAS mutations, but the differences did not reach statistical significance. Changes in tumor size were similar between groups with the best responses in tumors with G12V mutations. Few differences were observed between groups when treated with docetaxel + placebo. 26125448 PubMed Jänne et al., 2015, Br. J. Cancer NCT00890825 2 accepted 1142 78 30 12 25398285 25398285 C A ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2021-03-10 23:47:13 UTC https://civicdb.org/links/evidence_items/1142 https://civicdb.org/links/variants/78 https://civicdb.org/links/genes/30 false KRAS 3845 G12V Lung Non-small Cell Carcinoma 3908 Selumetinib,Docetaxel Combination Predictive Supports B Sensitivity/Response 83 patients from a phase II trial (docetaxel + placebo or selumetinib) with KRAS mutant tumors were retrospectively assessed for differences in OS, PFS, ORR and change in tumor size at week 6 according to type of KRAS mutation. G12C, G12D and G12V were the most common mutations (46%, 22%, 11%, respectively). Patients with G12C or G12V mutations receiving combination selumetinib and docetaxel had a trend towards longer OS, PFS and ORR compared to other KRAS mutations. Changes in tumor size were similar between groups with the best responses in tumors with G12V mutations. Few differences were observed between groups when treated with docetaxel + placebo. 26125448 PubMed Jänne et al., 2015, Br. J. Cancer NCT00890825 1 accepted 1143 425 30 12 25398284 25398284 C A ENST00000256078.4 75 GRCh37 KRAS mutations are the most common mutations in pancreatic cancer occurring in > 90% of cases. Of these the G12D activating mutation is the most prevalent and results in a loss of GTPase activity which in turn leads to a constitutively active form of KRAS. This is enough to cause pre-cancerous pancreatic intraepithelial lesions Somatic 2021-02-24 00:58:44 UTC https://civicdb.org/links/evidence_items/1143 https://civicdb.org/links/variants/425 https://civicdb.org/links/genes/30 false STK11 6794 Loss Lung Non-small Cell Carcinoma 3908 Docetaxel,Selumetinib Combination Predictive Supports D Resistance A clinical trial comparing selumetinib and docetaxel vs. docetaxel and placebo in KRAS mutant NSCLC was recapitulated in mice. Tumors were induced in lung epithelium by nasal instillation of CRE-bearing adenovirus in conditionally targeted mice. Kras(G12D) and Lkb1 (STK11) knockout mutant mice showed only mild response to combined treatment and very low response rates to docetaxel monotherapy compared to mice with Kras(G12D) alone or Kras(G12D) and Trp53 knockout. In a small number of human NSCLC patients with these genotypes FDG-PET signal intensity changes and pERK IHC staining correlated with mouse data. 22425996 PubMed Chen et al., 2012, Nature 3 accepted 1144 485 5534 19 1205740 1228428 ENST00000326873.7 75 GRCh37 Somatic 2016-08-29 09:38:57 UTC https://civicdb.org/links/evidence_items/1144 https://civicdb.org/links/variants/485 https://civicdb.org/links/genes/5534 false TP53 7157 Mutation Lung Non-small Cell Carcinoma 3908 Docetaxel,Selumetinib Combination Predictive Supports D Sensitivity/Response A clinical trial comparing selumetinib and docetaxel vs. docetaxel and placebo in KRAS mutant NSCLC was recapitulated in mice. Tumors were induced in lung epithelium by nasal instillation of CRE-bearing adenovirus in conditionally targeted mice. Kras(G12D) and Trp53 knockout mutant mice were resistant to docetaxel monotherapy but sensitive to combined treatment. In a small number of human NSCLC patients with these genotypes FDG-PET signal intensity changes and pERK IHC staining correlated with mouse data. 22425996 PubMed Chen et al., 2012, Nature 3 accepted 1145 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2016-10-10 22:57:10 UTC https://civicdb.org/links/evidence_items/1145 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false TP53 7157 Mutation Lung Non-small Cell Carcinoma 3908 Docetaxel Predictive Supports D Resistance A clinical trial comparing selumetinib and docetaxel vs. docetaxel and placebo in KRAS mutant NSCLC was recapitulated in mice. Tumors were induced in lung epithelium by nasal instillation of CRE-bearing adenovirus in conditionally targeted mice. Kras(G12D) and Trp53 knockout mutant mice were resistant to docetaxel monotherapy but sensitive to combined treatment. In a small number of human NSCLC patients with these genotypes FDG-PET signal intensity changes and pERK IHC staining correlated with mouse data. 22425996 PubMed Chen et al., 2012, Nature 3 accepted 1146 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2016-07-25 16:56:07 UTC https://civicdb.org/links/evidence_items/1146 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false TP53 7157 Deleterious Mutation Lung Non-small Cell Carcinoma 3908 Prognostic Does Not Support B Poor Outcome Pooled analysis of TP53 mutations (exons 5-8) from 4 randomized trials (IALT, JBR10, CALGB-9633 and ANITA). Mutations (434; 36%) had no prognostic effect (OBS: HROS=0.99; [95%CI 0.77-1.28], p=0.95; HRDFS=0.99 [0.78-1.25], p=0.92) but were marginally predictive of benefit from ACT for OS (test for interaction: OS: p=0.06; DFS: p=0.11). 26899019 PubMed Ma et al., 2016, J Thorac Oncol 4 accepted 1147 221 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Deleterious mutations are mutations of TP53 with prior characterization demonstrating significant deleterious effect on TP53 protein function. Inactivating TP53 mutations prevent on target activity and efficacy of MDM2-TP53 interaction inhibitors. Somatic 2016-05-03 16:53:16 UTC https://civicdb.org/links/evidence_items/1147 https://civicdb.org/links/variants/221 https://civicdb.org/links/genes/45 false TP53 7157 Deleterious Mutation Lung Non-small Cell Carcinoma 3908 Adjuvant Chemotherapy Predictive Does Not Support B Sensitivity/Response Pooled analysis of TP53 mutations (exons 5-8) from 4 randomized trials (IALT, JBR10, CALGB-9633 and ANITA) of platinum-based adjuvant chemotherapy (ACT) versus observation (OBS). Patients with TP53wt had significantly better PFS and OS with ACT vs. OBS (p=0.005, p=0.02, respectively) whereas patients with TP53 mutations did not show significant differences in PFS and OS between ACT and OBS (p=0.86, p=0.63). 26899019 PubMed Ma et al., 2016, J Thorac Oncol 2 accepted 1148 221 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Deleterious mutations are mutations of TP53 with prior characterization demonstrating significant deleterious effect on TP53 protein function. Inactivating TP53 mutations prevent on target activity and efficacy of MDM2-TP53 interaction inhibitors. Somatic 2016-07-26 14:55:03 UTC https://civicdb.org/links/evidence_items/1148 https://civicdb.org/links/variants/221 https://civicdb.org/links/genes/45 false TP53 7157 Wildtype Lung Non-small Cell Carcinoma 3908 Adjuvant Chemotherapy Predictive Supports B Sensitivity/Response Pooled analysis of TP53 mutations (exons 5-8) from 4 randomized trials (IALT, JBR10, CALGB-9633 and ANITA, 1209 patients, median follow-up 5.5 years) of platinum-based adjuvant chemotherapy (ACT) versus observation (OBS). Patients with wild-type TP53 had better outcomes with ACT than OBS (HROS=0.77 [0.62-0.95], p=0.02; HRDFS=0.75 [0.62-0.92], p=0.005). 26899019 PubMed Ma et al., 2016, J Thorac Oncol 3 accepted 1149 369 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 N/A 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1149 https://civicdb.org/links/variants/369 https://civicdb.org/links/genes/45 false HAVCR2 84868 Overexpression Lung Non-small Cell Carcinoma 3908 PD1 Inhibitor Predictive Supports C Resistance In a preclinical study in an immunocompetent mouse model of lung adenocarcinoma, upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3, aka HAVCR2) was observed after progression under PD-1 antibody. A survival advantage was observed with the addition of a TIM-3 blocking antibody. Two patients who developed adaptive resistance to anti-PD-1 treatment also showed TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. 26883990 PubMed Koyama et al., 2016, Nat Commun 3 accepted 1150 486 16394 5 156512843 156536725 ENST00000307851.4 75 GRCh37 N/A 2016-06-14 04:25:38 UTC https://civicdb.org/links/evidence_items/1150 https://civicdb.org/links/variants/486 https://civicdb.org/links/genes/16394 false HAVCR2 84868 Overexpression Lung Non-small Cell Carcinoma 3908 PD1 Inhibitor,Anti-TIM-3 Monoclonal Antibody Combination Predictive Supports D Sensitivity/Response In a preclinical study in an immunocompetent mouse model of lung adenocarcinoma, upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3, aka HAVCR2) was observed after progression under PD-1 antibody. A survival advantage was observed with the addition of a TIM-3 blocking antibody. 26883990 PubMed Koyama et al., 2016, Nat Commun 3 accepted 1151 486 16394 5 156512843 156536725 ENST00000307851.4 75 GRCh37 N/A 2016-07-13 23:31:23 UTC https://civicdb.org/links/evidence_items/1151 https://civicdb.org/links/variants/486 https://civicdb.org/links/genes/16394 false ERBB3 2065 Overexpression Cancer 162 Afatinib,Selumetinib Combination Predictive Supports D Sensitivity/Response Preclinical study in KRAS mutant lung and colon cancer models. A synthetic lethal screen using a total of 3,530 shRNAs to target 518 human kinases identified ERBB3 knockdown to confer sensitivity of selumetinib-resistant H358 cells (NSCLC cell line) to the MEK inhibitor selumetinib. The dual EGFR-ERBB2 inhibitors afatinib and dacomitinib each showed synergy with MEK Inhibition via selumetinib in 4 KRAS mutant cell lines. Western blot evaluation of 9 NSCLC and 12 CRC cell lines showed ERBB3 expression correlated with the synergy score for combination afatinib and trametinib treatment. I.e. the synergy score was low in cells having low basal levels of ERBB3 protein and high for cells having high basal ERBB3 expression. Using selumetinib in patient-derived CRC xenografts or trametinib in NSCLC xenografts, MEK inhibition by selumetinib or trametinib in combination with afatinib more effectively inhibited increases in tumor volume than either monotherapy. 24685132 PubMed Sun et al., 2014, Cell Rep 3 accepted 1152 289 1733 12 56473645 56497289 ENST00000267101.3 75 GRCh37 N/A 2016-03-12 02:21:02 UTC https://civicdb.org/links/evidence_items/1152 https://civicdb.org/links/variants/289 https://civicdb.org/links/genes/1733 false ERBB3 2065 Overexpression Cancer 162 Selumetinib,Gefitinib,HER2 Inhibitor CP-724,714 Substitutes Predictive Supports D Resistance Preclinical study in KRAS mutant lung and colon cancer models. A synthetic lethal screen identified ERBB3 blockade to confer sensitivity to MEK inhibitors. The dual EGFR-ERBB2 (both forming heterodimers with ERBB3) inhibitors afatinib and dacomitinib each showed strong synergy with MEK Inhibition (trametinib or selumetinib) in several KRAS mutant cell lines. MEK Inhibitors alone or the combination with gefitinib (EGFRi) or CP724714 (ERBB2i) showed strong synergy. Results were validated in-vivo. Basal ERBB3 expression was associated with higher synergy scores. 24685132 PubMed Sun et al., 2014, Cell Rep 4 accepted 1153 289 1733 12 56473645 56497289 ENST00000267101.3 75 GRCh37 N/A 2016-06-23 22:10:52 UTC https://civicdb.org/links/evidence_items/1153 https://civicdb.org/links/variants/289 https://civicdb.org/links/genes/1733 false CDKN2A 1029 p16 Expression Head And Neck Squamous Cell Carcinoma 5520 Afatinib Predictive Supports B Resistance Phase III trial to compare afatinib or metothrexate in recurrent or metastatic head and neck squamous cell carcinoma. 483 patients were randomized to either afatinib (n=322) or methotrexate (n=161). 285 patients were assessed for p16 Status (IHC). In the post-hoc analysis, benefit of afatinib compared with methotrexate was more pronounced in p16-negative disease (HR 0·69 [95% CI 0·50–0·96], p=0.022) than in p16-positive disease (HR 0·95 [CI 0·51–1·75], p=0.67, interaction test p=0·32). 25892145 PubMed Machiels et al., 2015, Lancet Oncol. NCT01345682 2 accepted 1155 272 14 9 21968055 21974865 ENST00000498124.1 75 GRCh37 CDKN2A (p16) expression is a surrogate marker of HPV infection in oropharyngeal squamous cell carcinoma. CDKN2A and p53 are inactivated through HPV proteins E6 and E7 and therefore not altered in expression level in HPV-associated carcinomas. However, there is no perfect overlap between p16 expression and HPV status with some 10-12.5% of HPV-negative tumors expressing p16. (Seiwert, T JCO, 2014). p16 positivity is a well-established positive prognostic factor in squamous cell cancer of the head and neck in the primary and, as increasing evidence suggests, recurrent/metastatic disease settings. Predictive information from HPV status have not been established to date. A lack of benefit from EGFR-inhibitors has been proposed by some studies. Other studies were not able to reproduce this finding. N/A 2016-05-08 16:06:58 UTC https://civicdb.org/links/evidence_items/1155 https://civicdb.org/links/variants/272 https://civicdb.org/links/genes/14 false MMP2 4313 SERUM LEVELS Inflammatory Breast Carcinoma 6263 Bevacizumab Predictive Supports B Sensitivity/Response MMP2 serum levels were assessed (ELISA) at baseline (b) and before surgery in 45 available samples from patients with inflammatory breast cancer treated with bevacizumab-based neoadjuvant therapy. High bMMP2 was correlated with better disease-free survival (DFS, p=0.001) and overall survival (OS, p=0.032). Correlation to DFS was also found after multivariate analysis (p=0.003, Hazard Ratio [HR]: 0.115). bMMP2 was associated with relapse (p=0.002) and death (p=0.049). During treatment, significant increase in MMP2 was observed in 100% of patients. 26921265 PubMed Tabouret et al., 2016, Oncotarget 3 accepted 1156 487 3549 16 55512883 55540603 ENST00000219070.4 75 GRCh37 N/A 2016-06-14 04:27:35 UTC https://civicdb.org/links/evidence_items/1156 https://civicdb.org/links/variants/487 https://civicdb.org/links/genes/3549 false MMP9 4318 SERUM LEVELS Inflammatory Breast Carcinoma 6263 Bevacizumab Predictive Supports B Resistance MMP9 serum levels were assessed (ELISA) at baseline (b) and before surgery in 45 available samples from patients with inflammatory breast cancer treated with bevacizumab-based neoadjuvant therapy. Low bMMP9 was correlated with better OS (p=0.022) and non-significantly associated with longer DFS (p=0.071). Correlation to DFS was also found after multivariate analysis (p=0.041, HR: 3.511). bMMP9 was associated with death (p=0.035). During treatment, a significant decrease in MMP9 levels (p<0.001) was observed in 87% of patients. 26921265 PubMed Tabouret et al., 2016, Oncotarget 3 accepted 1157 488 3553 20 44637547 44645200 ENST00000372330.3 75 GRCh37 N/A 2016-06-27 00:57:47 UTC https://civicdb.org/links/evidence_items/1157 https://civicdb.org/links/variants/488 https://civicdb.org/links/genes/3553 false MMP2 4313 SERUM LEVELS Brain Glioma 0060108 Bevacizumab Predictive Supports B Sensitivity/Response Plasma levels of 11 potential biomarkers were tested at baseline and 2 weeks after bevacizumab initiation in a prospective cohort of 26 patients with recurrent high-grade gliomas. Results were validated in a separate retrospective cohort (n = 50) and also tested in patients treated with cytotoxic agents without bevacizumab (n = 34). MMP2 level was correlated with PFS (hazard ratio, 3.92; 95% confidence interval [CI]:1.46-10.52; P = .007) and OS (hazard ratio, 4.62; 95% CI: 1.58-13.53; P = .005) in the discovery and validation cohorts but not in patients treated without bevacizumab. 24327581 PubMed Tabouret et al., 2014, Neuro-oncology 2 accepted 1158 487 3549 16 55512883 55540603 ENST00000219070.4 75 GRCh37 N/A 2016-06-14 04:26:37 UTC https://civicdb.org/links/evidence_items/1158 https://civicdb.org/links/variants/487 https://civicdb.org/links/genes/3549 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Emtansine Predictive Supports B Sensitivity/Response The Phase III trial, TH3RESA (NCT01419197), was performed in patients with advanced HER2 breast cancer that was heavily pretreated. Patients were required to have prior exposure to trastuzumab and lapatinib as well as a taxane. This patient population has not seen many studies, responds poorly to late-line treatment with trastuzumab, and in this study was treated with trastuzumab emtansine (T-DM1, n=404) vs. physician's choice (usually trastuzumab plus chemotherapy, n=198). Results showed progression free survival was 6.2 months in T-DM1 treatment vs. 3.3 months under physician's choice, along with lower incidence of grade 3 or worse events with T-DM1. The authors conclude that their findings in this heavily pretreated population, along with findings in the EMILIA trial, indicate promise for antibody-drug conjugates. The NCI-MATCH trial with further study T-DM1 in the context of HER2 amplification. 24793816 PubMed Krop et al., 2014, Lancet Oncol. NCT01419197 4 accepted 1159 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-02-18 04:12:34 UTC https://civicdb.org/links/evidence_items/1159 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Emtansine Predictive Supports B Sensitivity/Response The EMILIA study (NCT00829166) was a Phase II trial to assess the efficacy of trastuzumab emtansine (T-DM1, n=495) in comparison to lapatinib plus capecitabine (n=496), in treatment of advanced HER2 positive breast cancer. Patients were required to have progressed on or after treatments involving trastuzumab and a taxane, and no prior exposure to lapatinib or T-DM1. Primary endpoints included independently assessed progression free survival (PFS) and safety. PFS was 9.6 months in T-DM1 group vs. 6.4 months in lapatinib plus capecitabine. Rates of adverse events of grade 3 or higher were greater with lapatinib plus capecitabine. These results, together with other trials such as TH3RESA indicate promise for T-DM1 therapy in HER2 amplification, and this will be further studied in an arm of the NCI-MATCH trial. 23020162 PubMed Verma et al., 2012, N. Engl. J. Med. NCT00829166 4 accepted 1160 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-02-18 03:59:15 UTC https://civicdb.org/links/evidence_items/1160 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ACTA1 58 EXPRESSION Lung Adenocarcinoma 3910 Prognostic Supports B Poor Outcome ActA level was measured in serum and plasma samples of 64/87 lung adenocarcinoma patients and 46/66 age- and gender-matched controls (ELISA). ActA Levels were higher in patients than in controls and were significantly correlated with disease stage and metastasis. Patients were stratified as having high or low ActA levels using the median expression level. LADC patients with high serum or plasma ActA levels had significantly shorter OS than those with low circulating ActA concentrations (p < 0.0001 in both) and were identified as an independent prognostic factor (p=0.004 and p=0.002, respectively). 26950277 PubMed Hoda et al., 2016, Oncotarget 2 accepted 1161 546 128 1 229566992 229569841 ENST00000366684.3 75 GRCh37 N/A 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1161 https://civicdb.org/links/variants/546 https://civicdb.org/links/genes/128 false HSPH1 10808 NUCLEAR EXPRESSION Gastric Adenocarcinoma 3717 Prognostic Supports B Poor Outcome HSP110 (HSPH1) expression was immunohistochemically assessed using a tissue microarray in 210 gastric cancer patients. The overall survival rate was significantly lower in patients with high nuclear expression (N=121, 2+ moderate/3+ strong staining) than patients with low nuclear staining (N=89, 0 no/1+ weak staining)(P = 0.0169). Multivariate regression analysis identified expression of nuclear HSP110 as an independent prognostic factor for gastric cancer outcome (P = 0.0068). This was not found for cytoplasmic expression. 26943774 PubMed Kimura et al., 2016, Oncotarget 2 accepted 1162 490 8614 13 31710765 31736064 ENST00000320027.5 75 GRCh37 N/A 2016-06-29 20:13:40 UTC https://civicdb.org/links/evidence_items/1162 https://civicdb.org/links/variants/490 https://civicdb.org/links/genes/8614 false HSPH1 10808 NUCLEAR EXPRESSION Gastric Adenocarcinoma 3717 Fluorouracil,Cisplatin Substitutes Predictive Supports D Sensitivity/Response 49 patients gastric cancer patients treated with adjuvant chemotherapy were immunohistochemically assessed for nuclear HSPH1 (HSP110) expression. Overall survival rate in the high expression group (2+ moderate/3+ strong staining) was significantly lower compared with the low expression group (0 no/1+ weak staining) (P = 0.0364). In gastric cancer cell lines (MKN7, MKN45), siRNA mediated HSP110 knockdown led to a higher sensitivity to 5-FU and cisplatin compared with the parent and control cells (p < 0.05). 26943774 PubMed Kimura et al., 2016, Oncotarget 1 accepted 1163 490 8614 13 31710765 31736064 ENST00000320027.5 75 GRCh37 N/A 2016-05-17 19:37:22 UTC https://civicdb.org/links/evidence_items/1163 https://civicdb.org/links/variants/490 https://civicdb.org/links/genes/8614 false HSPH1 10808 T17 DELETION Colorectal Cancer 9256 Oxaliplatin,Fluorouracil Combination Predictive Supports B Sensitivity/Response 329 consecutive patients with stage II–III colorectal tumors with MSI after surgical resection at tertiary medical centers were screened for HSP110 T(17) by PCR. Patients underwent adjuvant chemotherapy with 5-fluorouracil and oxaliplatin. Patients with large HSP110 T(17) deletions (≥5 bp; 18 of 77 patients, 23.4%) had longer times of relapse-free survival than patients with small or no deletions (≤4 bp; 59 of 77 patients, 76.6%) in multivariate analysis (hazard ratio, 0.16; 95% confidence interval, 0.012–0.8; P = .03). A significant interaction between chemotherapy and T17 deletion was found (P =.009). 24512910 PubMed Collura et al., 2014, Gastroenterology 2 accepted 1164 491 8614 13 31722621 31722637 ENST00000320027.5 75 GRCh37 Somatic 2016-05-10 02:11:13 UTC https://civicdb.org/links/evidence_items/1164 https://civicdb.org/links/variants/491 https://civicdb.org/links/genes/8614 false ECSCR 641700 EXPRESSION Cancer 162 Angiogenesis Inhibitor Predictive Does Not Support B Sensitivity/Response Biomarkers for response to antiangiogenic treatment were screened for in hepatocellular cancer (n = 11), renal cell cancer (n = 7) and non-small cell lung cancer (n = 2). Increased expression of tumor endothelial markers: Robo4 and ECSCR, nonsignificantly correlated with prolonged antiangiogenic time to progression (ECSCR high = 275 days vs. ECSCR low = 92.5 days; p = 0.07 and for Robo4 high = 387 days vs. Robo4 low = 90.0 days; p = 0.08). 26956051 PubMed Pircher et al., 2016, Oncotarget 1 accepted 1165 492 26599 N/A 2016-11-03 21:48:26 UTC https://civicdb.org/links/evidence_items/1165 https://civicdb.org/links/variants/492 https://civicdb.org/links/genes/26599 false ROBO4 54538 EXPRESSION Cancer 162 Angiogenesis Inhibitor Predictive Does Not Support B Sensitivity/Response Biomarkers for Response to antiangiogenic treatment were screened for in hepatocellular cancer (n = 11), renal cell cancer (n = 7) and non-small cell lung cancer (n = 2). Increased expression of tumor endothelial markers: Robo4 and ECSCR, nonsignificantly correlated with prolonged antiangiogenic time to progression (ECSCR high = 275 days vs. ECSCR low = 92.5 days; p = 0.07 and for Robo4 high = 387 days vs. Robo4 low = 90.0 days; p = 0.08). 26956051 PubMed Pircher et al., 2016, Oncotarget 1 accepted 1166 493 12367 11 124753587 124768177 ENST00000306534.3 75 GRCh37 N/A 2016-06-27 23:48:22 UTC https://civicdb.org/links/evidence_items/1166 https://civicdb.org/links/variants/493 https://civicdb.org/links/genes/12367 false CD274 29126 Expression Lung Non-small Cell Carcinoma 3908 Nivolumab,Pembrolizumab,Atezolizumab,Avelumab Substitutes Predictive Supports B Sensitivity/Response Meta-Analysis of PD-L1 (CD274) Expression Status in 914 patients (7 studies) and response to PD-1/PD-L1 monoclonal antibodies. Patients with PD-L1 positive tumors (PD-L1 tumor cell staining ≥1%), had a significantly higher ORR, compared to patients with PD-L1 negative tumors (OR: 2.44; 95% CIs: 1.61-3.68). 26918451 PubMed Passiglia et al., 2016, Oncotarget 4 accepted 1167 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2016-06-20 20:51:27 UTC https://civicdb.org/links/evidence_items/1167 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false PIM1 5292 NUCLEAR EXPRESSION Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome The expression of PIM1, p-STAT3, and c-MYC was tested (IHC) in 194 NSCLC archival tumor samples. High nuclear expression of PIM1 was detected in 43.3% of cases and was significantly correlated with advanced clinical stage (p<0.001) and poor pathologic differentiation (P = 0.004) and was an independent unfavorable prognostic factors for overall and disease-free survival (OS, P=0.009; DFS, P=0.034). 26918046 PubMed Jiang et al., 2016, J Cancer 2 accepted 1168 494 4286 6 37137979 37143202 ENST00000373509.5 75 GRCh37 N/A 2016-06-29 20:03:49 UTC https://civicdb.org/links/evidence_items/1168 https://civicdb.org/links/variants/494 https://civicdb.org/links/genes/4286 false MDM2 4193 SNP309 Head And Neck Cancer 11934 Prognostic Supports B Poor Outcome 66 HNSCC patients treated with chemoradiation were assessed for survival after a follow-up time of 10 years. Median OS was significantly shorter in patients with MDM2 SNP309 GG or GT genotypes compared with the TT genotype (p = 0.002). 26916894 PubMed Vivenza et al., 2016, Int. J. Biol. Markers 2 accepted 1169 495 3465 12 69202580 69202580 T G ENST00000462284.1 75 GRCh37 Common Germline 2016-06-28 20:43:51 UTC https://civicdb.org/links/evidence_items/1169 https://civicdb.org/links/variants/495 https://civicdb.org/links/genes/3465 false TP53 7157 Deleterious Mutation Sarcoma 1115 Pazopanib Predictive Supports B Sensitivity/Response 19 advanced sarcoma patients treated with pazopanib were retrospectively assessed for mutations associated with response using the Foundation one sarcoma/heme panel. Progression-free survival (PFS) of patients with TP53 mutations (all predicted to be loss of function) was significantly greater than TP53 wild-type tumors with the median PFS of 208 versus 136 days, respectively [P = 0.036, hazards ratio 0.38 (95% confidence interval 0.09-0.83)]. 26646755 PubMed Koehler et al., 2016, Ann. Oncol. 2 accepted 1170 221 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Deleterious mutations are mutations of TP53 with prior characterization demonstrating significant deleterious effect on TP53 protein function. Inactivating TP53 mutations prevent on target activity and efficacy of MDM2-TP53 interaction inhibitors. Somatic 2016-06-29 20:03:29 UTC https://civicdb.org/links/evidence_items/1170 https://civicdb.org/links/variants/221 https://civicdb.org/links/genes/45 false PIK3CA 5290 E545K Lung Adenocarcinoma 3910 Gefitinib Predictive Supports D Resistance HCC827 cell lines harboring activated PI3K (HCC827 p110α E545K cells) were more resistant to gefitinib in vitro (IC50, 1 μM) compared with those harboring GFP alone (IC50, 0.01 μM). The presence of p110α E545K also protected HCC827 cells from gefitinib-mediated apoptosis. 16906227 PubMed Engelman et al., 2006, J. Clin. Invest. 2 accepted 1171 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1171 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false CD274 29126 Expression Lung Non-small Cell Carcinoma 3908 Atezolizumab Predictive Supports B Sensitivity/Response Exploratory biomarker analysis from a phase-II randomized trial comparing atezolizumab (PD-L1) and docetaxel in previously treated, advanced or metastatic non-small cell lung cancer. Baseline PD-L1 expression (IHC) was assessed in tumour cells (as percentage of PD-L1-expressing tumour cells TC3≥50%, TC2≥5% and <50%, TC1≥1% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3≥10%, IC2≥5% and <10%, IC1≥1% and <5%, and IC0<1%). Increasing PD-L1 Expression was associated with improved overall survival (TC3 or IC3 HR 0·49 [0·22-1·07; p=0·068], TC2/3 or IC2/3 HR 0·54 [0·33-0·89; p=0·014], TC1/2/3 or IC1/2/3 HR 0·59 [0·40-0·85; p=0·005], TC0 and IC0 HR 1·04 [0·62-1·75; p=0·871]) but not progression free survival or overall response rate. 26970723 PubMed Fehrenbacher et al., 2016, Lancet NCT01903993 4 accepted 1172 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2016-03-26 15:41:41 UTC https://civicdb.org/links/evidence_items/1172 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false KRAS 3845 G12C Cancer 162 ARS-853,Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Combination Predictive Supports D Sensitivity/Response Preclinical study to investigate mechanisms of KRAS G12C activity and inhibition with ARS-853, a covalent (irreversible) inhibitor which binds KRAS G12C in the GDP-bound state to prevent activation. Results from a mass spectrometry-based assay to evaluate KRAS activity suggests that G12C mutant KRAS is in a “hyperexcitable” rather than a “statically active” state. ARS-853 targets the inactive state and inhibited proliferation in a subset (3/11) of KRAS G12C mutant cell lines in 2-D growth assays and 11/11 cell lines in soft-agar colony formation and 3-D assays. This effect was specific for KRAS G12C as 12/12 cell lines with other KRAS mutations (including other G12 mutations V, D and A) were not inhibited in either soft-agar assay. Relative resistance to ARS-853 developed after epidermal growth factor (50 ng/mL) administration and the combination of erlotinib or afatinib (EGFR-inhibitors) with ARS-853 greatly potentiated growth arrest, apoptosis and decrease of PI3K and MAPK-signaling over single-agent ARS-853 treatment, even in the presence of added EGF. 26739882 PubMed Patricelli et al., 2016, Cancer Discov 3 accepted 1173 78 30 12 25398285 25398285 C A ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2016-10-10 22:44:00 UTC https://civicdb.org/links/evidence_items/1173 https://civicdb.org/links/variants/78 https://civicdb.org/links/genes/30 false ERBB2 2064 V842I Colon Cancer 219 Lapatinib,Trastuzumab,Neratinib Combination Predictive Supports D Sensitivity/Response Colon cancer patient derived xenografts with HER2 mutations are sensitive to HER2 targeted drugs and the greatest tumor reduction was seen with the combination of a tyrosine kinase inhibitor with trastuzumab. 26243863 PubMed Kavuri et al., 2015, Cancer Discov 4 accepted 1174 45 20 17 37881332 37881332 G A ENST00000269571.5 75 GRCh37 ERBB2 V842I was one of the first ERBB2 variants to be functionally classified (Bose et al. 2013). This mutation was shown to be an activating mutation in an in vitro assay. In the same paper, this mutation (along with other ERBB2 activating mutations) in MCF10A breast cancer cell lines have been shown to be sensitive to the kinase inhibitor neratinib. More recent evidence may show that HER2 acitivating mutations confer sensitivity to a host of tyrosine kinase inhibitors, which is the topic of current clinical trials and research. Somatic 2016-03-17 20:41:30 UTC https://civicdb.org/links/evidence_items/1174 https://civicdb.org/links/variants/45 https://civicdb.org/links/genes/20 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Ceritinib Predictive Supports B Sensitivity/Response Updated results from ASCEND-1 trial assessing safety and activity of ceritinib in ALK rearranged locally advanced or metastatic NSCLC. 255 patients were enrolled and received at least one dose of ceritinib 750 mg/day, of whom 246 had ALK-rearranged NSCLC (Median follow-up: 11.1 months). Overall response rate was 72% [95% CI 61-82] of 83 ALK inhibitor-naive patients and 56% [49-64] of 163 ALK inhibitor-pretreated patients. Median duration of response was 17·0 months (95% CI 11.3-non-estimable [NE]) in ALK inhibitor-naive patients and 8.3 months (6.8-9.7) in ALK inhibitor-pretreated patients. Median progression-free survival was 18.4 months (95% CI 11.1-NE) in ALK inhibitor-naive patients and 6.9 months (5.6-8.7) in ALK inhibitor-pretreated patients. Brain metastases control was reported in 79% [95% CI 54-94] of 19 ALK inhibitor-naive patients and in 65% [54-76] of 75 ALK inhibitor-pretreated patients. 26973324 PubMed Kim et al., 2016, Lancet Oncol. NCT01283516 4 accepted 1175 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-06-27 16:24:43 UTC https://civicdb.org/links/evidence_items/1175 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ERBB2 2064 L755S Colon Cancer 219 Lapatinib,Neratinib,Trastuzumab Combination Predictive Supports D Sensitivity/Response Colon cancer patient derived xenografts with HER2 mutations are sensitive to HER2 targeted drugs and the greatest tumor reduction was seen with the combination of a tyrosine kinase inhibitor with trastuzumab. 26243863 PubMed Kavuri et al., 2015, Cancer Discov 4 accepted 1176 39 20 17 37880220 37880220 T C ENST00000269571.5 75 GRCh37 ERBB2 L755S was one of the first ERBB2 variants to be functionally classified (Bose et al. 2013). This mutation was not shown to be an activating mutation, unlike many of the other variants queried. This mutation was also shown to confer resistance to the tyrosine kinase inhibitor lapatinib in MCF10A cell lines. Somatic 2016-03-17 22:21:46 UTC https://civicdb.org/links/evidence_items/1176 https://civicdb.org/links/variants/39 https://civicdb.org/links/genes/20 false ERBB2 2064 V777L Colon Cancer 219 Neratinib,Lapatinib,Trastuzumab Combination Predictive Supports D Sensitivity/Response Colon cancer patient derived xenografts with HER2 mutations are sensitive to HER2 targeted drugs and the greatest tumor reduction was seen with the combination of a tyrosine kinase inhibitor with trastuzumab. 26243863 PubMed Kavuri et al., 2015, Cancer Discov 4 accepted 1177 44 20 17 37881000 37881000 G T ENST00000269571.5 75 GRCh37 ERBB2 V777L was one of the first ERBB2 variants to be functionally classified (Bose et al. 2013). This mutation was shown to be an activating mutation in an in vitro assay. In the same paper, this mutation (along with other ERBB2 activating mutations) in MCF10A breast cancer cell lines have been shown to be sensitive to the kinase inhibitor neratinib. More recent evidence may show that HER2 acitivating mutations confer sensitivity to a host of tyrosine kinase inhibitors, which is the topic of current clinical trials and research. Somatic 2016-03-17 22:20:55 UTC https://civicdb.org/links/evidence_items/1177 https://civicdb.org/links/variants/44 https://civicdb.org/links/genes/20 false ERBB2 2064 L866M Colon Cancer 219 Neratinib,Trastuzumab,Lapatinib Combination Predictive Supports D Sensitivity/Response Colon cancer patient derived xenografts with HER2 mutations are sensitive to HER2 targeted drugs and the greatest tumor reduction was seen with the combination of a tyrosine kinase inhibitor with trastuzumab. 26243863 PubMed Kavuri et al., 2015, Cancer Discov 4 accepted 1178 496 20 17 37881404 37881404 C A ENST00000269571.5 75 GRCh37 This mutation was shown to be an activating mutation and conferred sensitivity to a combination of trastuzumab with neratinib or lapatinib in colorectal cancer patient-derived xenografts. Somatic 2016-03-17 22:19:29 UTC https://civicdb.org/links/evidence_items/1178 https://civicdb.org/links/variants/496 https://civicdb.org/links/genes/20 false ERBB2 2064 S310F/Y Colon Cancer 219 Lapatinib,Neratinib,Trastuzumab Combination Predictive Supports D Sensitivity/Response Colon cancer patient derived xenografts with HER2 mutations are sensitive to HER2 targeted drugs and the greatest tumor reduction was seen with the combination of a tyrosine kinase inhibitor with trastuzumab. 26243863 PubMed Kavuri et al., 2015, Cancer Discov 4 accepted 1179 497 20 17 37868208 37868208 ENST00000269571.5 75 GRCh37 ERBB2 S310F/Y was one of the first ERBB2 variants to be functionally classified (Greulich et al. 2012). This mutation was shown to be an activating mutation (through hyperphosphorylation) in an in vitro assay. In the same paper, this mutation (along with other ERBB2 activating mutations) in murine Ba/F3 cells have been shown to be sensitive to the ERBB2 inhibitors (afatinib, lapatinib and neratinib). More recent evidence may show that HER2 acitivating mutations confer sensitivity to a host of tyrosine kinase inhibitors, which is the topic of current clinical trials and research. Somatic 2016-03-17 22:17:05 UTC https://civicdb.org/links/evidence_items/1179 https://civicdb.org/links/variants/497 https://civicdb.org/links/genes/20 false KRAS 3845 G13D Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance 12 patients with KRAS G13D mutant, metastatic colorectal cancer were treated with single agent cetuximab in a prospective phase II study. The primary endpoint of the trial was 4-month progression-free survival, with a benefit to treatment evaluated to be 50% of patients were progression free at this point. None of 12 patients achieved response by RECIST 1.1 criteria and three patients (25%) were progression-free at 4 months, with disease control rate at 6 months reaching 0%. Median PFS and OS were 1.9 (95% CI 1.7–3.8) and 7.2 months (95% CI 5.7–9.7). 26371285 PubMed Schirripa et al., 2015, Ann. Oncol. 3 accepted 1180 81 30 12 25398281 25398281 C T ENST00000256078.4 75 GRCh37 While the KRAS G13 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort. This mutation, along with the mutations affecting the neighboring G12 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, results are conflicting with retrospective analyses suggesting a better response to EGFR-Inhibition. A recent prospective phase-II study (12 patients, Schirripa et. al. 2015) could not reproduce this finding and another prospective phase II trial is currently ongoing. Somatic 2016-03-23 22:01:26 UTC https://civicdb.org/links/evidence_items/1180 https://civicdb.org/links/variants/81 https://civicdb.org/links/genes/30 false KRAS 3845 G13D Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance Meta-analysis encompassing eight randomized controlled trials (n = 5967) for assessment of both overall survival (OS) and progression-free survival (PFS) of patients with KRAS mutant metastatic colorectal cancer. For other KRAS MT the hazard ratio for OS benefit with addition of anti-EGFR mAb therapy was 1.06 (95% confidence interval [CI]; 0.96, 1.17), compared to 1.08 (95% CI; 0.73, 1.60) for KRAS G13D [test for interaction p=0.99]. In contrast, the hazard ratio for KRAS wild-type (WT) tumours was 0.85 (95% CI; 0.76, 0.95). Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 1.07 (95% CI; 0.92, 1.26) for other KRAS MT, 0.96 (95% CI; 0.73, 1.27) for KRAS G13D, and 0.68 (95% CI; 0.54, 0.85) for KRAS wild-type. Again, the test for interaction (p=0.46) demonstrated no significant difference in PFS benefit for anti-EGFR mAb therapy between KRAS G13D and other KRAS MT. 26812186 PubMed Rowland et al., 2016, Eur. J. Cancer 4 accepted 1181 81 30 12 25398281 25398281 C T ENST00000256078.4 75 GRCh37 While the KRAS G13 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort. This mutation, along with the mutations affecting the neighboring G12 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, results are conflicting with retrospective analyses suggesting a better response to EGFR-Inhibition. A recent prospective phase-II study (12 patients, Schirripa et. al. 2015) could not reproduce this finding and another prospective phase II trial is currently ongoing. Somatic 2016-07-13 18:40:04 UTC https://civicdb.org/links/evidence_items/1181 https://civicdb.org/links/variants/81 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Colorectal Cancer 9256 Ixazomib Predictive Supports D Resistance Preclinical study in colorectal cancer xenografts. KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cell line. KRAS wild-type, but not KRAS mutant tumors were sensitive to proteasome inhibitor ixazomib 26709701 PubMed Chattopadhyay et al., 2015, PLoS ONE 1 accepted 1182 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-07-13 18:40:12 UTC https://civicdb.org/links/evidence_items/1182 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Cancer 162 AZD5438 Predictive Supports D Sensitivity/Response CDK1 was identified in a preclinical siRNA screen to identify targets in KRAS mutant tumors. Cell viability was evaluated following knockdown of 834 genes in isogenic LIM1215 colorectal cancer cell lines harboring wildtype (parental), G12S, G12D or G12V KRAS. 6 targets identified by this screen were evaluated in a second set of isogenic colorectal cancer cell lines (SW48) harboring wildtype (parental), G12S, G12D, G12V or G13D KRAS where only CDK1 knockdown more profoundly reduced survival in mutant cells compared to wildtype. Results were validated in 5 KRAS mutant (BRAF WT) and 10 KRAS WT colorectal cancer cell lines. Chemical inhibition of CDK1 by AZD5438 in KRAS mutant vs WT pancreatic and colorectal cancer cell lines showed increased efficacy in mutant cell lines. Finally, AZD5438 reduced tumor growth induced by SW620 (KRAS p.G12V) colorectal tumour cells xenografted into immunodeficient mice. 26881434 PubMed Costa-Cabral et al., 2016, PLoS ONE 3 accepted 1183 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-07-25 16:58:42 UTC https://civicdb.org/links/evidence_items/1183 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false MIR218-1 407000 UNDEREXPRESSION Pancreatic Cancer 1793 Prognostic Supports D Poor Outcome The study found mir-218 was significantly under-expressed when compared to matched adjacent normal tissue in 107 samples via qPCR. Further, low expression of mir-218 was revealed to be associated with lower overall survival (p < .001), and multivariate analysis revealed that low expression of mir-218 as an independent predictor of poor prognosis (p < .007). 26662432 PubMed Li et al., 2015, Genet. Mol. Res. 3 accepted 1184 498 24938 4 20529898 20530007 ENST00000384999.1 75 GRCh37 Somatic 2016-06-29 21:02:02 UTC https://civicdb.org/links/evidence_items/1184 https://civicdb.org/links/variants/498 https://civicdb.org/links/genes/24938 false MET 4233 EXON 14 SKIPPING MUTATION Lung Adenocarcinoma 3910 Crizotinib Predictive Supports C Sensitivity/Response A single patient with a MET c.3028G>A (splice donor site of exon 14) mutation exhibited clinical sensitivity to the c-Met inhibitor crizotinib. Exon 14 skipping was detected using qRT-PCR. Response to the therapy was demonstrated by comparing CAT scans obtained before treatment to those obtained during treatment (at 2 months of crizotinib therapy). 26729443 PubMed Awad et al., 2016, J. Clin. Oncol. 3 accepted 1185 324 52 7 116411903 116412043 ENST00000318493.6 75 GRCh37 Exon 14 mutations have been observed in ~3% of patients with NSCLC (28/933 reported by Awad et al J Clin Onc 2016), confirmed to cause exon skipping when available, and associated with concurrent MET amplification. Responses to the c-MET inhibitor crizotinib have been reported in preclinical models and in individual case reports as well as a small-scale clinical trial (17 patients treated, Drilon et al., 2016 (suppl; abstr 108; ASCO ID 167889-176)). Larger studies are needed but enrollment of patients with MET exon 14 skipping mutation in trials with MET inhibitors or off-label treatment is encouraged (Paik et al., 2015 (suppl; abstr 8021)). Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1185 https://civicdb.org/links/variants/324 https://civicdb.org/links/genes/52 false MET 4233 EXON 14 SKIPPING MUTATION Lung Adenocarcinoma 3910 Capmatinib Predictive Supports C Sensitivity/Response A patient with MET c.3028+1G>T mutation (METex14) had partial response (tumor reduction of 61%) after 13 months capmatinib. MET gene copy number was four, MET FISH 13.8 copy number, and IHC 3+. 25971938 PubMed Frampton et al., 2015, Cancer Discov 3 accepted 1186 324 52 7 116411903 116412043 ENST00000318493.6 75 GRCh37 Exon 14 mutations have been observed in ~3% of patients with NSCLC (28/933 reported by Awad et al J Clin Onc 2016), confirmed to cause exon skipping when available, and associated with concurrent MET amplification. Responses to the c-MET inhibitor crizotinib have been reported in preclinical models and in individual case reports as well as a small-scale clinical trial (17 patients treated, Drilon et al., 2016 (suppl; abstr 108; ASCO ID 167889-176)). Larger studies are needed but enrollment of patients with MET exon 14 skipping mutation in trials with MET inhibitors or off-label treatment is encouraged (Paik et al., 2015 (suppl; abstr 8021)). Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1186 https://civicdb.org/links/variants/324 https://civicdb.org/links/genes/52 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports A Sensitivity/Response In the Phase I study PROFILE 1001 (NCT00585195), a recommended crizotinib dose of 250 mg twice daily for 28 day cycles was established. Among 1,500 advanced NSCLC patients who were screened for ALK-rearrangement using a break-apart FISH assay, 82 patients were eligible for crizotinib treatment. Overall response rate was 57%, with 46 partial responses and one complete response. Since crizotinib inhibits MET, 33 patients with available tissue were screened for MET amplification and were found negative, further indicating that patient response was due to ALK inhibition. 31 patients were tested via RT-PCR for known EML4-ALK fusions, and 13 were shown to have EML4-ALK variant 1, four cases had variant 3, and one instance of variants 2, 3b and 5 were seen. 9 were unidentified, suggesting other fusion partners in these instances. 20979469 PubMed Kwak et al., 2010, N. Engl. J. Med. NCT00585195 5 accepted 1187 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2020-05-08 15:46:46 UTC https://civicdb.org/links/evidence_items/1187 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK Lung Non-small Cell Carcinoma 3908 WHI-P154 Predictive Supports D Sensitivity/Response A retroviral cDNA expression library was constructed using a lung adenocarcinoma specimen from a 67 year old NSCLC patient, and transfected into mouse 3T3 fibroblasts which were assessed for transformed foci. Analysis of clones from one transformed focus yielded a novel fusion. This fusion generated a protein with N-terminal consisting of EML4 exons 1-13 and C-terminal consisting of ALK exons 20-29, which comprise the intracellular kinase domain of ALK. In subsequent experiments using EML4-ALK or altered versions, the transforming potential of EML4-ALK was found to be dependent on a functional ALK kinase activity as well as the EML4 basic domain, which was shown to have an important role in EML4-ALK dimer formation. BA/F3 cells expressing EML4-ALK were able to grow independently of IL3 addition, but addition of ALK inhibitor WHI-P154 induced cell death and inhibited tyrosine phosphorylation of EML4-ALK. These results indicated that EML4-ALK may be a driver mutation in NSCLC, and a target for ALK inhibitor treatment. 17625570 PubMed Soda et al., 2007, Nature 5 accepted 1188 5 1 2 42396490 42522656 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The EML4-ALK fusion variant 1 consisting of ALK kinase domain (exons 20-29) fused to EML4 exons 1-13 is the most common EML4-ALK variant, and was discovered in non-small cell lung cancer. Multiple EML4 breakpoint shave been described with differential sensitivity to inhibitors with variant 1 showing greater sensitivity than 3a in cell lines. EML4-ALK is crizotinib sensitive; however, several mutations that confer resistance mutations have been described in case studies. In the only clinical trial for crizotinib that included determination of EML4-ALK variant type in a subset of its participants, a very high response rate was observed, although the numbers were insufficient to validate correlation of variant type to outcome. Preclinical studies with this variant have indicated sensitivity to Hsp90 inhibitors. Somatic 2016-04-04 22:58:19 UTC https://civicdb.org/links/evidence_items/1188 https://civicdb.org/links/variants/5 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK e20-e20 Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Sensitivity/Response In the PROFILE 1001 study, from 31 NSCLC tumors positive for ALK fusions with sufficient material for RT-PCR aided exon breakpoint identification, 1 case of EML4-ALK variant 2 (EML4 exon 20 fused to ALK exon 20) was found. This patient had adenocarcinoma and a 9 pack year smoking history. Crizotinib treatment duration was over 16 weeks. The patient had multiple lines of prior treatment and showed a partial response to first-time crizotinib treatment. Overall, in the 82 ALK positive patients treated in the study, 46 had partial responses (including this patient) and 1 had a complete response for an overall response rate of 57%. 20979469 PubMed Kwak et al., 2010, N. Engl. J. Med. NCT00585195 2 accepted 1189 500 1 2 42396490 42552694 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 EML4-ALK variant 2 consists of a fusion of the ALK kinase domain (exons 20-29) with EML4 exons 1-20. Variant 2 has cytoplasmic distribution and makes up ~10% of EML4-ALK fusions found in NSCLC,. Although the specific variant is not consistently reported, single cases demonstrating response to crizotinib treatment in NSCLC and a differentiated malignant neoplasm of unknown origin have been reported. In vitro, this variant has shown greater sensitivity to ALK inhibition with TAE684 and crizotinib than the EML4-ALK variants 1 (E13;A20), 3a (E6;A20) and 3b (E6ins33;A20). The variant was reported to be less stable in cells than other variants, and may be a client protein of Hsp90. Along these lines the variant has shown preclinical sensitivity to Hsp90 inhibition. Somatic 2016-06-27 16:27:03 UTC https://civicdb.org/links/evidence_items/1189 https://civicdb.org/links/variants/500 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK e2-e20 Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports E Sensitivity/Response Multiplex RT-PCR to detect in-frame fusions of EML4 to ALK was performed on total RNA from 253 lung adenocarcinomas, and 9 samples were found to contain such fusions, one of which was a novel fusion containing EML4 exon 2 and exon 20 of ALK. This was called variant 5. Two versions of this variant were seen: 5a consisted of EML4 exon 2 fused to ALK exon 20 while 5b contained a 117bp intronic ALK region between the two exons. Genomic PCR showed that EML4-ALK variant 5 tumor cells contained a single EML4-ALK fusion, suggesting 5a and 5b arise from alternate splicing. 5a and 5b showed in-vitro kinase activity and transformed 3T3 cells in cell culture. 5a and 5b transformed 3T3 cells formed tumors when injected in 8/8 nude mice, but 3T3 transformed with ALK alone did not. These results suggest that EML4-ALK variant 5 is a driver mutation in lung adenocarcinoma targetable by ALK inhibitors like crizotinib. 18927303 PubMed Takeuchi et al., 2008, Clin. Cancer Res. 4 accepted 1190 501 1 2 42396490 42472827 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Somatic 2016-06-14 22:22:27 UTC https://civicdb.org/links/evidence_items/1190 https://civicdb.org/links/variants/501 https://civicdb.org/links/genes/1 false KDR 3791 R961W Colorectal Adenocarcinoma 0050861 Regorafenib Predictive Supports C Sensitivity/Response Case Report of a 84-year-old woman with stage IVb CRC after progression under 5-fluorouracil and bevacizumab. NGS revealed a frameshift mutation in APC, a missense mutation in KRAS. Variants of uncertain significance were: a missense variant in ERBB2 and a missense variant in KDR at amino acid 961 converting the wild type residue, Arginine, to Tryptophan (frequency 28.25%). Because of the high frequency of the KDR (VEGFR2) mutation, the patient was considered a suitable candidate for a VEGFR inhibitor and received regorafenib monotherapy, which is approved for this situation, at 80mg daily which was later reduced to 40mg daily and had CEA normalization as well as partial metabolic and radiologic response. The patient remained almost asymptomatic and without disease progression after 39 weeks. 27004155 PubMed Loaiza-Bonilla et al., 2016, Cureus 1 accepted 1191 502 3153 4 55961059 55961059 G A ENST00000263923.4 75 GRCh37 Somatic 2016-04-08 02:05:50 UTC https://civicdb.org/links/evidence_items/1191 https://civicdb.org/links/variants/502 https://civicdb.org/links/genes/3153 false ALK 238 EML4::ALK e6-e20 Lung Non-small Cell Carcinoma 3908 2,4-pyrimidinediamine Predictive Supports D Sensitivity/Response In a cohort of 75 NSCLC patients that had tested positive for 3 EML4-ALK rearrangements, two individuals were identified via RT-PCR with a novel EML4-ALK translocation involving the first 6 exons of EML4 fused to the kinase domain of ALK. Genomic PCR resolved a single breakpoint, but 2 variants of the fusion were observed in cells. Variant 3a consisted of fusion at EML4 exon 6 and ALK exon 20, while variant 3b fused a 33 bp intronic EML4 region between EML4 exon 6 and ALK exon 20. 3a and 3b showed strong in-vitro kinase activity, transformed mouse 3T3 cells, and 3b-transformed 3T3 cells formed tumors in 8/8 nude mice. The ALK inhibitor 2,4-pyrimidinediamine inhibited growth of the 3a/b containing NCI-H2228 NSCLC cell line. The results indicate that 3a/b is a targetable driver-mutation as other EML4-ALK variants. 18593892 PubMed Choi et al., 2008, Cancer Res. 4 accepted 1192 503 1 2 42396490 42491871 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The EML4-ALK variant 3a consists of the ALK kinase domain fused to EML4 exons 1-6, while the 3b variant has an additional 33bp of intronic EML4 sequence between EML4 and ALK regions. The two variants were found to originate from a single genomic rearrangement, and 3a/3b is found in ~ 30% of EML4-ALK positive NSCLC. Variant 3a has cytoplasmic and nuclear distribution. In vitro, these variants have shown sensitivity to ALK inhibitors TAE684 and crizotinib but less sensitive than other EML4-ALK variants. The H2228 cell line contains 3a and 3b variants and is described as having cyctostatic response to ALK inhibition as opposed to apoptotic. In a study of 31 NSCLC patients with EML4-ALK rearrangements, 4/5 patients with the 3a variant showed a partial response while 1 showed progressive disease (the only PD observed). In cells the 3a variant was reported to be more stable than other variants, less sensitive to crizotinib and not to respond to Hsp90 inhibition. Somatic 2016-06-28 00:24:43 UTC https://civicdb.org/links/evidence_items/1192 https://civicdb.org/links/variants/503 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK e6-e20 Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Sensitivity/Response In a set of 31 patients with NSCLC, RT-PCR was performed to test for known EML4-ALK variants. Five patients tested positive for the 3a/3b EML4-ALK variant. Of these, 4 had partial response (PR), and one had disease progression (DP), and this was the only DP in the group of 31. In contrast, of the 13 testing positive for EML4-ALK variant 1, 12 showed PR, and 1 showed stable disease. These results potentially mirror findings in the H2228 3a/3b containing NSCLC cell line where some literature indicates it does respond as strongly to ALK inhibition as other EML4-ALK NSCLC cell lines. 20979469 PubMed Kwak et al., 2010, N. Engl. J. Med. NCT00585195 4 accepted 1193 503 1 2 42396490 42491871 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The EML4-ALK variant 3a consists of the ALK kinase domain fused to EML4 exons 1-6, while the 3b variant has an additional 33bp of intronic EML4 sequence between EML4 and ALK regions. The two variants were found to originate from a single genomic rearrangement, and 3a/3b is found in ~ 30% of EML4-ALK positive NSCLC. Variant 3a has cytoplasmic and nuclear distribution. In vitro, these variants have shown sensitivity to ALK inhibitors TAE684 and crizotinib but less sensitive than other EML4-ALK variants. The H2228 cell line contains 3a and 3b variants and is described as having cyctostatic response to ALK inhibition as opposed to apoptotic. In a study of 31 NSCLC patients with EML4-ALK rearrangements, 4/5 patients with the 3a variant showed a partial response while 1 showed progressive disease (the only PD observed). In cells the 3a variant was reported to be more stable than other variants, less sensitive to crizotinib and not to respond to Hsp90 inhibition. Somatic 2016-06-28 00:25:22 UTC https://civicdb.org/links/evidence_items/1193 https://civicdb.org/links/variants/503 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK e6-e20 Lung Non-small Cell Carcinoma 3908 TAE684 Predictive Supports D Sensitivity/Response In a panel of 602 cancer cell lines, 3/134 NSCLC cell lines showed <0.5% cell viability following treatment with the ALK inhibitor TAE684. Of these, NCI-H2228 harbored EML4-ALK variant 3a/b (EML4 exon 6 and ALK exon 20). TAE684 inhibited Akt and Erk1/2 phosphorylation in H2228 cells and appeared to induce a cytostatic response. 18451166 PubMed McDermott et al., 2008, Cancer Res. 2 accepted 1194 503 1 2 42396490 42491871 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The EML4-ALK variant 3a consists of the ALK kinase domain fused to EML4 exons 1-6, while the 3b variant has an additional 33bp of intronic EML4 sequence between EML4 and ALK regions. The two variants were found to originate from a single genomic rearrangement, and 3a/3b is found in ~ 30% of EML4-ALK positive NSCLC. Variant 3a has cytoplasmic and nuclear distribution. In vitro, these variants have shown sensitivity to ALK inhibitors TAE684 and crizotinib but less sensitive than other EML4-ALK variants. The H2228 cell line contains 3a and 3b variants and is described as having cyctostatic response to ALK inhibition as opposed to apoptotic. In a study of 31 NSCLC patients with EML4-ALK rearrangements, 4/5 patients with the 3a variant showed a partial response while 1 showed progressive disease (the only PD observed). In cells the 3a variant was reported to be more stable than other variants, less sensitive to crizotinib and not to respond to Hsp90 inhibition. Somatic 2016-06-23 22:54:40 UTC https://civicdb.org/links/evidence_items/1194 https://civicdb.org/links/variants/503 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK e6-e20 Lung Non-small Cell Carcinoma 3908 TAE684 Predictive Does Not Support D Sensitivity/Response Exon-array and RT-PCR was used to screen a panel of 83 NSCLC cell lines for EML4-ALK variants. The cell lines NCI-H3122 (containing EML4-ALK variant 1) and NCI-H2228 (containing the EML4 exon 6 and ALK exon 20 fusion-variant 3a/3b) were identified. TAE684 (0.1uM) appreciably inhibited growth as well as Akt and Erk1/2 phosphorylation in variant 1 containing H3122 cells. However, incomplete inhibition in 3a/3b containing H2228 cells was observed. H2228 growth inhibition by TAE684 was more similar to NSCLC cell lines harboring KRAS and EGFR mutations. 18594010 PubMed Koivunen et al., 2008, Clin. Cancer Res. 2 accepted 1195 503 1 2 42396490 42491871 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The EML4-ALK variant 3a consists of the ALK kinase domain fused to EML4 exons 1-6, while the 3b variant has an additional 33bp of intronic EML4 sequence between EML4 and ALK regions. The two variants were found to originate from a single genomic rearrangement, and 3a/3b is found in ~ 30% of EML4-ALK positive NSCLC. Variant 3a has cytoplasmic and nuclear distribution. In vitro, these variants have shown sensitivity to ALK inhibitors TAE684 and crizotinib but less sensitive than other EML4-ALK variants. The H2228 cell line contains 3a and 3b variants and is described as having cyctostatic response to ALK inhibition as opposed to apoptotic. In a study of 31 NSCLC patients with EML4-ALK rearrangements, 4/5 patients with the 3a variant showed a partial response while 1 showed progressive disease (the only PD observed). In cells the 3a variant was reported to be more stable than other variants, less sensitive to crizotinib and not to respond to Hsp90 inhibition. Somatic 2016-06-23 22:57:50 UTC https://civicdb.org/links/evidence_items/1195 https://civicdb.org/links/variants/503 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK e20-e20 Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports D Sensitivity/Response EML4-ALK variants v1 (E13;A20), v2 (E20;A20), v3a (E6;A20) and v3b (E6ins33;A20) were expressed in Ba/F3 cells using retrovirus. While all constructs rendered Ba/F3 cells IL3-independant, marked differences in sensitivity to ALK inhibitors TAE684 and crizotinib were observed, where v2 was most sensitized to growth inhibition and v3a the least, with v1 and v3b intermediate. While phospho-ALK western blots indicated that the ALK inhibitors acted similarly on both v2 and v3a EML4-ALK variants, blots of cyclohexamide-treated cells showed that v2 had a shorter half-life than 3a in the transduced cells, potentially explaining increased v2 sensitivity. Assays with a panel of mutated EML4-ALK variants of varied length suggested that longer EML4-ALK variants are less stable in cells, although this tendency was not observed across other types of ALK fusion. 22912387 PubMed Heuckmann et al., 2012, Clin. Cancer Res. 2 accepted 1196 500 1 2 42396490 42552694 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 EML4-ALK variant 2 consists of a fusion of the ALK kinase domain (exons 20-29) with EML4 exons 1-20. Variant 2 has cytoplasmic distribution and makes up ~10% of EML4-ALK fusions found in NSCLC,. Although the specific variant is not consistently reported, single cases demonstrating response to crizotinib treatment in NSCLC and a differentiated malignant neoplasm of unknown origin have been reported. In vitro, this variant has shown greater sensitivity to ALK inhibition with TAE684 and crizotinib than the EML4-ALK variants 1 (E13;A20), 3a (E6;A20) and 3b (E6ins33;A20). The variant was reported to be less stable in cells than other variants, and may be a client protein of Hsp90. Along these lines the variant has shown preclinical sensitivity to Hsp90 inhibition. Somatic 2016-05-23 15:21:17 UTC https://civicdb.org/links/evidence_items/1196 https://civicdb.org/links/variants/500 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK e6-e20 Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Does Not Support D Sensitivity/Response Ba/F3 cells transduced with EML4-ALK variants v1 (E13;A20), v2 (E20;A20), v3a (E6;A20) and v3b (E6ins33;A20) showed differential sensitivity to both crizotinib and TAE684, with variant 3a (E6;A20) being the least sensitive. The authors suggest that the type/structure of ALK fusion may have some impact on patient outcome in targeted therapy. 22912387 PubMed Heuckmann et al., 2012, Clin. Cancer Res. 2 accepted 1197 503 1 2 42396490 42491871 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The EML4-ALK variant 3a consists of the ALK kinase domain fused to EML4 exons 1-6, while the 3b variant has an additional 33bp of intronic EML4 sequence between EML4 and ALK regions. The two variants were found to originate from a single genomic rearrangement, and 3a/3b is found in ~ 30% of EML4-ALK positive NSCLC. Variant 3a has cytoplasmic and nuclear distribution. In vitro, these variants have shown sensitivity to ALK inhibitors TAE684 and crizotinib but less sensitive than other EML4-ALK variants. The H2228 cell line contains 3a and 3b variants and is described as having cyctostatic response to ALK inhibition as opposed to apoptotic. In a study of 31 NSCLC patients with EML4-ALK rearrangements, 4/5 patients with the 3a variant showed a partial response while 1 showed progressive disease (the only PD observed). In cells the 3a variant was reported to be more stable than other variants, less sensitive to crizotinib and not to respond to Hsp90 inhibition. Somatic 2016-06-23 23:12:10 UTC https://civicdb.org/links/evidence_items/1197 https://civicdb.org/links/variants/503 https://civicdb.org/links/genes/1 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports A Sensitivity/Response This two arm Phase III study named PROFILE 1007 (NCT00932893) was performed to assess crizotinib vs. established chemotherapy in non-small cell lung cancer patients positive for ALK rearrangement (assessed by break-apart FISH) with locally advanced or metastatic disease. 347 patients with disease progression after one round of platinum-based chemotherapy were randomized to receive crizotinib (N=173) or chemotherapy (N=174) consisting of pemetrexed in pemetrexed-naive patients and docetaxel for patients previously treated with pemetrexed. The primary endpoint - progression free survival (PFS) - was found to be significantly better for patients treated with crizotinib (median 7.7 months) than with chemotherapy (median 3.0 months) (hazard ratio for disease progression or death with crizotinib, 0.49; 95% CI, 0.37 to 0.64; P<0.001). Response rates were 65% for crizotinib treatment and 20% for chemotherapy (P<0.001). Improvements in quality of life were also reported. 23724913 PubMed Shaw et al., 2013, N. Engl. J. Med. NCT00932893 5 accepted 1198 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-06-22 19:04:42 UTC https://civicdb.org/links/evidence_items/1198 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports A Sensitivity/Response This phase 3 trial named PROFILE 1014 (NCT01154140) compared crizotinib to established chemotherapy in first-line treatment for this disease. The study consisted of 343 patients with advanced or metastatic NSCLC that tested positive for ALK rearrangement via break-apart FISH assay, and had no prior systemic treatment. Patients were assigned in a 1:1 ratio to crizotinib (N=172) or pemetrexed with cisplatin or carboplatin (N=171). Progression free survival was significantly longer with crizotinib treatment than chemotherapy (10.9 vs. 7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% CI, 0.35 to 0.60;P<0.001), and objective response rate was higher with crizotinib treatment than chemotherapy (75% vs. 45%, P<0.001). Improvement in quality of life was also reported. 25470694 PubMed Solomon et al., 2014, N. Engl. J. Med. NCT01154140 5 accepted 1199 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-06-22 19:09:07 UTC https://civicdb.org/links/evidence_items/1199 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports B Sensitivity/Response This retrospective study of patients from the PROFILE 1001 and 1005 studies of crizotinib in advanced ALK-rearranged NSCLC assessed the potential benefit of crizotinib beyond progressive disease (CBPD), defined as continuation of crizotinib for 3 or more weeks after disease progression on crizotinib. 194 patients who had developed PD by data cutoff were studied, where 120 received crizotinib for a median duration of 19.4 weeks and 74 discontinued crizotinib after PD. No gross imbalances in clinicopathologic features of the two groups were evident. Significantly longer overall survival was observed in the crizotinib continuing group from time of PD (16.4 vs. 3.9 months; hazard ratio 0.27, 95% CI: 0.17–0.42; P < 0.0001), and from the time of initial crizotinib (29.6 vs. 10.8 months; HR 0.30, 95% CI: 0.19–0.46; P < 0.0001). 24478318 PubMed Ou et al., 2014, Ann. Oncol. 4 accepted 1200 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-08-15 19:55:59 UTC https://civicdb.org/links/evidence_items/1200 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Brain neoplasm Crizotinib Predictive Supports B Sensitivity/Response This prospective Phase III study named Profile 1014 on NSCLC ALK-rearranged patients assessed intracranial disease control rate (IC-DCR) in the subset of patients entering the study with preexisting treated brain metastasis (tBM). IC-DCR was significantly improved in the tBM group given crizotinib (N=39) over chemotherapy (pemetrexed + cisplatin or carboplatin; N=40) at 12 weeks (85% vs. 45%, P<0.001), and at 24 weeks (56% vs. 25%, P=0.006). Progression free survival was also significantly improved with crizotinib over chemotherapy in the tBM subgroup (9.0 vs. 4.0 months; HR 0.40; P<0.001), where in the intent to treat population it was 10.9 vs. 7.0 months (HR 0.45; P<0.001), indicating that the difficult to treat BM population obtained benefit from crizotinib at both the brain and systemic level. 27022118 PubMed Solomon et al., 2016, J. Clin. Oncol. NCT01154140 4 accepted 1201 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-08-15 19:57:14 UTC https://civicdb.org/links/evidence_items/1201 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Retaspimycin Hydrochloride Predictive Supports C Sensitivity/Response In this study, heavily pretreated advanced NSCLC patients with various molecular tumor makeup were treated with Hsp90 inhibitor IPI-504 to assess overall response rate. The study did not reach the targeted endpoint of 20% ORR. However, of 3/12 patients found to be ALK-rearranged via break apart FISH assay, 2 showed a partial response and the third stable disease, which was durable for 7.2 months. The authors note that the break apart FISH assay used to determine ALK-rearrangement status does not determine the identity of the ALK fusion partner and the promising results shown here may be dependent on the nature of the ALK fusion partner. 20940188 PubMed Sequist et al., 2010, J. Clin. Oncol. 2 accepted 1202 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-11-04 16:51:07 UTC https://civicdb.org/links/evidence_items/1202 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK Lung Non-small Cell Carcinoma 3908 Retaspimycin Hydrochloride,Crizotinib Combination Predictive Supports D Sensitivity/Response In preclinical work using H3122 NSCLC cells which contain the EML4-ALK variant 1, administration of the Hsp90 inhibitor IPI-504 caused marked decrease of EML4-ALK protein levels at concentrations lower than those used to knock down protein levels of drivers such as HER2 or EGFR in other cell lines, making it the most sensitive Hsp90 client protein the authors had encountered. IPI-504 treatment caused regression of H3122 tumors in nude mice, whereas Hsp90 inhibitors usually only cause growth inhibition in these models. Combined treatment of these mice with IPI-504 and crizotinib caused an even stronger tumor regression. 21258415 PubMed Normant et al., 2011, Oncogene 4 accepted 1203 5 1 2 42396490 42522656 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The EML4-ALK fusion variant 1 consisting of ALK kinase domain (exons 20-29) fused to EML4 exons 1-13 is the most common EML4-ALK variant, and was discovered in non-small cell lung cancer. Multiple EML4 breakpoint shave been described with differential sensitivity to inhibitors with variant 1 showing greater sensitivity than 3a in cell lines. EML4-ALK is crizotinib sensitive; however, several mutations that confer resistance mutations have been described in case studies. In the only clinical trial for crizotinib that included determination of EML4-ALK variant type in a subset of its participants, a very high response rate was observed, although the numbers were insufficient to validate correlation of variant type to outcome. Preclinical studies with this variant have indicated sensitivity to Hsp90 inhibitors. Somatic 2016-06-27 21:07:36 UTC https://civicdb.org/links/evidence_items/1203 https://civicdb.org/links/variants/5 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK e20-e20 Lung Non-small Cell Carcinoma 3908 Crizotinib,Alvespimycin Combination Predictive Supports D Sensitivity/Response EML4-ALK fusions occur in 2-7% of lung adenocarcinomas. Transduction of Ba/F3 cells with EML4-ALK variant 2 (EML4 exon 20 fused to ALK exon 20) caused the cells to grow independently of IL3 addition. EML4-ALK may be a client protein of Hsp90. Addition of Hsp90 inhibitor 17-DMAG to the EML4-ALK variant 2 cells induced cell death which was rescued at lower 17-DMAG concentrations by IL3 addition. This result suggests that 17-DMAG specifically targeted the EML4-ALK driver in these cells. Finally, 17-DMAG and crizotinib showed a synergistic effect in killing EML4-ALK variant 2 cells. 22912387 PubMed Heuckmann et al., 2012, Clin. Cancer Res. 2 accepted 1204 500 1 2 42396490 42552694 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 EML4-ALK variant 2 consists of a fusion of the ALK kinase domain (exons 20-29) with EML4 exons 1-20. Variant 2 has cytoplasmic distribution and makes up ~10% of EML4-ALK fusions found in NSCLC,. Although the specific variant is not consistently reported, single cases demonstrating response to crizotinib treatment in NSCLC and a differentiated malignant neoplasm of unknown origin have been reported. In vitro, this variant has shown greater sensitivity to ALK inhibition with TAE684 and crizotinib than the EML4-ALK variants 1 (E13;A20), 3a (E6;A20) and 3b (E6ins33;A20). The variant was reported to be less stable in cells than other variants, and may be a client protein of Hsp90. Along these lines the variant has shown preclinical sensitivity to Hsp90 inhibition. Somatic 2016-05-23 15:16:06 UTC https://civicdb.org/links/evidence_items/1204 https://civicdb.org/links/variants/500 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK e6-e20 Lung Non-small Cell Carcinoma 3908 Alvespimycin Predictive Does Not Support D Sensitivity/Response Transduction of Ba/F3 cells with EML4-ALK variant 3a caused the cells to grow independently of IL3 addition. While incubation of Ba/F3 cells transduced with EML4-ALK variants 1 and 2 with Hsp90 inhibitor 17-DMAG caused cell death that was reversible with IL3 addition, Ba/F3 cells with variant 3a were not sensitized to 17-DMAG induced death, suggesting that 17-DMAG was effecting the EML4-ALK driver of IL3-independant proliferation. This in turn suggests that variant 3a may not rely on Hsp90 for stability in cancer cells to the extent of other variants. 22912387 PubMed Heuckmann et al., 2012, Clin. Cancer Res. 2 accepted 1205 503 1 2 42396490 42491871 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The EML4-ALK variant 3a consists of the ALK kinase domain fused to EML4 exons 1-6, while the 3b variant has an additional 33bp of intronic EML4 sequence between EML4 and ALK regions. The two variants were found to originate from a single genomic rearrangement, and 3a/3b is found in ~ 30% of EML4-ALK positive NSCLC. Variant 3a has cytoplasmic and nuclear distribution. In vitro, these variants have shown sensitivity to ALK inhibitors TAE684 and crizotinib but less sensitive than other EML4-ALK variants. The H2228 cell line contains 3a and 3b variants and is described as having cyctostatic response to ALK inhibition as opposed to apoptotic. In a study of 31 NSCLC patients with EML4-ALK rearrangements, 4/5 patients with the 3a variant showed a partial response while 1 showed progressive disease (the only PD observed). In cells the 3a variant was reported to be more stable than other variants, less sensitive to crizotinib and not to respond to Hsp90 inhibition. Somatic 2016-07-02 15:41:21 UTC https://civicdb.org/links/evidence_items/1205 https://civicdb.org/links/variants/503 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK Lung Non-small Cell Carcinoma 3908 Crizotinib,Alvespimycin Combination Predictive Supports D Sensitivity/Response Transduction of Ba/F3 cells with EML4-ALK variant 1 causes IL3 independent growth. Incubation of EML4-ALK variant 1 transduced Ba/F3 cells with Hsp90 inhibitor 17-DMAG caused cell death that was reversible with IL3 addition, suggesting that 17-DMAG was effecting the EML4-ALK driver of IL3-independant proliferation, and that EML4-ALK variant 1 is a client protein of Hsp90. The degree of Hsp90 dependence, and targetability of EML4-ALK for Hsp90 inhibition, may vary among ALK fusion variants. Addition of crizotinib to 17-DMAG caused synergistic death effects, suggesting potential clinical benefit for this inhibitor combination in targeting EML4-ALK variant 1. 22912387 PubMed Heuckmann et al., 2012, Clin. Cancer Res. 2 accepted 1206 5 1 2 42396490 42522656 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The EML4-ALK fusion variant 1 consisting of ALK kinase domain (exons 20-29) fused to EML4 exons 1-13 is the most common EML4-ALK variant, and was discovered in non-small cell lung cancer. Multiple EML4 breakpoint shave been described with differential sensitivity to inhibitors with variant 1 showing greater sensitivity than 3a in cell lines. EML4-ALK is crizotinib sensitive; however, several mutations that confer resistance mutations have been described in case studies. In the only clinical trial for crizotinib that included determination of EML4-ALK variant type in a subset of its participants, a very high response rate was observed, although the numbers were insufficient to validate correlation of variant type to outcome. Preclinical studies with this variant have indicated sensitivity to Hsp90 inhibitors. Somatic 2016-07-01 16:15:13 UTC https://civicdb.org/links/evidence_items/1206 https://civicdb.org/links/variants/5 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Sensitivity/Response In the PROFILE 1001 study of crizotinib in 82 patients with ALK-rearranged NSCLC, 31 patients with sufficient tumor material were tested using RT-PCR for the presence of certain EML4-ALK variants. 13/31 tested patients had the EML4-ALK variant 1. Of these, 12/13 had a partial response, and 1 had stable disease. This response rate of 92% is in contrast to the 57% response rate in the overall patient population, but the numbers of patients with specific EML4-ALK breakpoints were insufficient to correlate with patient response rate. 20979469 PubMed Kwak et al., 2010, N. Engl. J. Med. NCT00585195 4 accepted 1207 5 1 2 42396490 42522656 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The EML4-ALK fusion variant 1 consisting of ALK kinase domain (exons 20-29) fused to EML4 exons 1-13 is the most common EML4-ALK variant, and was discovered in non-small cell lung cancer. Multiple EML4 breakpoint shave been described with differential sensitivity to inhibitors with variant 1 showing greater sensitivity than 3a in cell lines. EML4-ALK is crizotinib sensitive; however, several mutations that confer resistance mutations have been described in case studies. In the only clinical trial for crizotinib that included determination of EML4-ALK variant type in a subset of its participants, a very high response rate was observed, although the numbers were insufficient to validate correlation of variant type to outcome. Preclinical studies with this variant have indicated sensitivity to Hsp90 inhibitors. Somatic 2016-04-04 22:55:00 UTC https://civicdb.org/links/evidence_items/1207 https://civicdb.org/links/variants/5 https://civicdb.org/links/genes/1 false KRAS 3845 Exon 2 Mutation Colorectal Cancer 9256 Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Predictive Supports B Resistance 102 mCRC patients treated with anti-EGFR therapy were analyzed for 34 hotspot mutations in KRAS, NRAS and BRAF with nanofluidic digital PCR and quantitative PCR. dPCR and qPCR results were correlated to PFS and OS. Analysis of only KRAS exon 2 hotspot mutations showed that patients with more than 1% mutant allele fraction (n = 19/83) had a hazard ratio of 3.43 for PFS (95% CI, 1.67–7.02; P=0.002) and 2.72 for OS (95% CI, 1.52–4.88; P=0.002) compared to wild-type patients or patients with less than 1% mutant allele fraction. Considering all RAS and BRAF mutations, the patients with more than 1% mutant allele fraction (n = 37/65) had a hazard ratio of 4.52 for PFS (95% CI, 2.25–9.07; P<0.001) and 2.5 for OS (95% CI, 1.57–4.02; P<0.001). ROC analysis showed that a cut-off of 1% for any mutated allele offered the best predictive value. 27037411 PubMed Azuara et al., 2016, Mol. Cancer Ther. 3 accepted 1208 75 30 12 25398208 25398329 ENST00000256078.4 75 GRCh37 Exon 2 mutations have been associated with reduced response rates or resistance to EGFR inhibitors in non-small cell lung and colorectal cancer. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. Somatic 2016-10-10 22:54:31 UTC https://civicdb.org/links/evidence_items/1208 https://civicdb.org/links/variants/75 https://civicdb.org/links/genes/30 false TP53 7157 P47S Cancer 162 Cisplatin Predictive Supports E Resistance The P47S (rs1800371) variant of TP53 is observed in 1.5% in African Americans and between 6% and 8% in certain African populations but has not been detected in Caucasian Americans. This paper reports functional studies of this variant. Mouse models with this variant show an increase in spontaneous tumor formation. 16 out of 20 (80%) of S47 homozygous mice developed cancer between 12 and 18 months of age. Cancers predominantly included hepatocellular carcinoma, B-cell lymphoma, and histiocytic sarcoma, as well as other tumor types. In S47/wild-type heterozygote mice an increased cancer incidence, with a predisposition for hepatocellular carcinoma, was also found. Mouse embryonic fibroblasts and human lymphoblastoid cell lines with S47 mutations were significantly less sensitive to cisplatinum treatment compared to TP53 wild-type cells (apoptosis and viability). 27034505 PubMed Jennis et al., 2016, Genes Dev. 2 accepted 1209 504 45 17 7579548 7579548 G A ENST00000269305.4 75 GRCh37 Common Germline 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1209 https://civicdb.org/links/variants/504 https://civicdb.org/links/genes/45 false GNAQ 2776 Mutation Uveal Melanoma 6039 JQ1 Predictive Supports D Sensitivity/Response Preclinical study in uveal melanoma cell lines. Cell lines (n=4) with GNAQ mutation (92.1, Omm1.3, Mel270, Mel202) were more sensitive to BRD4 inhibition with JQ1 than GNAQ/GNA11 wild type (n=3) cell line. JQ1 also inhibited growth of a GNAQ mutant cell line (92.1) in a mouse xenograft model compared to vehicle (N=5 mice/group). 26397223 PubMed Ambrosini et al., 2015, Oncotarget 2 accepted 1210 505 2317 9 80331003 80646374 ENST00000286548.4 75 GRCh37 Somatic 2016-06-28 00:23:22 UTC https://civicdb.org/links/evidence_items/1210 https://civicdb.org/links/variants/505 https://civicdb.org/links/genes/2317 false GNA11 2767 Mutation Uveal Melanoma 6039 JQ1 Predictive Supports D Sensitivity/Response Preclinical study in uveal melanoma cell lines. Cell lines (n=5) with GNAQ (92.1, Omm1.3, Mel270, Mel202) or GNA11 (Omm1) mutation were more sensitive to BRD4 inhibition with JQ1 than GNAQ/11 wild type (n=3) cell line. 26397223 PubMed Ambrosini et al., 2015, Oncotarget 1 accepted 1211 506 2308 19 3094408 3124002 ENST00000078429.4 75 GRCh37 Somatic 2016-06-28 00:19:50 UTC https://civicdb.org/links/evidence_items/1211 https://civicdb.org/links/variants/506 https://civicdb.org/links/genes/2308 false GNA11 2767 Q209 Uveal Melanoma 6039 Selumetinib Predictive Does Not Support B Sensitivity/Response 101 patients with metastatic uveal melanoma were randomized 1:1 to receive selumetinib or chemotherapy. Median PFS among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) vs. 15.9 weeks with selumetinib (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < 0.001). Most patients (80/96 evaluable harbored a mutation in exon 5 of GNAQ or GNA11) but PFS benefit from Selumetinib compared to chemotherapy was greater in the GNAQ and GNA11 wild-type population (25.9 weeks [range, 3.7-40.4 weeks] vs 15.4 weeks [range, 8.1-16.9 weeks]). However, PFS was still better with Selumetinib than chemotherapy in the GNA mutant population (hazard ratio 0.55, 95% CI, 0.34-0.87; P = 0.01). The difference was explained by potential GNAQ or GNA11 mutations outside of exon 5 in the GNA wild-type population. Another three mutations in exon 4 were retrospectively identified in the wild-type population and one had a major response. 24938562 PubMed Carvajal et al., 2014, JAMA NCT01143402 3 accepted 1212 558 2308 19 3118942 3118942 ENST00000078429.4 75 GRCh37 Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1212 https://civicdb.org/links/variants/558 https://civicdb.org/links/genes/2308 false GNAQ 2776 Q209 Uveal Melanoma 6039 Selumetinib Predictive Does Not Support B Sensitivity/Response 101 patients with metastatic uveal melanoma were randomized 1:1 to receive selumetinib or chemotherapy. Median PFS among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) vs. 15.9 weeks with selumetinib (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < 0.001). Most patients (80/96 evaluable harbored a mutation in exon 5 of GNAQ or GNA11) but PFS benefit from Selumetinib compared to chemotherapy was greater in the GNAQ and GNA11 wild-type population (25.9 weeks [range, 3.7-40.4 weeks] vs 15.4 weeks [range, 8.1-16.9 weeks]). However, PFS was still better with Selumetinib than chemotherapy in the GNA mutant population (hazard ratio 0.55, 95% CI, 0.34-0.87; P = 0.01). The difference was explained by potential GNAQ or GNA11 mutations outside of exon 5 in the GNA wild-type population. Another three mutations in exon 4 were retrospectively identified in the wild-type population and one had a major response. 24938562 PubMed Carvajal et al., 2014, JAMA NCT01143402 3 accepted 1213 507 2317 9 80409487 80409489 ENST00000286548.4 75 GRCh37 Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1213 https://civicdb.org/links/variants/507 https://civicdb.org/links/genes/2317 false PMS2 5395 K706FS*19 Glioblastoma 3068 Nivolumab Predictive Supports C Sensitivity/Response Two siblings (6 and 3.5 years) from nonconsanguineous parents were diagnosed with glioblastoma multiforme. Both tumors harbored TP53 mutations and lack of MGMT promoter hypermethylation as poor prognostic markers. Germline homozygous c.2117delA, p. Lys706SerfsX19 mutation in PMS2, loss of PMS2 staining in the tumor and normal tissue confirmed a diagnosis of biallelic mismatch repair deficiency (bMMRD). Both tumors harbored driver mutations in POLE and were found to harbor 24,680 and 21,919 mutations per exome. Neoantigen load was assessed in 37 bMMRD patients and all malignant tumors had high numbers of predicted neoantigens (7-16x as high as in melanoma, lung or other immunoresponsive cancers). Treatment with nivolumab was begun and both patients had radiologic response. After 9 and 5 months of therapy, respectively, the patient and her brother resumed normal schooling and daily activities. 27001570 PubMed Bouffet et al., 2016, J. Clin. Oncol. 4 accepted 1214 508 4371 7 6022512 6022512 ENST00000265849.7 75 GRCh37 Rare Germline 2016-06-17 05:18:01 UTC https://civicdb.org/links/evidence_items/1214 https://civicdb.org/links/variants/508 https://civicdb.org/links/genes/4371 false KRAS 3845 G12D Colorectal Cancer 9256 Prognostic Supports B Better Outcome In 119 metastatic colorectal cancer patients treated with cetuximab-based first-line chemotherapy, KRAS G12D mutations (N=44) were associated with longer overall patient survival when compared to other KRAS G12 mutations (23.3 vs 14-18 months; G12V, A, C, S, R). 22948721 PubMed Modest et al., 2012, Oncology 3 accepted 1215 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2021-03-10 04:45:05 UTC https://civicdb.org/links/evidence_items/1215 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false KRAS 3845 G12C Colorectal Cancer 9256 Erlotinib,Gefitinib Substitutes Predictive Supports B Resistance In a study of 448 metastatic colorectal cancer patients treated with EGFR-TKIs and tested for EGFR and KRAS mutations, 69 tested positive for KRAS mutations. In 38 EGFR wildtype patients treated with erlotinib or gefitinib, those with KRAS G12C mutations (n=24) had shorter progression free survival rates compared to patients with non-G12C KRAS mutations (n=14; 4.3 vs 9 weeks; P = 0.009; HR=2.7). This was true when restricted to patients with an adenocarcinoma subtype only (n=18 vs 12; 4.1 vs 9 weeks; P = 0.007; HR=3.1). Overall survival was not different between groups. 23313110 PubMed Fiala et al., Cancer Genet 3 accepted 1216 78 30 12 25398285 25398285 C A ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2016-10-10 22:52:55 UTC https://civicdb.org/links/evidence_items/1216 https://civicdb.org/links/variants/78 https://civicdb.org/links/genes/30 false KRAS 3845 G12C Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome In a study of 48 NSCLC patients, those with G12C or G12V mutant KRAS were associated with decreased progression free survival (1.84 months) compared with other KRAS mutants or with wild-type KRAS (3.35 and 1.95 months). 22247021 PubMed Ihle et al., 2012, J. Natl. Cancer Inst. 3 accepted 1217 78 30 12 25398285 25398285 C A ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2016-04-06 16:52:40 UTC https://civicdb.org/links/evidence_items/1217 https://civicdb.org/links/variants/78 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Lung Adenocarcinoma 3910 Salirasib Predictive Does Not Support B Sensitivity/Response In a study of 30 lung adenocarcinoma patients with documented KRAS mutations, farnesylthiosalicylic acid (Salirasib) mono-therapy resulted in no partial responses and did not improve overall survival rates compared to previously untreated patients. 21847063 PubMed Riely et al., 2011, J Thorac Oncol 3 accepted 1218 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1218 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Exon 2 Mutation Pancreatic Cancer 1793 Erlotinib,Gemcitabine Combination Predictive Supports B Resistance In a retrospective study of 136 pancreatic cancer patients, point mutations in KRAS exon 2 were associated with worse overall survival compared to that of wild-type KRAS (5.8 vs 8.0 months; P = 0.001; multivariate analysis). This difference was largely driven by the subgroup of patients with reduced response to gemcitabine-erlotinib combination therapy (7.5% vs 23.3%) with overall survival of 5.2 vs 9.7 months (N=40 vs 30) compared to those that received other therapies with an overall survival of 7.0 months for both KRAS mutated (N=31) and KRAS wildtype (N=35) patients. 21862683 PubMed Kim et al., 2011, Mol. Cancer Ther. 4 accepted 1219 75 30 12 25398208 25398329 ENST00000256078.4 75 GRCh37 Exon 2 mutations have been associated with reduced response rates or resistance to EGFR inhibitors in non-small cell lung and colorectal cancer. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. Somatic 2016-08-15 19:58:46 UTC https://civicdb.org/links/evidence_items/1219 https://civicdb.org/links/variants/75 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Trametinib Predictive Supports B Sensitivity/Response In a phase 1 clinical trial for the use of trametinib for various advanced solid tumors, 22 out of 30 NSCLC patients harbored KRAS mutations. Of those 22 patients with mutant KRAS, 8 saw reductions in tumor size ranging from 6-52% including 2 partial responses. 22805291 PubMed Infante et al., 2012, Lancet Oncol. NCT00687622 2 accepted 1220 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-07-14 22:32:55 UTC https://civicdb.org/links/evidence_items/1220 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KIT 3815 Exon 9 Mutation Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports B Sensitivity/Response In a phase III clinical trial comparing different doses of imatinib in GIST patients, KIT exon 9 mutations were associated with significantly improved progression free survival (P=0.0013) and a 61% relative risk reduction in response to the higher dose regimen (N=31; 800mg/daily) when compared to the lower dose regimen (N=27; 400 mg/daily; HR 0.329; 95% CI 0.218–0.706). The same dose dependent responses were not observed with KIT exon 11 mutations (N=130 vs 118; P=0.25; HR 0.821; 95% CI 0.585–1.151) or with wild-type KIT (N=25 vs 27; P=0.07; HR 1.823; 95% CI 0.938–3.543). 16624552 PubMed Debiec-Rychter et al., 2006, Eur. J. Cancer 4 accepted 1221 509 29 4 55592023 55592216 ENST00000288135.5 75 GRCh37 In patients with gastrointestinal stromal tumors (GIST), imatinib has improved outcomes for patients with KIT mutations. However, acquired resistance to imatinib is common. Patients harboring exon 9 KIT mutations may benefit from higher imatinib doses (800mg/daily). Similarly, imatinib-refractory tumors showed sensitivity to sunitinib treatment. Improved responses to either treatment were not observed in patients with exon 11 mutations. Somatic 2016-06-28 00:14:29 UTC https://civicdb.org/links/evidence_items/1221 https://civicdb.org/links/variants/509 https://civicdb.org/links/genes/29 false KIT 3815 Mutation Melanoma 1909 Imatinib Predictive Supports B Sensitivity/Response In a phase II clinical trial of 43 melanoma patients harboring KIT mutations or amplifications, imatinib treatment exhibited significant anti-tumor activity with a median progression free survival of 3.5 months, tumor regression in 41.9% of patients, and a 1-year overall survival rate of 51%. 9/10 partial responses were in patients with exon 11 or 13 KIT mutations. 21690468 PubMed Guo et al., 2011, J. Clin. Oncol. 3 accepted 1222 388 29 4 55524085 55606881 ENST00000288135.5 75 GRCh37 Somatic 2016-06-28 00:07:02 UTC https://civicdb.org/links/evidence_items/1222 https://civicdb.org/links/variants/388 https://civicdb.org/links/genes/29 false KIT 3815 Exon 9 Mutation Gastrointestinal Stromal Tumor 9253 Sunitinib Predictive Supports B Sensitivity/Response Primary tumor genotyping of 89 patients with metastatic GIST given 2nd-line sunitinib treatment after prior imatinib therapy failure, revealed an improved response to sunitinib in patients with KIT exon 9 mutations or with wild-type KIT compared those with KIT exon 11 or PDGFRA mutations. 1-year progression free survival rates for exon 9 mutants and wild type were 68% and 57%, compared with 34% and 15% for exon 11 and PDGFRA mutants. 22439647 PubMed Rutkowski et al., 2012, BMC Cancer 3 accepted 1223 509 29 4 55592023 55592216 ENST00000288135.5 75 GRCh37 In patients with gastrointestinal stromal tumors (GIST), imatinib has improved outcomes for patients with KIT mutations. However, acquired resistance to imatinib is common. Patients harboring exon 9 KIT mutations may benefit from higher imatinib doses (800mg/daily). Similarly, imatinib-refractory tumors showed sensitivity to sunitinib treatment. Improved responses to either treatment were not observed in patients with exon 11 mutations. Somatic 2016-06-17 05:28:20 UTC https://civicdb.org/links/evidence_items/1223 https://civicdb.org/links/variants/509 https://civicdb.org/links/genes/29 false KIT 3815 Exon 11 Mutation Melanoma 1909 Sunitinib Predictive Supports C Sensitivity/Response 10 melanoma patients were evaluated after sunitinib treatment, among which 3 out of the 4 patients with KIT exon 11 mutations showed either complete or partial response. 22261812 PubMed Minor et al., 2012, Clin. Cancer Res. 3 accepted 1224 66 29 4 55593582 55593708 ENST00000288135.5 75 GRCh37 c-KIT mutations in exon 11 lie within the juxtamembrane domain, and are very recurrent in gastrointestinal stromal tumors, often bearing a poorer prognosis than other KIT mutations. Cells harboring exon 11 mutations have shown sensitivity to the tyrosine kinase inhibitor imatinib, offering a better prognosis to patients treated with the drug in the first year. Small cohorts of melanoma patients harboring exon 11 KIT mutations have shown response to imatinib and sunitinib. Somatic 2016-06-28 00:08:52 UTC https://civicdb.org/links/evidence_items/1224 https://civicdb.org/links/variants/66 https://civicdb.org/links/genes/29 false NRAS 4893 Mutation Skin Melanoma 8923 Trametinib,Docetaxel Combination Predictive Supports B Sensitivity/Response Phase 1 trial of trametinib and docetaxel in patients with advanced melanoma lacking BRAF V600 mutations. 15 patients were enrolled (14 BRAF wt). Six patients had a partial response, including four out of eight patients with NRAS mutations. 25542057 PubMed Coupe et al., 2015, Eur. J. Cancer 2 accepted 1225 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2016-06-20 04:13:11 UTC https://civicdb.org/links/evidence_items/1225 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false NRAS 4893 Q61 Skin Melanoma 8923 Binimetinib Predictive Supports B Sensitivity/Response Phase 2 study of MEK162 in patients with advanced melanoma and NRAS or BRAF mutation. 71 patients were enrolled, 6/30 patients with NRAS mutation had a partial response (Gln61Leu 1 Patient, Gln61Lys 9 Patients, Gln61Arg 15 Patients). Another 13 patients had stable disease (63% disease control rate). 23414587 PubMed Ascierto et al., 2013, Lancet Oncol. NCT01320085 2 accepted 1226 94 36 1 115256528 115256530 ENST00000369535.4 75 GRCh37 NRAS Q61 mutations have been found in multiple myeloma, gastrointestinal stromal tumors, melanoma, and others. Two melanoma patients, each harboring mutations at this locus (Q61L and Q61R), responded to treatment with the akylating agent temozolomide. However, in colorectal cancer patients, mutations at this locus have been shown to confer resistance to cetuximab. The prognostic impact of mutations at this locus is currently under study. Somatic 2016-06-21 18:50:15 UTC https://civicdb.org/links/evidence_items/1226 https://civicdb.org/links/variants/94 https://civicdb.org/links/genes/36 false NRAS 4893 Mutation Melanoma 1909 Trametinib Predictive Does Not Support B Sensitivity/Response Phase 1 trial in 97 patients with melanoma (81 cutaneous or unknown, 16 uveal). Seven patients were found to harbor an NRAS mutation and two of them experienced stable disease (one 48 weeks on treatment). Patients with concurrent BRAFV600wt/NRASwt (n=20) had a trend of higher response rates (20%) than BRAFV600wt/NRAS-mutant patients (n=11; RR=0%; p=0.27), as well as a trend of higher percentage of patients on study at Week 24 or at 1 year (40% vs. 18% [p=0.26] and 30% vs. 0% [p=0.07], respectively). 22805292 PubMed Falchook et al., 2012, Lancet Oncol. NCT00687622 2 accepted 1227 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2016-06-28 00:06:28 UTC https://civicdb.org/links/evidence_items/1227 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false GNA11 2767 Mutation Uveal Melanoma 6039 Trametinib Predictive Supports C Sensitivity/Response Phase 1 study of trametinib in 97 patients with melanoma (16 with uveal melanoma). Analysis in patients with uveal melanoma identified GNAQ and GNA11 mutations in six patients, in which three SD and three PD were the best responses. One patient with a GNA11 mutation identified by Illumina genotyping stayed on study treatment for >40 weeks. 22805292 PubMed Falchook et al., 2012, Lancet Oncol. NCT00687622 2 accepted 1228 506 2308 19 3094408 3124002 ENST00000078429.4 75 GRCh37 Somatic 2016-06-28 00:17:17 UTC https://civicdb.org/links/evidence_items/1228 https://civicdb.org/links/variants/506 https://civicdb.org/links/genes/2308 false GNAQ 2776 Mutation Uveal Melanoma 6039 Trametinib Predictive Supports B Sensitivity/Response Phase 1 study of trametinib in 97 patients with melanoma (16 with uveal melanoma). Analysis in patients with uveal melanoma identified GNAQ and GNA11 mutations in six patients, in which three SD and three PD were the best responses. One patient with a GNA11 mutation identified by Illumina genotyping stayed on study treatment for >40 weeks. 22805292 PubMed Falchook et al., 2012, Lancet Oncol. NCT00687622 2 accepted 1229 505 2317 9 80331003 80646374 ENST00000286548.4 75 GRCh37 Somatic 2016-06-15 03:05:54 UTC https://civicdb.org/links/evidence_items/1229 https://civicdb.org/links/variants/505 https://civicdb.org/links/genes/2317 false NRAS 4893 Mutation Cancer 162 Metformin,Trametinib Combination Predictive Supports D Sensitivity/Response Preclinical study in 16 NRAS mutant cell lines (melanoma, lung carcinoma, neuroblastoma with various Q61, G13, G12 mutations). The combination of metformin and trametinib shown synergistic effects in most tested cell lines (no antagonistic effects observed) and a melanoma xenograft model. Metformin-induced PI3K pathway suppression was identified as a potential mechanism. 25504439 PubMed Vujic et al., 2015, Oncotarget 3 accepted 1230 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2016-06-20 04:26:21 UTC https://civicdb.org/links/evidence_items/1230 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false PTEN 5728 Deletion Prostate Cancer 10283 Everolimus Predictive Supports B Sensitivity/Response In a phase II trial on castration-resistant prostate cancer patients, FISH detection of PTEN deletion was associated with increased progression free survival (p=0.07) and with improved PSA response (p=0.02) in response to everolimus, an mTOR pathway inhibitor. 23582881 PubMed Templeton et al., 2013, Eur. Urol. NCT00976755 3 accepted 1231 213 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-06-21 18:30:14 UTC https://civicdb.org/links/evidence_items/1231 https://civicdb.org/links/variants/213 https://civicdb.org/links/genes/41 false PTEN 5728 Mutation Endometrial Carcinoma 2871 Everolimus Predictive Does Not Support B Sensitivity/Response Tumors from 35 patients (12 with partial response or stable disease) with advanced endometrial carcinoma were assessed for PTEN mutational status, revealing 12 tumors with non-identical PTEN gene mutations. No mutations found in PTEN were effective in predicting tumor response to everolimus treatment. The clinical trial associated with this study is NCT00870337. 23238879 PubMed Trédan et al., 2013, Target Oncol NCT00870337 3 accepted 1232 510 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-04-08 02:47:02 UTC https://civicdb.org/links/evidence_items/1232 https://civicdb.org/links/variants/510 https://civicdb.org/links/genes/41 false GNAQ 2776 Q209 Uveal Melanoma 6039 Refametinib Predictive Supports C Sensitivity/Response Phase 1 study of MAPK1/2 inhibitor BAY 86-9766. 53 patients were evaluated for efficacy, one patients achieved a PR and 11 patients had stable disease. One ocular melanoma patient with prolonged stable disease, who later went on to complete 28 courses, was positive for GNAQ Q209L and PTEN R173S mutations. The PTEN mutation was identified only in the postdose biopsy and not in the predose biopsy. 23434733 PubMed Weekes et al., 2013, Clin. Cancer Res. 2 accepted 1233 507 2317 9 80409487 80409489 ENST00000286548.4 75 GRCh37 Somatic 2016-04-08 02:12:44 UTC https://civicdb.org/links/evidence_items/1233 https://civicdb.org/links/variants/507 https://civicdb.org/links/genes/2317 false BAP1 8314 Mutation Uveal Melanoma 6039 Valproic Acid,Trichostatin A,Vorinostat,Panobinostat Substitutes Predictive Supports D Sensitivity/Response Somatic and germline BAP1 mutations are associated with uveal melanoma. In this preclinical study, gene set enrichment analysis revealed HDAC inhibitors as potential drugs in BAP1 mutant uveal melanomas. HDAC inhibitors VPA, TSA, LBH-589, and SAHA (vorinostat) were tested in-vitro and led to decreased proliferation (all inhibitors) decreased viability and cytotoxicity (TSA, SAHA, LBH-589) in-vitro and in-vivo (VPA). RNAi mediated BAP1 knockdown increased sensitivity to HDAC inhibition (VPA). 22038994 PubMed Landreville et al., 2012, Clin. Cancer Res. 3 accepted 1234 183 70 3 52435029 52444366 ENST00000460680.1 75 GRCh37 BAP1 is a tumor suppressor gene, mutations in this gene have been observed in a number of cancers including melanoma, and renal cancers. These mutations generally lead to loss-of-function and mutations in the UHC domain of BAP1 have been shown to lead to structural instability and β-amyloid aggregation in models. Germline mutations are associated with an increased risk of tumorgenesis and can lead to the development of "atypical Spitz tumours (ASTs), cutaneous melanoma (CM), epithelioid malignant mesothelioma (MM) and clear cell RCC". Somatic 2016-07-13 23:32:08 UTC https://civicdb.org/links/evidence_items/1234 https://civicdb.org/links/variants/183 https://civicdb.org/links/genes/70 false BAP1 8314 Mutation Malignant Mesothelioma 1790 Vorinostat,Mocetinostat,MC1568 Substitutes Predictive Supports E Sensitivity/Response A siRNA screen identified BAP1 associated with HDAC1 and HDAC2 expression. HDAC2 or BAP1 depletion sensitized a mesothelioma cell line (MSTO-211H) to HDAC inhibitors MC1568, vorinostat or mocetinostat. The paper indicates however, that temporary BAP knockdown might not adequately reflect long-term BAP1 mutation. 25970771 PubMed Sacco et al., 2015, Oncotarget 2 accepted 1235 183 70 3 52435029 52444366 ENST00000460680.1 75 GRCh37 BAP1 is a tumor suppressor gene, mutations in this gene have been observed in a number of cancers including melanoma, and renal cancers. These mutations generally lead to loss-of-function and mutations in the UHC domain of BAP1 have been shown to lead to structural instability and β-amyloid aggregation in models. Germline mutations are associated with an increased risk of tumorgenesis and can lead to the development of "atypical Spitz tumours (ASTs), cutaneous melanoma (CM), epithelioid malignant mesothelioma (MM) and clear cell RCC". Somatic 2016-07-01 16:28:57 UTC https://civicdb.org/links/evidence_items/1235 https://civicdb.org/links/variants/183 https://civicdb.org/links/genes/70 false FGFR2 2263 Mutation Endometrial Cancer 1380 Ponatinib Predictive Supports D Sensitivity/Response Preclinical study in endometrial cancer cell lines (MFE-296, AN3CA, MFE-280 and Ishikawa). In cell proliferation assays, the three FGFR2 mutant cell lines were more sensitive to the pan-FGFR inhibitor ponatinib (AP24534) than the FGFR2 wild type cell line (Ishikawa) and human embryonic kidney cell line (HEK293). Ponatinib also inhibited FGFR2 kinase activity and phosphorylation (MFE-296 and MFE-280) as well as cell migration and invasion (MFE-296 and AN3CA) of FGFR2 mutated cancer cell lines. 26574622 PubMed Kim et al., 2016, Cancer Biol. Ther. 3 accepted 1236 511 22 10 123239371 123357917 ENST00000457416.2 75 GRCh37 Somatic 2016-06-23 23:12:32 UTC https://civicdb.org/links/evidence_items/1236 https://civicdb.org/links/variants/511 https://civicdb.org/links/genes/22 false ALK 238 Mutation Lung Non-small Cell Carcinoma 3908 Ceritinib Predictive Supports B Sensitivity/Response In a phase 1 clinical trial (NCT01283516) 130 patients with advanced cancers all harboring ALK alterations were treated with ceritinib. Of 114 NSCLC patients treated with at least 400 mg/daily ceritinib, 1 had a complete response, 65 had a partial response, 25 had stable disease, 12 had progressive disease, and 11 withdrew from the study early. Ceritinib dosed at 400 mg or higher had similar results in patients who had or had not received prior crizotinib treatment. Overall response rate for patients with prior crizotinib treatment (83 out of 122) was 56% with median progression free survival of 6.9 months. For patients who had no prior crizotinib treatment, median progression free survival was 10.4 months. 24670165 PubMed Shaw et al., 2014, N. Engl. J. Med. NCT01283516 4 accepted 1237 512 1 2 29415640 30144432 ENST00000389048.3 75 GRCh37 Somatic 2016-06-28 00:03:31 UTC https://civicdb.org/links/evidence_items/1237 https://civicdb.org/links/variants/512 https://civicdb.org/links/genes/1 false DNMT3A 1788 Mutation Myelodysplastic Syndrome 0050908 Prognostic Supports B Poor Outcome 12/150 patients with de novo myelodysplastic syndrome screened for DNMT3A mutations (bone marrow and paired normal skin) had heterozygous mutations with predicted translational consequences. 1 patient was identified with 2 nonsynonymous coding mutations. R882 mutations accounted for 4/13 reported mutations, P904L for 2/13 mutations and the remaining had not been previously reported at the time of this report. Overall and event-free survival were worse for DNMT3A mutant patients although transplantation status was not considered (log-rank p=0.005 and p=0.009). Transformation to AML was increased for mutant 7/12 (58%) versus wildtype 39/138 (28%) patients (p=0.007). The authors note larger cohorts will be required to confirm these results. 21415852 PubMed Walter et al., 2011, Leukemia 3 accepted 1238 189 18 2 25455845 25565459 ENST00000264709.3 75 GRCh37 DNMT3A mutations occur in a variety of myeloid malignancies. These mutations are associated with adverse prognosis in acute myeloid leukemia (AML), particularly in the context of NPM1 and FLT3-ITD mutations, which often co-occur. Early results indicate AML patients with DNMT3A mutations may respond better to decitabine than those with wild-type. Shorter survival has been indicated in patients with T-cell acute lymphoblastic leukemia and myelodysplastic syndrome, however, larger cohorts are required to verify this finding. DNMT3A mutations have been suggested as a pre-leukemic lesion and found in older individuals with clonal hematopoiesis but no overt malignancy. Somatic 2016-04-08 14:33:33 UTC https://civicdb.org/links/evidence_items/1238 https://civicdb.org/links/variants/189 https://civicdb.org/links/genes/18 false ALK 238 NPM::ALK Anaplastic Large Cell Lymphoma 0050744 Crizotinib Predictive Supports D Sensitivity/Response NPM-ALK in anaplastic large cell lymphoma (ALCL) was the first ALK-fusion to be discovered and characterized. In this study, targeted activity against NPM-ALK by the ALK and MET inhibitor crizotinib was assessed in cell lines and tumor xenograft models. Treatment of NPM-ALK positive ALCL cell lines Karpas299 and SU-DHL-1 potently inhibited growth, and this was seen to occur at concentrations which also inhibited NPM-ALK phosphorylation in these cells. Administration of 100mg/kg/d crizotinib resulted in complete regression of all tumors, indicating that NPM-ALK could be an effective target for crizotinib in ALCL. 18089725 PubMed Christensen et al., 2007, Mol. Cancer Ther. 5 accepted 1239 513 1 5 170814120 170818803 ENST00000517671.1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Somatic 2016-06-22 19:12:54 UTC https://civicdb.org/links/evidence_items/1239 https://civicdb.org/links/variants/513 https://civicdb.org/links/genes/1 false ALK 238 Fusion Anaplastic Large Cell Lymphoma 0050744 Crizotinib Predictive Supports C Sensitivity/Response Crizotinib at 250mg daily was given to two patients with relapsed ALK-rearranged anaplastic large cell lymphoma (ALCL). Patient one, 26 yrs old, had been treated with the CHOP-15 chemotherapy regimen, then salvage chemotherapy to prepare for autologous bone marrow transplant but ultimately relapsed. After initiation of crizotinib, PET, CT and bone marrow aspirates showed complete remission of previous lesions at 28 days. At time of publication the patient continued to show persistent response at 6 months. A 20 year old patient relapsed after one month of CHOP, and was treated with further chemotherapy and autologous bone marrow transplantation resulting in partial response of 1 month. Crizotinib was initialized, and after 12 days PET scan showed complete regression of all lesions. On day 60 bone marrow aspirates were ALK-negative (pretreatment evaluation showed 8% ALK-positive). The authors conclude these two cases indicate sensitivity to crizotinib of relapsed ALK-rearranged ALCL. 21345110 PubMed Gambacorti-Passerini et al., 2011, N. Engl. J. Med. 4 accepted 1240 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-11-03 18:32:09 UTC https://civicdb.org/links/evidence_items/1240 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ALK 238 NPM::ALK Anaplastic Large Cell Lymphoma 0050744 Crizotinib Predictive Supports B Sensitivity/Response In the second part of this Phase I study NCT00939770, nine patients between the ages of 12 months and 22 years with anaplastic large cell lymphoma (ALCL), who were refractory to treatment and for whom no further known treatments were available, were treated with crizotinib. Six patients with detectable NPM-ALK transcript levels responded with partial response, 1 with complete response, and 1 with stable disease. Crizotinib was well tolerated in these children. 23598171 PubMed Mossé et al., 2013, Lancet Oncol. NCT00939770 4 accepted 1241 513 1 5 170814120 170818803 ENST00000517671.1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Somatic 2016-06-23 17:59:19 UTC https://civicdb.org/links/evidence_items/1241 https://civicdb.org/links/variants/513 https://civicdb.org/links/genes/1 false ALK 238 Fusion Inflammatory Myofibroblastic Tumor 0050905 Crizotinib Predictive Supports B Sensitivity/Response As part of a phase 1 dose-escalation trial (NCT00939770), seven patients between ages 12 months and 22 years with relapsed or refractory inflammatory myofibroblastic tumors with ALK-rearrangement were given crizotinib. In six patients with measurable disease, responses included 3 with partial response and 3 with stable disease. One patient with evaluable disease had stable disease with treatment ongoing at the time of publication. Crizotinib was well tolerated in this group of pediatric patients. 23598171 PubMed Mossé et al., 2013, Lancet Oncol. NCT00939770 3 accepted 1243 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-08-15 19:59:21 UTC https://civicdb.org/links/evidence_items/1243 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ALK 238 RANBP2::ALK Inflammatory Myofibroblastic Tumor 0050905 Crizotinib Predictive Supports C Sensitivity/Response ALK-rearrangements are seen in 50% of inflammatory myofibroblastic tumor (IMT) cases. A 44 year old man was diagnosed with IMT. He was treated with surgery and catheter placement for administration of cisplatin, doxyrubicin and mitomycin C. Break-apart FISH showed ALK rearrangement, and immunohistochemical staining was characteristic of RANBP2 rearrangement. After further chemotherapy along with maintenance imatinib, crizotinib was started at 200mg twice daily, and a maximal partial response was achieved 5 months later, with regrowth occurring 2 months later. After further surgery, crizotinib was restarted at 250mg twice daily and almost 2 years later the patient was in complete radiographic remission. Another patient with non-ALK rearranged IMT was administered crizotinib in this study but did not respond. 20979472 PubMed Butrynski et al., 2010, N. Engl. J. Med. NCT00585195 4 accepted 1244 514 1 2 109335937 109375004 ENST00000283195.6 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Somatic 2016-06-27 23:49:13 UTC https://civicdb.org/links/evidence_items/1244 https://civicdb.org/links/variants/514 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK e20-e20 Cancer 162 Crizotinib Predictive Supports C Sensitivity/Response This case study presented a 53-year-old never-smoker with a poorly differentiated malignant neoplasm. Morphology and immunohistochemistry were unable to establish the primary tumor site. Right upper extremity (RUE), scalp, and multiple lung lesions were apparent. A lung lesion sample with sufficient material for molecular profiling was not attainable but sufficient material was present from the RUE for hybrid capture genomic profiling (FoundationOne kit was used). EML4-ALK variant 2 was found, and the patient was started on crizotinib. Rapid symptom improvement was seen. After 1 month, a CT scan showed significant size reduction in lung tumors, and after 5 months the patient was asymptomatic with an entirely negative examination. 25408655 PubMed Chung et al., 2014, Case Rep Oncol 3 accepted 1245 500 1 2 42396490 42552694 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 EML4-ALK variant 2 consists of a fusion of the ALK kinase domain (exons 20-29) with EML4 exons 1-20. Variant 2 has cytoplasmic distribution and makes up ~10% of EML4-ALK fusions found in NSCLC,. Although the specific variant is not consistently reported, single cases demonstrating response to crizotinib treatment in NSCLC and a differentiated malignant neoplasm of unknown origin have been reported. In vitro, this variant has shown greater sensitivity to ALK inhibition with TAE684 and crizotinib than the EML4-ALK variants 1 (E13;A20), 3a (E6;A20) and 3b (E6ins33;A20). The variant was reported to be less stable in cells than other variants, and may be a client protein of Hsp90. Along these lines the variant has shown preclinical sensitivity to Hsp90 inhibition. Somatic 2016-04-24 17:19:39 UTC https://civicdb.org/links/evidence_items/1245 https://civicdb.org/links/variants/500 https://civicdb.org/links/genes/1 false FGFR1 2260 N546K Ewing Sarcoma Of Bone 3368 Ponatinib Predictive Supports E Sensitivity/Response 116 Ewing's sarcoma tumor samples were analyzed in this study. 2 patient's samples underwent whole genome sequencing, tumor samples from 51 patients underwent exome sequencing and expression analysis, 63 samples underwent FGFR1 copy number analysis, mRNA analysis and IHC. A FGFR1 N546K mutation was detected in one patient. Gain of the FGFR1 locus (qPCR) was observed in 13 of 41 patients (31.7%) and Ewing sarcoma cell lines (A673, CADO, SK-NMC, SK-ES, and VH-64). FGFR1 was also highly expressed in Ewing sarcoma (mRNA and IHC) and correlated with copy number. Retroviral transduction of FGFR1 wild-type or the FGFR1 N546K mutant into NIH3T3 cells led to enhanced proliferation especially for cells harboring the FGFR1 mutation. ShRNA mediated knockdown of FGFR1 inhibited growth of Ewing sarcoma and other cancer cells (A549 lung carcinoma cell line or leukemia cell lines HL60 and Kasumi) with almost complete growth suppression only in the Ewing sarcoma cell lines and knockdown of FGFR1 abrogated growth of cell lines in xenograft. Ponatinib treatment inhibited growth of Ewing sarcoma cell lines. 26179511 PubMed Agelopoulos et al., 2015, Clin. Cancer Res. 2 accepted 1246 515 1885 8 38274849 38274849 G T ENST00000341462.5 75 GRCh37 Somatic 2016-07-02 15:36:54 UTC https://civicdb.org/links/evidence_items/1246 https://civicdb.org/links/variants/515 https://civicdb.org/links/genes/1885 false FGFR1 2260 Amplification Ewing Sarcoma Of Bone 3368 Ponatinib Predictive Supports D Sensitivity/Response 116 Ewing's sarcoma tumor samples were analyzed in this study. 2 patient's samples underwent whole genome sequencing, tumor samples from 51 patients underwent exome sequencing and expression analysis, 63 samples underwent FGFR1 copy number analysis, mRNA analysis and IHC. A FGFR1 N546K mutation was detected in one patient. Gain of the FGFR1 locus (qPCR) was observed in 13 of 41 patients (31.7%) and Ewing sarcoma cell lines (A673, CADO, SK-NMC, SK-ES, and VH-64). FGFR1 was also highly expressed in Ewing sarcoma (mRNA and IHC) and correlated with copy number. Retroviral transduction of FGFR1 wild-type or the FGFR1 N546K mutant into NIH3T3 cells led to enhanced proliferation especially for cells harboring the FGFR1 mutation. ShRNA mediated knockdown of FGFR1 inhibited growth of Ewing sarcoma and other cancer cells (A549 lung carcinoma cell line or leukemia cell lines HL60 and Kasumi) with almost complete growth suppression only in the Ewing sarcoma cell lines and knockdown of FGFR1 abrogated growth of cell lines in xenograft. Ponatinib treatment inhibited growth of Ewing sarcoma cell lines. 26179511 PubMed Agelopoulos et al., 2015, Clin. Cancer Res. 3 accepted 1247 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). N/A 2016-07-11 04:11:48 UTC https://civicdb.org/links/evidence_items/1247 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false ROS1 6098 Rearrangement Lung Adenocarcinoma 3910 Ceritinib Predictive Supports C Sensitivity/Response Case report of a 77-year old male patient with lung adenocarcinoma (T2aN1M0, stage IIA) without EGFR, KRAS, or BRAF mutations, and no ALK gene rearrangement. CD72-ROS1 was identified in sequencing after progression on chemotherapy. Crizotinib at 250 mg orally twice daily led to resolution of metastatic disease. The patient remained disease-free for 13 months when a CT-scan showed a relapse with two nodules in the right lower lobe. Stereotactic radiation therapy, gamma knife radiosurgery, and ipilimumab did not lead to a relevant response (new pleural nodules, new intracranial metastases). The patient next received ceritinib on a “Signature Trial" for tumors with aberrations in ALK or ROS1 that are treated with oral ceritinib (LDK378) at 750 mg daily (NCT02186821). Restaging scans after two cycles showed a partial response confirmed after four cycles (56% decrease) per RECIST1.1. MRI showed that his brain metastases decreased as well. 26917690 PubMed Subbiah et al., 2016, Proc. Natl. Acad. Sci. U.S.A. 1 accepted 1248 269 4941 6 117609463 117747018 ENST00000368508.3 75 GRCh37 ROS1 is a receptor tyrosine kinase that frequently forms gene fusions in several cancer types. Approximately 2% of NSCLC patients harbor a ROS1 gene fusion. Several fusion partners have been described with a constant ROS1-breakpoint, maintaining the kinase domain (Solomon B, 2015). Following case-studies and retrospective analyses, an expansion cohort of a phase-1 study showed clinical benefit of crizotinib in ROS1 rearranged NSCLC. The benefit was independent of the type of ROS1-rearrangement (Shaw et. al.,2014). Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1248 https://civicdb.org/links/variants/269 https://civicdb.org/links/genes/4941 false ROS1 6098 CD74::ROS1 G2032R Lung Non-small Cell Carcinoma 3908 Foretinib,Cabozantinib Substitutes Predictive Supports D Sensitivity/Response Preclinical study analyzing the efficacy of dual ROS1/ALK and more specific ROS1 inhibitors on cell lines (Ba/F3) expressing CD74-ROS1 with and without the G2032R mutation. Selective ROS1 inhibitors retained activity against the G2032R mutation (cabozatinib, foretinib), whereas dual ALK/ROS inhibitors (crizotinib, brigatinib, ceritinib, AZD3463) or ALK-selective inhibitors (alectinib) were ineffective. 26372962 PubMed Davare et al., 2015, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 1249 465 4941 6 117638347 117638347 C T ENST00000368508.3 75 GRCh37 The G2032R missense mutation has been observed in patients with crizotinib-resistant non-small cell lung cancer harboring CD74-ROS1 rearrangement. Independent in vitro studies have confirmed that this mutation confers marked resistance to crizotinib cells over CD74-ROS1 alone. Multiple groups have indicated CD74-ROS1 G2032R expressing cell lines are sensitive to both cabozantinib and foretinib individually administered in vitro. One group additionally showed this mutation conferred relative resistance to alectinib, brigatinib, ceritinib, and AZD3463 in vitro. Somatic 2016-06-29 21:01:24 UTC https://civicdb.org/links/evidence_items/1249 https://civicdb.org/links/variants/465 https://civicdb.org/links/genes/4941 false ROS1 6098 CD74::ROS1 G2032R Lung Non-small Cell Carcinoma 3908 Ceritinib,AZD3463,Brigatinib,Crizotinib Substitutes Predictive Supports D Resistance Preclinical study analyzing the efficacy of dual ROS1/ALK and more specific ROS1 inhibitors on cell lines (Ba/F3) expressing CD74-ROS1 with and without the G2032R mutation. Selective ROS1 inhibitors retained activity against the G2032R mutation (cabozatinib, foretinib), whereas dual ALK/ROS inhibitors (crizotinib, brigatinib, ceritinib, AZD3463) or ALK-selective inhibitors (alectinib) were ineffective. 26372962 PubMed Davare et al., 2015, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 1250 465 4941 6 117638347 117638347 C T ENST00000368508.3 75 GRCh37 The G2032R missense mutation has been observed in patients with crizotinib-resistant non-small cell lung cancer harboring CD74-ROS1 rearrangement. Independent in vitro studies have confirmed that this mutation confers marked resistance to crizotinib cells over CD74-ROS1 alone. Multiple groups have indicated CD74-ROS1 G2032R expressing cell lines are sensitive to both cabozantinib and foretinib individually administered in vitro. One group additionally showed this mutation conferred relative resistance to alectinib, brigatinib, ceritinib, and AZD3463 in vitro. Somatic 2016-06-29 21:01:42 UTC https://civicdb.org/links/evidence_items/1250 https://civicdb.org/links/variants/465 https://civicdb.org/links/genes/4941 false ROS1 6098 CD74::ROS1 G2032R Lung Non-small Cell Carcinoma 3908 Lorlatinib Predictive Supports D Sensitivity/Response Preclinical study of PF-06463922 in NSCLC in-vitro, in-vivo and in enzyme assays. PF-06463922 showed inhibition of kinase activity, cell viability and tumor growth in wild-type, G2032R and L2026M mutations in ROS1. 25733882 PubMed Zou et al., 2015, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 1251 465 4941 6 117638347 117638347 C T ENST00000368508.3 75 GRCh37 The G2032R missense mutation has been observed in patients with crizotinib-resistant non-small cell lung cancer harboring CD74-ROS1 rearrangement. Independent in vitro studies have confirmed that this mutation confers marked resistance to crizotinib cells over CD74-ROS1 alone. Multiple groups have indicated CD74-ROS1 G2032R expressing cell lines are sensitive to both cabozantinib and foretinib individually administered in vitro. One group additionally showed this mutation conferred relative resistance to alectinib, brigatinib, ceritinib, and AZD3463 in vitro. Somatic 2016-05-27 15:26:16 UTC https://civicdb.org/links/evidence_items/1251 https://civicdb.org/links/variants/465 https://civicdb.org/links/genes/4941 false ROS1 6098 CD74::ROS1 L2026M Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports D Resistance Preclinical study of PF-06463922 in NSCLC in-vitro, in-vivo and in enzyme assays. BaF3 cells expressing CD74-ROS1 L2026M were more resistant to crizotinib treatment than wildtype CD74-ROS1 in both cell viability and ROS1 phosphorylation. Crizotinib was also less effective at inhibiting kinase activity in ROS1 with L2026M mutation than wildtype. In contrast, PF-06463922 was effectively inhibited the fusion harboring this mutation in these assays. 25733882 PubMed Zou et al., 2015, Proc. Natl. Acad. Sci. U.S.A. 2 accepted 1252 516 4941 6 117638365 117638365 G T ENST00000368508.3 75 GRCh37 The L2026M mutation is considered a gatekeeper mutation located in the inhibitor binding pocket of ROS1 and corresponding to L1196M in ALK and T790M in EGFR. This mutation has not been reportedly observed in a patient but inferred as a variant likely to emerge in crizotinib-resistant tumors. In vitro kinase activity, structural predictions and growth inhibition assays indicate the L2026M mutation in the CD74-ROS1 fusion provides crizotinib resistance. Additional preclinical assays have indicated that crizotinib resistant cells harboring this mutation are sensitive to PF-06463922 and foretinib. Somatic 2016-06-22 19:35:09 UTC https://civicdb.org/links/evidence_items/1252 https://civicdb.org/links/variants/516 https://civicdb.org/links/genes/4941 false ROS1 6098 CD74::ROS1 L2026M Lung Non-small Cell Carcinoma 3908 Lorlatinib Predictive Supports D Sensitivity/Response Preclinical study of PF-06463922 in NSCLC in-vitro, in-vivo, and in enzyme assays. After establishing that the CD74-ROS1 L2026M mutation confers crizotinib resistance in kinase activity and cell viability assays (in transduced BaF3 cells), response to PF-06463922 was tested. Wild-type CD74-ROS1, CD74-ROS1 G2032R, and CD74-ROS1 L2026M all showed sensitivity to PF-06463922 in these assays. 25733882 PubMed Zou et al., 2015, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 1253 516 4941 6 117638365 117638365 G T ENST00000368508.3 75 GRCh37 The L2026M mutation is considered a gatekeeper mutation located in the inhibitor binding pocket of ROS1 and corresponding to L1196M in ALK and T790M in EGFR. This mutation has not been reportedly observed in a patient but inferred as a variant likely to emerge in crizotinib-resistant tumors. In vitro kinase activity, structural predictions and growth inhibition assays indicate the L2026M mutation in the CD74-ROS1 fusion provides crizotinib resistance. Additional preclinical assays have indicated that crizotinib resistant cells harboring this mutation are sensitive to PF-06463922 and foretinib. Somatic 2016-06-28 01:51:02 UTC https://civicdb.org/links/evidence_items/1253 https://civicdb.org/links/variants/516 https://civicdb.org/links/genes/4941 false ROS1 6098 CD74::ROS1 G2032R Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Resistance ROS1 kinase domain mutations were assessed in two patients with stage IIIa/IV pulmonary adenocarcinoma and a cell line. The ROS1 G2032R mutation was identified in a crizotinib-resistant tumor from one of the patients harboring the CD74–ROS1 fusion. Expression of CD74–ROS1 G2032R in Ba/F3 cells conferred resistance to crizotinib combared to CD74–ROS1 (IC50=353.62+/-20.15 vs. 2.76+/-0.82). 25688157 PubMed Song et al., 2015, Clin. Cancer Res. 3 accepted 1254 465 4941 6 117638347 117638347 C T ENST00000368508.3 75 GRCh37 The G2032R missense mutation has been observed in patients with crizotinib-resistant non-small cell lung cancer harboring CD74-ROS1 rearrangement. Independent in vitro studies have confirmed that this mutation confers marked resistance to crizotinib cells over CD74-ROS1 alone. Multiple groups have indicated CD74-ROS1 G2032R expressing cell lines are sensitive to both cabozantinib and foretinib individually administered in vitro. One group additionally showed this mutation conferred relative resistance to alectinib, brigatinib, ceritinib, and AZD3463 in vitro. Somatic 2016-11-04 18:17:34 UTC https://civicdb.org/links/evidence_items/1254 https://civicdb.org/links/variants/465 https://civicdb.org/links/genes/4941 false ROS1 6098 CD74::ROS1 G2032R Lung Non-small Cell Carcinoma 3908 Foretinib Predictive Supports D Sensitivity/Response Ba/F3 cells expressing CD74–ROS1 G2032R showed resistance to crizotinib, compared with those expressing wild-type CD74–ROS1 (~128 fold higher IC50); however, showed relative sensitivity to foretinib (only ~6 fold higher IC50 than WT). 25688157 PubMed Song et al., 2015, Clin. Cancer Res. 2 accepted 1255 465 4941 6 117638347 117638347 C T ENST00000368508.3 75 GRCh37 The G2032R missense mutation has been observed in patients with crizotinib-resistant non-small cell lung cancer harboring CD74-ROS1 rearrangement. Independent in vitro studies have confirmed that this mutation confers marked resistance to crizotinib cells over CD74-ROS1 alone. Multiple groups have indicated CD74-ROS1 G2032R expressing cell lines are sensitive to both cabozantinib and foretinib individually administered in vitro. One group additionally showed this mutation conferred relative resistance to alectinib, brigatinib, ceritinib, and AZD3463 in vitro. Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1255 https://civicdb.org/links/variants/465 https://civicdb.org/links/genes/4941 false ROS1 6098 CD74::ROS1 L2155S Lung Non-small Cell Carcinoma 3908 Foretinib,Crizotinib,TAE684 Substitutes Predictive Supports D Resistance The L2155S mutation in ROS1 was identified in the HCC78CR1, -2 and -3 cell lines which harbor the SLC34A2–ROS1 rearrangement and in 2 patients with NSCLC with progressive disease following crizotinib treatment and CD74–ROS1 rearrangment. Crystal structure predicted ROS1 L2155S mutation to be highly destabilizating and cause protein structural modification. HCC78CR1, 2, and 3 cells and Ba/F3 cells transfected with CD74–ROS1 L2155S, showed resistance to crizotinib compared with parental HCC78 and Ba/F3 cells. In addition, these cell lines showed resistance to foretinib, a potent ROS1 inhibitor that is effective against ROS1 G2032R-mutant cells (16), and TAE684, a potent ALK inhibitor 25688157 PubMed Song et al., 2015, Clin. Cancer Res. 3 accepted 1256 517 4941 6 117630062 117630062 A G ENST00000368508.3 75 GRCh37 Somatic 2016-06-29 20:26:10 UTC https://civicdb.org/links/evidence_items/1256 https://civicdb.org/links/variants/517 https://civicdb.org/links/genes/4941 false ROS1 6098 CD74::ROS1 L2026M Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports D Resistance Ba/F3 cells expressing CD74–ROS1 L2026M mutation showed resistance to crizotinib (~10 fold higher IC50 value), compared with those expressing wild-type CD74–ROS1; however, showed similar sensitivity to foretinib. 25688157 PubMed Song et al., 2015, Clin. Cancer Res. 2 accepted 1257 516 4941 6 117638365 117638365 G T ENST00000368508.3 75 GRCh37 The L2026M mutation is considered a gatekeeper mutation located in the inhibitor binding pocket of ROS1 and corresponding to L1196M in ALK and T790M in EGFR. This mutation has not been reportedly observed in a patient but inferred as a variant likely to emerge in crizotinib-resistant tumors. In vitro kinase activity, structural predictions and growth inhibition assays indicate the L2026M mutation in the CD74-ROS1 fusion provides crizotinib resistance. Additional preclinical assays have indicated that crizotinib resistant cells harboring this mutation are sensitive to PF-06463922 and foretinib. Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1257 https://civicdb.org/links/variants/516 https://civicdb.org/links/genes/4941 false ROS1 6098 CD74::ROS1 L2026M Lung Non-small Cell Carcinoma 3908 Foretinib Predictive Supports D Sensitivity/Response Ba/F3 cells expressing CD74–ROS1 L2026M mutation showed similar sensitivity to foretinib compared with those expressing wild-type CD74–ROS1. This is in contrast to the increased resistance to crizotinib associated with this mutation in the same assay. 25688157 PubMed Song et al., 2015, Clin. Cancer Res. 2 accepted 1258 516 4941 6 117638365 117638365 G T ENST00000368508.3 75 GRCh37 The L2026M mutation is considered a gatekeeper mutation located in the inhibitor binding pocket of ROS1 and corresponding to L1196M in ALK and T790M in EGFR. This mutation has not been reportedly observed in a patient but inferred as a variant likely to emerge in crizotinib-resistant tumors. In vitro kinase activity, structural predictions and growth inhibition assays indicate the L2026M mutation in the CD74-ROS1 fusion provides crizotinib resistance. Additional preclinical assays have indicated that crizotinib resistant cells harboring this mutation are sensitive to PF-06463922 and foretinib. Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1258 https://civicdb.org/links/variants/516 https://civicdb.org/links/genes/4941 false ROS1 6098 CD74::ROS1 G2101A Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports D Resistance Ba/F3 cells expressing CD74–ROS1 G2101A showed resistance to crizotinib, compared with those expressing wild-type CD74–ROS1, and were sensitive to foretinib. 25688157 PubMed Song et al., 2015, Clin. Cancer Res. 2 accepted 1259 518 4941 6 117631376 117631376 C G ENST00000368508.3 75 GRCh37 Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1259 https://civicdb.org/links/variants/518 https://civicdb.org/links/genes/4941 false ROS1 6098 CD74::ROS1 G2101A Lung Non-small Cell Carcinoma 3908 Foretinib Predictive Supports D Sensitivity/Response Ba/F3 cells expressing CD74–ROS1 G2101A showed resistance to crizotinib, compared with those expressing wild-type CD74–ROS1, and were sensitive to foretinib. 25688157 PubMed Song et al., 2015, Clin. Cancer Res. 2 accepted 1260 518 4941 6 117631376 117631376 C G ENST00000368508.3 75 GRCh37 Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1260 https://civicdb.org/links/variants/518 https://civicdb.org/links/genes/4941 false ALK 238 CLTC::ALK Diffuse Large B-cell Lymphoma 0050745 TAE684 Predictive Supports D Sensitivity/Response A cell line called LM1 was established from the bone marrow of a 13 year old female patient with relapsed CLTC-ALK positive diffuse large B-cell lymphoma (DLBCL). The patient had been heavily treated with chemotherapy before establishment of the cell line. The cell line maintained the tumor immunophenotype. SNP analysis of patient bone marrow mononuclear cells and LM1 showed chromosomal changes associated with the cell line but 94.7% of SNPs were identically called. ALK kinase inhibitor TAE684 induced cell death in LM1 cells at low nanomolar concentrations, while it did not significantly effect the ALK-rearrangement negative DLBCL cell line Karpas422. LM1 cells formed tumors in 3/10 SCID and 9/10 NOD-SCID mice. CD30 and CD138 immmunostaining were maintained between original tumor and LM1 xenografts. In mice, LM1 but not Karpas422 xenografts regressed with TAE684 administration, and complete remission for 13 weeks was observed before experiment was terminated. 21494621 PubMed Cerchietti et al., 2011, PLoS ONE 4 accepted 1261 520 1 17 57697219 57768072 ENST00000269122.3 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The t(2;17)(p23;q23) translocation results in the CLTC-ALK fusion protein, the most common ALK fusion observed in diffuse large B cell lymphoma (DLBCL). ALK-rearranged DLBCL is less responsive to CHOP chemotherapy. Preclinical work indicates that CLTC-ALK DLBCL is responsive to ALK inhibition in cell lines and mouse models, and two case studies show short response followed by progression when heavily pretreated and advanced ALK-positive DLBCL is treated with crizotinib (one case CLTC-ALK, one case an unknown ALK fusion). Somatic 2016-06-27 18:45:05 UTC https://civicdb.org/links/evidence_items/1261 https://civicdb.org/links/variants/520 https://civicdb.org/links/genes/1 false U2AF1 7307 MUTATION Myelofibrosis 4971 Prognostic Supports B Poor Outcome In a large study of patients with primary myelofibrosis evaluating mutations associated with anemia, 457 patients were evaluated for U2AF1 mutations. U2AF1 mutations were significantly associated with anemia in univariate and multivariate analysis (72 mutated vs 385 wildtype; P<0.0001). U2AF1 mutations were significantly associated with shorter overall survival in univariate analysis (P < 0.0001) but not in multivariate analysis with adjustment for age and anemia (P=0.24). 27058230 PubMed Barraco et al., 2016, Blood Cancer J 4 accepted 1262 521 48 21 44513066 44527697 ENST00000291552.4 75 GRCh37 Somatic 2016-06-21 02:53:54 UTC https://civicdb.org/links/evidence_items/1262 https://civicdb.org/links/variants/521 https://civicdb.org/links/genes/48 false ALK 238 CLTC::ALK Diffuse Large B-cell Lymphoma 0050745 Prognostic Supports C Poor Outcome CLTC-ALK is one of the most common ALK fusions found in diffuse large B cell lymphoma (DLBCL). In a retrospective study of 38 patients with ALK-rearranged DLBCL, 3 were CD20 positive. Only one showed cytoplasmic, nuclear and nucleolar staining associated with NPM-ALK, while the others showed granular cytoplasmic ALK stain characteristic for CLTC-ALK. Seven molecularly characterized cases were positive for CLTC-ALK. 6/7 patients were treated with CHOP chemotherapy with survival of 5, 10, 26 and 27 months, and two alive at end of study, and one CD20 positive patient was treated with CHOP chemotherapy supplemented with CD20-targeted rituximab, with survival of 8 months, resulting in median survival of 26 months for this group. Although these numbers are not sufficient for statistical comparison, they compare unfavorably to 3.1 year overall survival and 45% 5 year survival of CHOP treated DLBCL patients, and even less favorably to R-CHOP standard of care for CD20 positive DLBCL, suggesting poor prognosis for CLTC-ALK DLBCL and need for updated treatment in this cohort. 19636007 PubMed Laurent et al., 2009, J. Clin. Oncol. 3 accepted 1263 520 1 17 57697219 57768072 ENST00000269122.3 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The t(2;17)(p23;q23) translocation results in the CLTC-ALK fusion protein, the most common ALK fusion observed in diffuse large B cell lymphoma (DLBCL). ALK-rearranged DLBCL is less responsive to CHOP chemotherapy. Preclinical work indicates that CLTC-ALK DLBCL is responsive to ALK inhibition in cell lines and mouse models, and two case studies show short response followed by progression when heavily pretreated and advanced ALK-positive DLBCL is treated with crizotinib (one case CLTC-ALK, one case an unknown ALK fusion). Somatic 2016-06-27 21:08:15 UTC https://civicdb.org/links/evidence_items/1263 https://civicdb.org/links/variants/520 https://civicdb.org/links/genes/1 false ALK 238 Fusion Diffuse Large B-cell Lymphoma 0050745 Crizotinib Predictive Supports C Sensitivity/Response A 27 year old female patient with advanced-stage IV, CD20 negative diffuse large B cell lymphoma (DLBCL). ALK rearrangement was determined by FISH, but the ALK fusion partner was not determined due to limited tissue. The patient underwent treatment with CHOP chemotherapy regimen and radiation but did not respond. The patient progressed following salvage chemotherapy and autologous stem cell transplant. Crizotinib was then administered at 250 mg twice daily, and LDH levels rapidly dropped along with disappearance of palpable lymphadenopathy, but progression ensued after 21 days and the patient died soon after. The authors attribute the short response to crizotinib to the possibility of this tumor having an ALK fusion variant less responsive to ALK inhibition and to a high Ki-67 index in the patient, and deem that despite the brief response, crizotinib shows promise in ALK rearranged DLBCL. 24330038 PubMed Wass et al., 2014, Eur. J. Haematol. 2 accepted 1264 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-11-04 18:12:02 UTC https://civicdb.org/links/evidence_items/1264 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ALK 238 CLTC::ALK Diffuse Large B-cell Lymphoma 0050745 Crizotinib Predictive Supports C Sensitivity/Response A 21 year old male presented with lymphadenopathy and a low density mass in pancreas. Histopathological analysis showed diffuse tumor cell infiltrate (CD20/EMA negative) with cytoplasmic ALK. RT-PCR indicated CLTC-ALK fusion. The patient was diagnosed with splenic ALK + diffuse large B cell lymphoma (DLBCL), Stage III, Group A with an IPI of 3. CHOP-21 chemotherapy regimen was administered with improvement in abdominal lymph nodes but worsening in retroperitoneal lymph nodes assessed via standardized uptake values. Subsequent ICE chemotherapy regiment relieved some symptoms prompting the patient to refuse further treatment despite other indications of disease progression. Therapy was reinstated after worsening of disease. GEMOX chemotherapy was administered with dexamethasone and 250mg crizotinib twice daily resulting in symptom relief, decreased lymphadenopathy and LDH decline. The disease then progressed and the patient died 2 months after crizotinib initiation. The authors conclude that partial response to crizotinib was observed and that in future trials ALK rearranged DLBCL patients might see increased benefit with earlier application of targeted therapy during the treatment course. 26221234 PubMed Li et al., 2015, Int J Clin Exp Med 3 accepted 1265 520 1 17 57697219 57768072 ENST00000269122.3 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The t(2;17)(p23;q23) translocation results in the CLTC-ALK fusion protein, the most common ALK fusion observed in diffuse large B cell lymphoma (DLBCL). ALK-rearranged DLBCL is less responsive to CHOP chemotherapy. Preclinical work indicates that CLTC-ALK DLBCL is responsive to ALK inhibition in cell lines and mouse models, and two case studies show short response followed by progression when heavily pretreated and advanced ALK-positive DLBCL is treated with crizotinib (one case CLTC-ALK, one case an unknown ALK fusion). Somatic 2016-11-04 18:19:24 UTC https://civicdb.org/links/evidence_items/1265 https://civicdb.org/links/variants/520 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK e2-e20 Renal Cell Carcinoma 4450 Predictive Supports E Sensitivity/Response Adenocarcinoma cells were detected via urinary cytology in a 53 year old woman. Cancer morphology suggested papillary renal cell carcinoma (RCC), type 2A. EML4-ALK variant 5 was discovered in tumor tissue using PCR with EML4 and ALK specific primers. The authors conclude that their findings confirm the potential for ALK targeting therapy in select cases of RCC. 22252991 PubMed Sugawara et al., 2012, Cancer 3 accepted 1266 501 1 2 42396490 42472827 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Somatic 2016-06-28 00:26:40 UTC https://civicdb.org/links/evidence_items/1266 https://civicdb.org/links/variants/501 https://civicdb.org/links/genes/1 false BRAF 673 DEL 485-490 Cancer 162 Pan-RAF Inhibitor LY3009120 Predictive Supports D Sensitivity/Response Cells harboring in-frame deletions in BRAF in the L485-P490 amino acid region were found to be sensitive to the RAF dimer inhibitor LY3009120, but not sensitive to the BRAF-selective inhibitors vemurafenib or dabrafenib. These deletions were observed in KRAS wildtype pancreatic, ovarian, NSCLC, and thyroid cancers. In three cell lines H2405 (NSCLC with L485-P490>Y), BxPC-3 (pancreatic with V487-P492>A), and OV-90 (ovarian with N486-P490del), BRAF deletion–mediated MAPK activation was found to be sensitive to LY3009120 as evidenced by dose-dependent inhibition of phospho-MEK and ERK and cell growth inhibition with IC50 values of 0.04, 0.087, and 0.007 μmol/L in these three cell lines. LY3009120, but not vemurafenib, also inhibited tumor growth of both H2405 and BxPC-3 cells xenografted into mice. 26732095 PubMed Chen et al., 2016, Cancer Discov 3 accepted 1267 522 5 7 140477838 140477855 AGGTGCTGTCACATTCAA ENST00000288602.6 75 GRCh37 Somatic 2016-11-04 21:37:43 UTC https://civicdb.org/links/evidence_items/1267 https://civicdb.org/links/variants/522 https://civicdb.org/links/genes/5 false ALK 238 R1275Q Neuroblastoma 769 Crizotinib Predictive Supports C Sensitivity/Response This Phase I study of crizotinib involved a cohort of pediatric neuroblastoma patients between ages 12 months and 22 years. In 11 patients with characterized ALK mutations, 4 had R1275Q mutations, and two of these were germline mutations. Of these 2 germline patients, 1 showed stable disease (SD) and 1 complete response (CR). In contrast, in the 7 characterized patients with ALK mutations that were not R1275Q, 6 showed PD and 1 SD. The authors conclude this finding is promising and merits further study. 23598171 PubMed Mossé et al., 2013, Lancet Oncol. NCT00939770 2 accepted 1269 9 1 2 29432664 29432664 C T ENST00000389048.3 75 GRCh37 ALK R1275Q has been observed as a recurrent mutation in neuroblastoma, non-small cell lung cancer (NSCLC), as well as other cancer types. Neuroblastoma cells with this mutation have shown sensitivity to the ALK-inhibitor TAE684. This and the geldanamycin deriviative 17-DMAG have been shown to be effective in NSCLC cell lines. Rare Germline 2016-06-28 00:35:18 UTC https://civicdb.org/links/evidence_items/1269 https://civicdb.org/links/variants/9 https://civicdb.org/links/genes/1 false ALK 238 R1275Q Neuroblastoma 769 Crizotinib Predictive Supports C Sensitivity/Response A cohort of pediatric neuroblastoma patients ages 12 months to 22 years were assessed for response to crizotinib in a Phase I study. 11 patients in this cohort had characterized ALK mutations, 4 of which were R1275Q mutation. Two of these R1275Q mutations were germline and two were somatic. Of these 2 somatic R1275Q patients, 1 showed progressive disease (PD) and 1 showed stable disease (SD). In contrast, of the 7 characterized patients with ALK mutations that were not R1275Q, 6 showed PD and 1 SD. The stable disease patient had an R1275L mutation in ALK. In general, patients with germline or somatic R1275Q mutations or R1275L mutations had 1 complete response, 3 SD and one PD, while patients with other ALK mutations had 6 PD. 23598171 PubMed Mossé et al., 2013, Lancet Oncol. NCT00939770 2 accepted 1270 9 1 2 29432664 29432664 C T ENST00000389048.3 75 GRCh37 ALK R1275Q has been observed as a recurrent mutation in neuroblastoma, non-small cell lung cancer (NSCLC), as well as other cancer types. Neuroblastoma cells with this mutation have shown sensitivity to the ALK-inhibitor TAE684. This and the geldanamycin deriviative 17-DMAG have been shown to be effective in NSCLC cell lines. Somatic 2016-06-28 00:30:02 UTC https://civicdb.org/links/evidence_items/1270 https://civicdb.org/links/variants/9 https://civicdb.org/links/genes/1 false ALK 238 F1174L Neuroblastoma 769 Crizotinib Predictive Does Not Support C Sensitivity/Response In a Phase I trial (NCT00939770) of the drug crizotinib in pediatric patients, a subset of 11 neuroblastoma patients were characterized for mutations in ALK. Of these 11 patients, 4 had the F1174L mutation. Among these 4 patients, stable disease (SD) was observed in one, and progressive disease (PD) was observed in 3 others after administration of crizotinib. In contrast, in the remaining 7 patients with mutations different than F1174L, 4 had PD, 2 had SD and one had complete response as best response after initiation of crizotinib. 23598171 PubMed Mossé et al., 2013, Lancet Oncol. NCT00939770 3 accepted 1271 8 1 2 29443695 29443695 G T ENST00000389048.3 75 GRCh37 ALK F1174L has been observed as recurrent in neuroblastoma, non-small cell lung cancer (NSCLC), and other cancer types. Neuroblastoma cells containing this mutation have shown resistance to low doses of criztonib. However, increased dosage can overcome this resistance in cell lines studies. TAE684 has also proven effective in both NSCLC and neuroblastoma F1174L containing cells. Somatic 2017-10-19 15:57:43 UTC https://civicdb.org/links/evidence_items/1271 https://civicdb.org/links/variants/8 https://civicdb.org/links/genes/1 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Alectinib Predictive Supports B Sensitivity/Response In this initial report of a single-arm Phase I and II study (JapicCTI-101264) of alectinib (CH5424802), 46 patients with advanced or metastatic ALK-rearranged non small cell lung cancer (NSCLC) were assessed for objective response during phase II. ALK positivity was assessed via IHC and verified with FISH or RT-PCR. Patients had received one or more rounds of previous chemotherapy, but no prior targeted therapy towards ALK. From the 46 patients, 41 showed partial response, and 2 showed complete response. CNS metastases in three patients which had not received prior brain irradiation showed response to alectinib. Alectinib was generally well tolerated, and the authors conclude that alectinib compared favorably to crizotinib and could be an effective and safe option in ALK-rearranged NSCLC. 23639470 PubMed Seto et al., 2013, Lancet Oncol. 3 accepted 1272 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-08-15 19:59:54 UTC https://civicdb.org/links/evidence_items/1272 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Alectinib Predictive Supports C Sensitivity/Response In this case study of a critically ill 29 year old male nonsmoker with advanced metastatic ALK-positive NSCLC, alectinib (CH5424802), was administered as first line treatment. Where most clinical trials only admit patients with Eastern Cooperative Oncology Performance status (PS) of 0 or 1, this patient had PS 4 due to respiratory failure, multiple bone metastases and complications from disseminated intravascular coagulation (DIC). Administration of alectinib at 300 mg twice daily was followed by marked improvement seen in tests associated with DIC, pulmonary metastasis and change in PS from 4 to 0. Further improvements after a couple of months suggested a rapid complete response. Alectinib was well tolerated in this first line treatment of a critically ill ALK-positive NSCLC patient. 26938871 PubMed Yoshida et al., 2016, Anticancer Drugs 3 accepted 1273 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-11-03 19:15:07 UTC https://civicdb.org/links/evidence_items/1273 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false CD274 29126 Expression Thyroid Gland Papillary Carcinoma 3969 Prognostic Supports B Poor Outcome Immunohistochemical analyses of PD-L1 protein was retrospectively performed on 251 archived FFPE surgical tissues (66 benign thyroid nodules and 185 papillary thyroid carcinomas PTC, E1L3N antibody). Patients with increased PD-L1 protein had significantly shorter median DFS (36 months [membranous staining] and 49 months [cytoplasmic staining] vs. 186 months [negative], p < 0.001 and p < 0.01, respectively). 27086918 PubMed Chowdhury et al., 2016, Oncotarget 3 accepted 1274 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2016-11-03 19:02:18 UTC https://civicdb.org/links/evidence_items/1274 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false CD274 29126 Expression Stomach Carcinoma 5517 Prognostic Supports B Better Outcome 465 gastric cancer samples and 15 corresponding liver metastases underwent IHC for PD1/PD-L1 protein expression. PD-L1 positivity in tumor cells was defined by at least 2% tumor cells with membranous positivity, PD-L1 positivity in immune cells by at least 10% PD-L1 positive immune cells. Patients with PD-L1 positive tumor cells had a significant better overall (p=0.028) and tumor specific survival (p=0.018). The same applied for patients with PD-L1 positive immune cells (p<0.001 each). 27009855 PubMed Böger et al., 2016, Oncotarget 3 accepted 1275 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2016-05-08 23:52:56 UTC https://civicdb.org/links/evidence_items/1275 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false DUX4 100288687 Fusion Acute Lymphoblastic Leukemia 9952 Diagnostic Supports D Positive A screen for fusion genes in Ph- AYA-ALL (Philadelphia chromosome negative acute lymphoblastic leukemia in adolescents and young adults) was performed using RNA-seq from multiple cohorts of ALL patients. DUX4, ZNF384 and MEF2D fusions were the most frequent found. DUX4 fusions were found only in AYA cases (age 15-39) and this was significant, p=0.016. DUX4 fusions clustered into groups distinct from the other fusions, and these fusions as a whole clustered with Ph- ALL cases. The authors performed extensive in vitro and in vivo experiments to demonstrate that DUX4 fusions are likely early initiating/events and that DUX4 fusion and not DUX4 wild type are tumorigenic. The authors conclude that DUX4 fusions may be a target driver resulting in AYA-ALL, and that AYA-ALL may be a distinct clinical entity. 27019113 PubMed Yasuda et al., 2016, Nat. Genet. 4 accepted 1276 524 34321 Somatic 2016-06-28 01:55:03 UTC https://civicdb.org/links/evidence_items/1276 https://civicdb.org/links/variants/524 https://civicdb.org/links/genes/34321 false DUX4 100288687 Fusion Acute Lymphoblastic Leukemia 9952 Prognostic Supports C Better Outcome Ph- ALL (Philadelphia chromosome negative acute lymphoblastic leukemia) gene expression profiles cluster into two main groups, Ph like and non-Ph like ALL. Non-Ph like ALL have favorable outcomes when compared with Ph like ALL. DUX4 fusions were discovered in a subset of Ph- ALL tumors through RNA-seq, and their mutation profile was found to cluster with non-Ph like ALL. It was found that patients with DUX4 fusions (N=9) had improved disease free survival over Ph like ALL patients (N=6) in the study. Eight years after complete remission, DUX4 fusion positive patients had over 0.8 disease free survival probability. 27019113 PubMed Yasuda et al., 2016, Nat. Genet. 3 accepted 1277 524 34321 Somatic 2016-06-29 21:07:19 UTC https://civicdb.org/links/evidence_items/1277 https://civicdb.org/links/variants/524 https://civicdb.org/links/genes/34321 false B4GALT1 2683 Overexpression Renal Cell Carcinoma 4450 Prognostic Supports B Poor Outcome 438 patients with non-metastatic clear-cell renal carcinoma were were retrospectively analysed for B4GALT1 expression via IHC. High B4GALT1 expression was associated with poor overall survival (P<0.001 and P<0.001 in training and validation cohort) and identified as an independent adverse prognostic factor for survival (P=0.007 and P=0.002). 27092876 PubMed Xie et al., 2016, Oncotarget 3 accepted 1278 525 2239 9 33110635 33167354 ENST00000379731.4 75 GRCh37 N/A 2016-06-21 18:29:40 UTC https://civicdb.org/links/evidence_items/1278 https://civicdb.org/links/variants/525 https://civicdb.org/links/genes/2239 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Alectinib Predictive Supports B Sensitivity/Response In this Phase I trial (NCT01588028) in 47 patients, alectinib was assessed for its effectiveness in treating locally advanced or metastatic ALK-positive NSCLC that had progressed or been resistant to crizotinib treatment. ALK rearrangement was assessed via approved break apart FISH kit, and patients with asymptomatic CNS metastases were also included. Patients were divided into different cohorts receiving different doses of alectinib. In the 600 mg cohort (N=13), there were 4 confirmed partial responses, 3 unconfirmed partial responses and 3 instances of stable disease. Also, five of nine patients throughout the cohorts with measurable baseline CNS lesions showed partial response to alectinib. Cerebrospinal fluid levels of alectinib increased linearly with blood alectinib levels, indicating it effectively crossed the blood-brain barrier. 25153538 PubMed Gadgeel et al., 2014, Lancet Oncol. NCT01588028 4 accepted 1279 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-06-22 19:06:51 UTC https://civicdb.org/links/evidence_items/1279 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false BCL2L11 10018 Deletion Polymorphism Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports B Resistance DNA sequencing was performed in five Ph+ CML samples with sensitivity or resistance to imatinib. A structural variation in BIM2 (BCL2L11) with an identical 2,903-bp genomic deletion was identified in all three resistant samples. 2,597 healthy individuals were screened and the deletion polymorphism was identified in 12.3% of East Asian Population but 0% in African or European Population. In-vitro, imatinib-induced apoptosis was reduced in cells harboring the BIM deletion polymorphism. Two East Asian CML cohorts (n=203) treated with imatinib were analzed for the polymorphism. Overall odds ratio for resistant disease among subjects with the deletion polymorphism compared to those without it was 2.94 (P = 0.02, 95% CI 1.17–7.43). Patients with the polymorphism, compared to those without, were more likely to be resistant without BCR-ABL mutations than resistant with BCR-ABL mutation or sensitive (odds ratio = 1.90, 95% CI 1.08–4.35). 22426421 PubMed Ng et al., 2012, Nat. Med. 4 accepted 1280 526 7953 2 111883195 111886097 ENST00000393256.3 75 GRCh37 Common Germline 2016-06-20 20:50:58 UTC https://civicdb.org/links/evidence_items/1280 https://civicdb.org/links/variants/526 https://civicdb.org/links/genes/7953 false BCL2L11 10018 Deletion Polymorphism Lung Non-small Cell Carcinoma 3908 Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Predictive Supports B Resistance The BIM (BCL2L11) deletion polymorphism was identified in an EGFR Mutant NSCLC cell line with resistance to EGFR-TKI (HCC2779). Introduction of this polymorphism in a previously EGFR-inhibitor sensitive cell line led to TKI-resistance. In 141 NSCLC patients with EGFR mutations, the presence of the polymorphism (N=26) was predictive of a significantly shorter PFS under treatment with EGFR-TKI (6.6 months vs. 11.9 months, p = 0.0027). Patients received either gefitinib only (N=136) or erlotinib only (N=5). 22426421 PubMed Ng et al., 2012, Nat. Med. 4 accepted 1281 526 7953 2 111883195 111886097 ENST00000393256.3 75 GRCh37 Common Germline 2016-08-15 20:00:20 UTC https://civicdb.org/links/evidence_items/1281 https://civicdb.org/links/variants/526 https://civicdb.org/links/genes/7953 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Alectinib Predictive Supports A Sensitivity/Response In this Phase II trial of 87 patients (NCT01871805), alectinib was assayed for safety and efficacy in ALK positive NSCLC that had progressed on crizotinib. Of 69 patients with measurable disease, 35 achieved objective response, with median duration of response 13.5 months. Of 16 patients with measurable CNS disease, four achieved CNS complete response and 8 showed CNS partial response. median duration of CNS response was 11.1 months. 2 deaths were observed, and 1 was judged related to study treatment. 26708155 PubMed Shaw et al., 2016, Lancet Oncol. NCT01871805 5 accepted 1282 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2020-05-08 15:45:09 UTC https://civicdb.org/links/evidence_items/1282 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion I1171 Lung Non-small Cell Carcinoma 3908 Alectinib Predictive Supports C Resistance The I1171T mutation in ALK fusions was found in a NSCLC patient shown positive for ALK rearrangement via break apart FISH assay, who progressed after 8 months of crizotinib, and then progressed again after 4 months of alectinib. The MGH056-1 cell line was derived from this patient, and this cell line was resistant to alectinib. Sequencing of MGH056-1 cells revealed the I1171T mutation in ALK. In cell culture studies Ba/F3 cells with EML4-ALK I1171T required more that 10x the concentration of alectinib to significantly reduce viability that was required for EML4-ALK wild-type expressing cells. Computer simulation studies indicated that the I1171T mutation interfered with alectinib binding at the ALK active site. 25228534 PubMed Katayama et al., 2014, Clin. Cancer Res. 4 accepted 1283 527 1 2 29445213 29445213 A G ENST00000389048.3 75 GRCh37 Multiple case reports indicate that the I1171T missense mutation in ALK-rearranged non-small cell lung cancer (NSCLC) confers resistance to crizotinib and alectinib but is sensitive to ceritinib treatment. These results have been validated in vitro. In vitro evidence indicates this mutation interferes with alectinib binding the active site of ALK and may explain the sensitivity to the structurally distinct ALK inhibitor ceritinib. Somatic 2016-11-04 16:33:22 UTC https://civicdb.org/links/evidence_items/1283 https://civicdb.org/links/variants/527 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion I1171 Lung Non-small Cell Carcinoma 3908 Ceritinib Predictive Supports C Sensitivity/Response The MGH056-1 cell line was derived from an NSCLC patient with ALK-rearrangement who had progressed on crizotinib and then on alectinib. the cell line was also resistant to crizotinib and alectinib, and sequencing of ALK from the cell line revealed the I1171T mutation. Further testing of this mutation in BaF3 cells revealed that cells expressing EML4-ALk with I1171T mutation required 10x higher concentration to induce cell death than BaF3 cells with wild-type EML4-ALK. In contrast, ceritinib caused loss of viability in EML4-ALK wild-type and I1171T BaF3 cells at comparable concentrations. Ceritinib was also effective at killing MGH056-1 cells that were resistant to alectinib, and reduced Akt and ERK phosphorylation in these cells. Finally, administration of ceritinib to the crizotinib and alectinib resistant patient let to tumor regression and partial response lasting 7 months. 25228534 PubMed Katayama et al., 2014, Clin. Cancer Res. 4 accepted 1284 527 1 2 29445213 29445213 A G ENST00000389048.3 75 GRCh37 Multiple case reports indicate that the I1171T missense mutation in ALK-rearranged non-small cell lung cancer (NSCLC) confers resistance to crizotinib and alectinib but is sensitive to ceritinib treatment. These results have been validated in vitro. In vitro evidence indicates this mutation interferes with alectinib binding the active site of ALK and may explain the sensitivity to the structurally distinct ALK inhibitor ceritinib. Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1284 https://civicdb.org/links/variants/527 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion I1171 Lung Non-small Cell Carcinoma 3908 TAE684 Predictive Supports D Sensitivity/Response The I1171T ALK kinase domain mutaion was found in the MGH056-1 cell line which was derived from an ALK rearranged NSCLC patient who had progressed on crizotinib and then on alectinib given at lower dose (300mg twice daily). Ectopic expression of EML4-ALK I1171T in Ba/F3 cells made these cells moderately resistant to crizotinib and resistant to alectinib. In contrast, the frequently used tool compound TAE684 was equally effective against EML4-ALK wild-type and I1171T, causing cell death at 1000x lower concentration then in unaltered Ba/F3 cells supplemented with IL3. 25228534 PubMed Katayama et al., 2014, Clin. Cancer Res. 3 accepted 1285 527 1 2 29445213 29445213 A G ENST00000389048.3 75 GRCh37 Multiple case reports indicate that the I1171T missense mutation in ALK-rearranged non-small cell lung cancer (NSCLC) confers resistance to crizotinib and alectinib but is sensitive to ceritinib treatment. These results have been validated in vitro. In vitro evidence indicates this mutation interferes with alectinib binding the active site of ALK and may explain the sensitivity to the structurally distinct ALK inhibitor ceritinib. Somatic 2016-11-03 18:58:46 UTC https://civicdb.org/links/evidence_items/1285 https://civicdb.org/links/variants/527 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK V1180L Lung Non-small Cell Carcinoma 3908 Alectinib Predictive Supports D Resistance The EML4 ALK variant 1 containing NSCLC cell line H3122 is highly sensitive to alectinib, and an alectinib resistant derivative cell line H3122 CHR-A1 was generated by incubation of H3122 in increasing levels of alectinib culminating in 1 micro-molar, over a course of 7 months. The ALK kinase domain mutation V1180L was found in these cells, and Ba/F3 cells expressing EML4 ALK V1180L were highly resistant to alectinib. Simulations indicated that the V1180L mutation interfered with alectinib binding. The V1180L mutation was found to be more resistant to alectinib than the I1171T mutation found in an ALK-positive NSCLC patient who developed alectinib resistance on lower dose alectinib (300mg twice daily). 25228534 PubMed Katayama et al., 2014, Clin. Cancer Res. 3 accepted 1286 528 1 2 29443679 29443679 C G ENST00000389048.3 75 GRCh37 The V1180L missense mutation was identified in a mutagenesis screen to find mutations that conferred resistance to alectinib in a non-small cell lung cancer cell line. This mutation shows resistance to crizotinib and alectinib but sensitivity to TAE684, ceritinib and more mild sensitivity to brigatinib. Similar to I1171T, it resides in the ATP pocket of ALK and likely interferes with alectinib and crizotinib binding as a mechanism of resistance. Somatic 2016-08-28 22:24:42 UTC https://civicdb.org/links/evidence_items/1286 https://civicdb.org/links/variants/528 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion I1171 Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports D Resistance The MGH056-1 cell line was derived from a patient with ALK rearranged NSCLC who had progressed on crizotinib and then on lower dose alectinib (300 mg twice daily). The I1171T ALK kinase domain mutation was found in this cell line (established after alectinib resistance). MGH056-1 cells were resistant to crizotinib (IC50 236nmol/L; aproximately 50x higher than for ceritinib). About 50 fold higher concentration of crizotinib was required to inhibit Ba/F3 cells expressing EML4 ALK I1171T than was required for EML4 ALK wild-type. 25228534 PubMed Katayama et al., 2014, Clin. Cancer Res. 3 accepted 1287 527 1 2 29445213 29445213 A G ENST00000389048.3 75 GRCh37 Multiple case reports indicate that the I1171T missense mutation in ALK-rearranged non-small cell lung cancer (NSCLC) confers resistance to crizotinib and alectinib but is sensitive to ceritinib treatment. These results have been validated in vitro. In vitro evidence indicates this mutation interferes with alectinib binding the active site of ALK and may explain the sensitivity to the structurally distinct ALK inhibitor ceritinib. Somatic 2016-07-13 18:40:04 UTC https://civicdb.org/links/evidence_items/1287 https://civicdb.org/links/variants/527 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK V1180L Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports D Resistance The alectinib resistant cell line H3122 CHR-A1 was generated by culturing of the EML4-ALK (variant 1) containing cell line H3122 with increasing levels of alectinib. Molecular characterization of H3122 CHR-A1 revealed a V1180L ALK kinase domain mutation. The H3122 CHR-A1 cell line required approximately 10 fold increase in crizotinib concentration to induce similar levels of cell death to H3122. Ectopic expression of EML4-ALK V1180L rendered Ba/F3 cells moderately less susceptible to crizotinib than ectopic EML4-ALK. 25228534 PubMed Katayama et al., 2014, Clin. Cancer Res. 2 accepted 1288 528 1 2 29443679 29443679 C G ENST00000389048.3 75 GRCh37 The V1180L missense mutation was identified in a mutagenesis screen to find mutations that conferred resistance to alectinib in a non-small cell lung cancer cell line. This mutation shows resistance to crizotinib and alectinib but sensitivity to TAE684, ceritinib and more mild sensitivity to brigatinib. Similar to I1171T, it resides in the ATP pocket of ALK and likely interferes with alectinib and crizotinib binding as a mechanism of resistance. Somatic 2016-06-22 19:30:08 UTC https://civicdb.org/links/evidence_items/1288 https://civicdb.org/links/variants/528 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK V1180L Lung Non-small Cell Carcinoma 3908 Ceritinib Predictive Supports D Sensitivity/Response Passaging of the alectinib sensitive EML4-ALK containing H3122 NSCLC cell line with increasing levels of alectinib resulted in an alectinib resistant derivative of this cell line named H3122 CHR-A1. A V1180L missense mutation was found in the kinase domain of ALK in H3122 CHR-A1 cells. Both H3122 and H3122 CHR-A1 cells were highly and equally sensitive to ceritinib induced death. In Ba/F3 cells, ectopic expression of EML4-ALK V1180L rendered cells significantly more sensitive to ceritinib than Ba/F3 containing EML4-ALK I1171T mutant (alectinib and crizotinib resistant) or EML4-ALK wt. 25228534 PubMed Katayama et al., 2014, Clin. Cancer Res. 3 accepted 1289 528 1 2 29443679 29443679 C G ENST00000389048.3 75 GRCh37 The V1180L missense mutation was identified in a mutagenesis screen to find mutations that conferred resistance to alectinib in a non-small cell lung cancer cell line. This mutation shows resistance to crizotinib and alectinib but sensitivity to TAE684, ceritinib and more mild sensitivity to brigatinib. Similar to I1171T, it resides in the ATP pocket of ALK and likely interferes with alectinib and crizotinib binding as a mechanism of resistance. Somatic 2016-08-07 00:34:45 UTC https://civicdb.org/links/evidence_items/1289 https://civicdb.org/links/variants/528 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK V1180L Lung Non-small Cell Carcinoma 3908 TAE684 Predictive Supports D Sensitivity/Response The V1180L mutation in the kinase domain of rearranged ALK was found in an alectinib resistant cell line named H3122 CHR-A1, which was derived from the alectinib sensitive EML4-ALK variant 1 containing NSCLC cell line H3122 by passaging into higher concentrations of alectinib. This cell line is a model for gain of alectinib resistance, and also shows resistance to crizotinib. On the other hand, the often used tool ALK inhibitor TAE684 was highly effective in killing H3122 CHR-A1, where H3122 cells were only slightly more sensitized to TAE684-induced cell death. Ectopic expression of EML4-ALK V1180L in Ba/F3 cells caused IL3 independent growth as well as marked sensitization to TAE684, to a level greater than that seen in EML4-ALK I1171T (alectinib resistance mutation) or EML4-ALK wt, and over 1000x greater sensitivity than unaltered Ba/F3 + IL3. 25228534 PubMed Katayama et al., 2014, Clin. Cancer Res. 3 accepted 1290 528 1 2 29443679 29443679 C G ENST00000389048.3 75 GRCh37 The V1180L missense mutation was identified in a mutagenesis screen to find mutations that conferred resistance to alectinib in a non-small cell lung cancer cell line. This mutation shows resistance to crizotinib and alectinib but sensitivity to TAE684, ceritinib and more mild sensitivity to brigatinib. Similar to I1171T, it resides in the ATP pocket of ALK and likely interferes with alectinib and crizotinib binding as a mechanism of resistance. Somatic 2016-08-28 22:25:36 UTC https://civicdb.org/links/evidence_items/1290 https://civicdb.org/links/variants/528 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK V1180L Lung Non-small Cell Carcinoma 3908 Brigatinib Predictive Supports D Sensitivity/Response ALK mutation V1180L was found in an H3122 derivative cell line that had become alectinib resistant after being passaged in increasing levels of alectinib. EML4-ALK V1180L and EML4-ALK wild-type were ectopically expressed in Ba/F3 cells, and brigatinib showed strong activity against both variants. The IC50 for brigatinib against EML4-ALK wild-type was 0.95, which is about 3x higher than the IC50 that was observed for alectinib, but about 6x lower than that for crizotinib. In contrast, the IC50 for brigatinib against the alectinib resistance variant EML4-ALK V1180L was 0.49, indicating increased sensitivity to brigatinib over non mutant EML4-ALK. 25228534 PubMed Katayama et al., 2014, Clin. Cancer Res. 2 accepted 1291 528 1 2 29443679 29443679 C G ENST00000389048.3 75 GRCh37 The V1180L missense mutation was identified in a mutagenesis screen to find mutations that conferred resistance to alectinib in a non-small cell lung cancer cell line. This mutation shows resistance to crizotinib and alectinib but sensitivity to TAE684, ceritinib and more mild sensitivity to brigatinib. Similar to I1171T, it resides in the ATP pocket of ALK and likely interferes with alectinib and crizotinib binding as a mechanism of resistance. Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1291 https://civicdb.org/links/variants/528 https://civicdb.org/links/genes/1 false ATM 472 Underexpression Pancreatic Cancer 1793 Prognostic Supports B Poor Outcome Absent expression of ATM, as assessed by IHC in 133 pancreatic ductal adenocarcinomas, was found to be associated with dismal prognosis (median survival, 9.6 months), whereas expression of ATM was associated with increased survival (17.7 months, P = 0.001). Furthermore loss of expression of nuclear phosphorylated Ser1981-ATM (IHC) was indicative of the worst prognosis (median survival, 10.8 vs 14.3 months [low expression] vs 31.1 months [high expression], P < 0.001). 25423555 PubMed Kamphues et al., 2015, Pancreas 2 accepted 1292 179 69 11 108093559 108239826 ENST00000278616.4 75 GRCh37 N/A 2016-05-04 21:28:10 UTC https://civicdb.org/links/evidence_items/1292 https://civicdb.org/links/variants/179 https://civicdb.org/links/genes/69 false SIRT1 23411 Overexpression Pancreatic Ductal Carcinoma 3587 Prognostic Supports B Poor Outcome Nuclear Sirt1 expression was identified by IHC in 36 (27.9%) of 129 pancreatic ductal adenocarcinoma cases. SIRT1 expression was associated with poor survival in univariate (p = 0.002) and multivariate (HR 1.65, p = 0.045) analyses. Overexpression of Sirt1 in pancreas cancer cell lines MiaPaCa-2 and PANC-1 led to increased cell viability. 24088390 PubMed Stenzinger et al., 2013, BMC Cancer 3 accepted 1293 529 9538 10 69644427 69678147 ENST00000212015.6 75 GRCh37 N/A 2016-05-04 21:35:02 UTC https://civicdb.org/links/evidence_items/1293 https://civicdb.org/links/variants/529 https://civicdb.org/links/genes/9538 false SIRT1 23411 Overexpression Pancreatic Cancer 1793 Niacinamide Predictive Supports D Resistance In-vitro study with MiaPaCa-2 and PANC-1 pancreatic cancer cell lines. Inhibition of Sirt1 by increasing concentrations of nicotinamide led to a decrease in viability. Gefitinib treatment with concentrations of 50 μM showed similar effects as observed for the application of 25 mM nicotinamide. Combinatory treatment with gefitinib and nicotinamide showed a synergistic effect on cell viability. In cell lines overexpressing Sirt1, higher concentrations of nicotinamide were required to abrogate increased cell viability mediated by Sirt1 overexpression compared to controls. 24088390 PubMed Stenzinger et al., 2013, BMC Cancer 1 accepted 1294 529 9538 10 69644427 69678147 ENST00000212015.6 75 GRCh37 N/A 2016-05-04 21:36:34 UTC https://civicdb.org/links/evidence_items/1294 https://civicdb.org/links/variants/529 https://civicdb.org/links/genes/9538 false FLT3 2322 TKD MUTATION Acute Myeloid Leukemia 9119 Midostaurin Predictive Supports B Sensitivity/Response In a phase 2 clinical study of 95 AML/high-risk MDS patients treated with either 50 or 100 mg midostaurin, 35 harbored FLT3 mutations (26 had FLT3 ITD, 9 had FLT3 D835Y mutations). A higher percentage of patients saw blast reductions in the FLT3 mutant group than in the FLT3 wild type group (71 vs 42%). Only one permanent response occurred in a FLT3 mutant patient receiving the 100 mg dose. No differences were observed in toxicity or response rate between the two doses of midostaurin. 20733134 PubMed Fischer et al., 2010, J. Clin. Oncol. 3 accepted 1295 56 24 13 28592642 28592642 C A ENST00000241453.7 75 GRCh37 FLT3 tyrosine kinase domain mutations (FLT3-TKD) are much less common than FLT3-ITD (internal tandem duplication) mutations and may not confer the same prognostic impact. Although the majority of mutations are point mutations effecting D835 (most frequently D835Y), a small proportion involve an in-frame deletion of I836. These mutations are within the activation loop of the second tyrosine kinase domain of FLT3 and thought to result in constitutive activation of the receptor. Somatic 2016-10-25 04:27:24 UTC https://civicdb.org/links/evidence_items/1295 https://civicdb.org/links/variants/56 https://civicdb.org/links/genes/24 false PIK3CA 5290 Mutation Her2-receptor Positive Breast Cancer 0060079 Everolimus Predictive Supports B Sensitivity/Response Archival tumor samples from 549 patients from the BOLERO-1 and -3 trials were analyzed for alterations in the PI3K pathway using next-generation sequencing, immunohistochemistry (IHC) and Sanger sequencing. In the BOLERO trials, patients with HER2-overexpressing advanced breast cancer were treated with trastuzumab, chemotherapy and randomized to receive either everolimus or placebo. In the pooled analysis of both trials, patients with PI3K mutations had longer progression-free survival with everolimus compared to placebo (HR 0.67 95%CI 0.45 to 1.00, P=0.05) whereas patients with PI3K wild type status did not benefit significantly (HR 1.1, 95%CI 0.83 to 1.46, P=0.5). The same was found when PI3K mutations, PTEN loss and AKT E17K mutations were combinedly analyzed as hyperactive PI3K pathway. Patients with PI3K hyperactive pathway had a hazard ratio of 0.67 (95%CI 0.48 to 0.93, P=0.02) compared to HR 1.19 (95%CI 0.87 to 1.62, P=0.28) in patients with PI3K normal pathway. These trends were independently confirmed in both trials but only pooled results showed consistent statistical significance. 27091708 PubMed André et al., 2016, J. Clin. Oncol. 4 accepted 1296 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-05-25 05:58:14 UTC https://civicdb.org/links/evidence_items/1296 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PTEN 5728 Loss Her2-receptor Positive Breast Cancer 0060079 Everolimus Predictive Supports B Sensitivity/Response Archival tumor samples from 549 patients from the BOLERO-1 and -3 trials were analyzed for alterations in the PI3K pathway using next-generation sequencing, immunohistochemistry (IHC) and Sanger sequencing. In the BOLERO trials, patients with HER2-overexpressing advanced breast cancer were treated with trastuzumab, chemotherapy and randomized to receive either everolimus or placebo. In the pooled analysis of both trials, patients with PTEN loss (as defined by IHC staining intensity and proportion of positive tumor cells) had a longer progression-free survival with everolimus compared to placebo (HR 0.54 (95%CI 0.31 to 0.96, P=0.04) whereas patients with PTEN normal status had a hazard ration of 1.00 (95%CI 0.8 to 1.26, P=0.97). The same was found when PI3K mutations, PTEN loss and AKT E17K mutations were combined and analyzed as hyperactive PI3K pathway. Patients with PI3K hyperactive pathway had a hazard ratio of 0.67 (95%CI 0.48 to 0.93, P=0.02) compared to HR 1.19 (95%CI 0.87 to 1.62, P=0.28) in patients with PI3K normal pathway. These trends were independently confirmed in both trials but only pooled results showed consistent statistical significance. 27091708 PubMed André et al., 2016, J. Clin. Oncol. 4 accepted 1297 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-06-28 00:04:21 UTC https://civicdb.org/links/evidence_items/1297 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false KRAS 3845 G12R Pancreatic Cancer 1793 Prognostic Supports B Poor Outcome In 242 patients with unresectable pancreatic cancer, the presence of KRAS G12R (N=17) or G12D (N=92) was associated with poorer prognosis (overall survival HR 1.6; 95% confidence interval 1.11-2.28). 22983505 PubMed Ogura et al., 2013, J. Gastroenterol. 4 accepted 1298 530 30 12 25398285 25398285 C G ENST00000256078.4 75 GRCh37 Somatic 2016-08-15 20:00:41 UTC https://civicdb.org/links/evidence_items/1298 https://civicdb.org/links/variants/530 https://civicdb.org/links/genes/30 false KRAS 3845 G12D Pancreatic Cancer 1793 Prognostic Supports B Poor Outcome In 219 patients with metastatic pancreatic ductal adenocarcinoma, a multivariate analysis identified KRAS G12D mutations as an independent predictor of poorer prognosis both in patients that have received chemotherapy (N=49/162), and the entire series (N=73/219). HR of 1.84 (P=0.02) and 1.44 (P=0.01), respectively. 27010960 PubMed Bournet et al., 2016, Clin Transl Gastroenterol 4 accepted 1300 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2016-08-15 20:00:59 UTC https://civicdb.org/links/evidence_items/1300 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false ROS1 6098 Rearrangement Colorectal Adenocarcinoma 0050861 Crizotinib Predictive Supports E Sensitivity/Response A tissue microarray of 268 patients with histologically confirmed colorectal adenocarcinoma was performed to search for ROS1 gene fusion events to guide potential targeted therapy in future cases. Break apart FISH assay, which does not distinguish ROS1-fusion partner, was used on the tissue microarray to determine ROS1 fusion status. 2 cases of ROS1 fusions were found. 1 case was verified by RT-PCR to be a SLC34A2-ROS1 fusion, but this case was also positive for BRAF V600E. The second case of ROS1 fusion was of undetermined fusion partner, where known ROS1 fusion parters SLC34A2, CD74 and SDC4 were tested. This case did not have KRAS or BRAF mutations, indicating that ROS1 fusion may act in a small subset of colorectal cancer as a driver targetable by crizotinib or other inhibitors. 24296758 PubMed Aisner et al., 2014, Mol. Cancer Res. 2 accepted 1301 269 4941 6 117609463 117747018 ENST00000368508.3 75 GRCh37 ROS1 is a receptor tyrosine kinase that frequently forms gene fusions in several cancer types. Approximately 2% of NSCLC patients harbor a ROS1 gene fusion. Several fusion partners have been described with a constant ROS1-breakpoint, maintaining the kinase domain (Solomon B, 2015). Following case-studies and retrospective analyses, an expansion cohort of a phase-1 study showed clinical benefit of crizotinib in ROS1 rearranged NSCLC. The benefit was independent of the type of ROS1-rearrangement (Shaw et. al.,2014). Somatic 2016-05-12 21:54:51 UTC https://civicdb.org/links/evidence_items/1301 https://civicdb.org/links/variants/269 https://civicdb.org/links/genes/4941 false TP53 7157 P72R Breast Cancer 1612 Predisposing Does Not Support B Positive Large meta-analysis of 5,191 breast cancer patients and 3,834 controls did not find a conclusive link between codon 72 allele and breast cancer susceptibility. Odds ratios were 0.98 (95% CI, 0.91–1.05) for heterozygotes and 0.97 (95% CI, 0.86–1.11) in homozygotes (per-allele OR, 0.98; 95% CI, 0.91–1.04). Median age of onset was also not different between genotypes (GG: 49 years, GC: 50, CC: 50). 17909070 PubMed Schmidt et al., 2007, Cancer Res. 4 accepted 1302 531 45 17 7579472 7579472 G C ENST00000269305.4 75 GRCh37 This polymorphism is relatively widely studied across cancer types, but meta-analyses in breast, lung and cervical cancer cohorts have so far been inconclusive as to the significance of a patient's genotype at this locus as it relates to cancer susceptibility and prognosis. Common Germline 2016-11-03 18:31:13 UTC https://civicdb.org/links/evidence_items/1302 https://civicdb.org/links/variants/531 https://civicdb.org/links/genes/45 false TP53 7157 P72R Lung Carcinoma 3905 Prognostic Does Not Support B Poor Outcome Pooled data from 13 studies of patients with lung cancer found little effect of codon 72 allele on the overall survival of patients with lung cancer. Proline homozygous patients were correlated with slightly poorer outcome, odds ratio 1.18 with a 95% confidence interval of 0.99-1.41. Heterozygotes had an OR of 1.02 (95% CI 0.86-1.20). Authors conclude that the effect of these alleles on prognosis in lung cancer is inconclusive at best. 12840112 PubMed Matakidou et al., 2003, Mutagenesis 3 accepted 1303 531 45 17 7579472 7579472 G C ENST00000269305.4 75 GRCh37 This polymorphism is relatively widely studied across cancer types, but meta-analyses in breast, lung and cervical cancer cohorts have so far been inconclusive as to the significance of a patient's genotype at this locus as it relates to cancer susceptibility and prognosis. Common Germline 2016-06-08 22:31:05 UTC https://civicdb.org/links/evidence_items/1303 https://civicdb.org/links/variants/531 https://civicdb.org/links/genes/45 false TP53 7157 P72R Cervical Cancer 4362 Prognostic Does Not Support B Poor Outcome In a relatively small meta-analysis of 119 women with cervical cancer and 127 controls, associations with homozygosity for arginine, and heterozygosity at this locus were both associated with odds ratios above one (3.5 and 2.2, respectively) after adjusting for age and HPV infection. However, both confidence intervals had minimums below one (0.9 and 0.6, respectively). So the overall conclusion remains mixed on the significance of this polymorphism in the prognosis for cervical cancer. 11535556 PubMed Klug et al., 2001, Cancer Epidemiol. Biomarkers Prev. 2 accepted 1304 531 45 17 7579472 7579472 G C ENST00000269305.4 75 GRCh37 This polymorphism is relatively widely studied across cancer types, but meta-analyses in breast, lung and cervical cancer cohorts have so far been inconclusive as to the significance of a patient's genotype at this locus as it relates to cancer susceptibility and prognosis. Common Germline 2016-06-08 22:34:06 UTC https://civicdb.org/links/evidence_items/1304 https://civicdb.org/links/variants/531 https://civicdb.org/links/genes/45 false PALB2 79728 Biallelic Inactivation Pancreatic Cancer 1793 Mitomycin Predictive Supports C Sensitivity/Response In a patient with gemcitabine-refractory pancreatic cancer, a tumor-derived xenograft was found to be responsive to Mitomycin C. After disease progression, the patient was started on a regimen of mitomycin C, and the patient was shown to be asymptomatic after 3 years of follow-up. 21135251 PubMed Villarroel et al., 2011, Mol. Cancer Ther. NCT00276744 4 accepted 1305 532 15013 16 23614491 23652631 ENST00000261584.4 75 GRCh37 Somatic 2016-11-03 18:34:35 UTC https://civicdb.org/links/evidence_items/1305 https://civicdb.org/links/variants/532 https://civicdb.org/links/genes/15013 false SMAD4 4089 Expression Pancreatic Ductal Adenocarcinoma 3498 Prognostic Supports B Better Outcome In 249 patients that have undergone a pancreaticoduodenectomy (Whipple) for the resection of pancreatic ductal adenocarcinoma, expression of SMAD4 is associated with favorable prognosis. SMAD4 was assessed by IHC in 56 of 249 (22%). Relative hazard of mortality for cancers lacking SMAD4 after adjusting for other prognostic factors was 1.36 (95% confidence interval, 1.01-1.83; P = 0.04). 11751510 PubMed Tascilar et al., 2001, Clin. Cancer Res. 3 accepted 1306 533 77 18 48556583 48611409 ENST00000342988.3 75 GRCh37 N/A 2016-07-04 20:34:39 UTC https://civicdb.org/links/evidence_items/1306 https://civicdb.org/links/variants/533 https://civicdb.org/links/genes/77 false FANCC 2176 Loss-of-function Pancreatic Cancer 1793 Gemcitabine,Cisplatin,Mitomycin,Chlorambucil,Melphalan Substitutes Predictive Supports D Sensitivity/Response In the pancreatic cell lines PL11 (FANCC homozygous deletion) and Hs766T (FANCG-mutated), sensitivity to DNA cross-linking agents was observed. PL11 cells (empty vector transduced) were more sensitive to mitomycin C (MMC), cisplatin, chlorambucil, and melphalan than PL11 cells transduced with a vector wildtype FANCC. Similarly, mouse xenografts of PL11 cells (empty vector) were more sensitive to MMC or gemcitabine than PL11 cells expressing a wildtype FANCC. 16243825 PubMed van der Heijden et al., 2005, Clin. Cancer Res. 3 accepted 1307 534 1811 9 97861336 98079984 ENST00000289081.3 75 GRCh37 Unknown 2016-06-27 23:42:12 UTC https://civicdb.org/links/evidence_items/1307 https://civicdb.org/links/variants/534 https://civicdb.org/links/genes/1811 false BRCA2 675 Loss-of-function Pancreatic Cancer 1793 Mitomycin Predictive Supports D Sensitivity/Response In pancreatic cell lines PL11 (FANCC-deficient) and CAPAN1 (BRCA2-mutated), sensitivity to DNA cross-linking agents was observed compared to FANCC/BRCA2 wildtype cell lines (Su86.86, CFPAC, AsPc1, and MiaPaCa2). Mitomycin C specifically led to regression in 8/11 xenografts of the CAPAN1 cell line compared to 2/9 in the CFPAC (BRCA2 wildtype) cell line. 16243825 PubMed van der Heijden et al., 2005, Clin. Cancer Res. 2 accepted 1308 132 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 BRCA2 loss of function mutations have been shown to increase risk of breast and ovarian cancer in those carrying the allele in their germline. Treating BRCA mutant patients with PARP inhibitors such as Olaparib has led to significant response. Rare Germline 2016-06-27 15:34:38 UTC https://civicdb.org/links/evidence_items/1308 https://civicdb.org/links/variants/132 https://civicdb.org/links/genes/7 false PDGFRA 5156 I843DEL Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports D Sensitivity/Response 15/127 patients with KIT-WT metastatic gastrointestinal stromal tumors were tested for PDGFRA mutations. 6 GISTs harbored PDGFRA mutations. 1 patient had a deletion of I843. CHO cells expressing this variant showed similar sensitivity to imatinib as cells expressing wildtype PDGFRA. 2/3 patients with a mutation determined to be sensitive in vitro achieved partial response on imatinib treatment. It is not noted whether the patient whose GISTs harbored I843del had partial response or progressive disease. 14645423 PubMed Heinrich et al., 2003, J. Clin. Oncol. 2 accepted 1309 101 38 4 55152095 55152097 ATC ENST00000257290.5 75 GRCh37 PDGFRA D842 mutations are characterized broadly as imatinib resistance mutations. This is most well characterized in gastrointestinal stromal tumors, but other cell lines containing these mutations have been shown to be resistant as well. In imatinib resistant cell lines, a number of other therapeutics have demonstrated efficacy. These include; crenolanib, sirolimus, and midostaurin (PKC412). Somatic 2019-02-23 02:08:02 UTC https://civicdb.org/links/evidence_items/1309 https://civicdb.org/links/variants/101 https://civicdb.org/links/genes/38 false PDGFRB 5159 EBF1::PDGFRB Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Juvenile onset Imatinib Predictive Supports C Sensitivity/Response A 10-year-old boy with B-cell acute lymphoblastic leukemia refractory to conventional chemotherapy and harboring an EBF1-PDGFRB fusion responded to imatinib plus induction chemotherapy (vincristine, daunorubicin, prednisone, and intrathecal methotrexate). Complete remission was achieved with bone marrow MRD of 0.059% by flow cytometry and normal PDGFRB by FISH. Consolidation therapy with cyclophosphamide, cytarabine, mercaptopurine, and imatinib followed and the patient was still in remission 10 months after beginning imatinib. 23835704 PubMed Weston et al., 2013, J. Clin. Oncol. 3 accepted 1310 535 4176 5 158134987 158526769 ENST00000517373.1 5 149493400 149505140 ENST00000261799.4 75 GRCh37 EBF1-PDGFRB fusions are associated with Ph-like acute lymphoblastic leukemia lacking the BCR-ABL fusion. Case reports have shown positive responses to imatinib treatment. Somatic 2021-05-11 02:35:40 UTC https://civicdb.org/links/evidence_items/1310 https://civicdb.org/links/variants/535 https://civicdb.org/links/genes/4176 false KRAS 3845 G12D Malignant Exocrine Pancreas Neoplasm 1795 Prognostic Supports B Poor Outcome In 171 patients with tumors of the exocrine pancreas, a KRAS G12D mutation (N=60) was associated with shorter overall survival than being wild-type for KRAS (N=21; Hazard Ratio: 95% CI between 1.14 and 2.67). Additionally, KRAS mutations combined with CDKN2A alterations (N=26) showed an even worse OS than those wild-type for both (N=17; HR: 95%CI 1.33-7.10). 23565280 PubMed Rachakonda et al., 2013, PLoS ONE 3 accepted 1311 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2016-11-03 19:02:35 UTC https://civicdb.org/links/evidence_items/1311 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false RB1 5925 EXPRESSION Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome Positive RB1 expression (2+ by IHC) was associated with adverse outcomes in a cohort of 73 cases with stage I and II NSCLC (P<0.001) in this retrospective study. This finding was independent from other genomic and clinical factors explored by the authors. 22619677 PubMed Zhao et al., 2012, J Oncol 2 accepted 1313 537 4795 13 48877911 49056122 ENST00000267163.4 75 GRCh37 N/A 2016-06-20 20:53:13 UTC https://civicdb.org/links/evidence_items/1313 https://civicdb.org/links/variants/537 https://civicdb.org/links/genes/4795 false CDKN2A 1029 p16 Expression Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome In a cohort of 73 patients with stage I or stage II NSCLC it was discovered that the CDKN2A protein (p16-INK4A) retrospectively evaluated via IHC was associated with adverse outcomes (p=0.004). 22619677 PubMed Zhao et al., 2012, J Oncol 2 accepted 1314 272 14 9 21968055 21974865 ENST00000498124.1 75 GRCh37 CDKN2A (p16) expression is a surrogate marker of HPV infection in oropharyngeal squamous cell carcinoma. CDKN2A and p53 are inactivated through HPV proteins E6 and E7 and therefore not altered in expression level in HPV-associated carcinomas. However, there is no perfect overlap between p16 expression and HPV status with some 10-12.5% of HPV-negative tumors expressing p16. (Seiwert, T JCO, 2014). p16 positivity is a well-established positive prognostic factor in squamous cell cancer of the head and neck in the primary and, as increasing evidence suggests, recurrent/metastatic disease settings. Predictive information from HPV status have not been established to date. A lack of benefit from EGFR-inhibitors has been proposed by some studies. Other studies were not able to reproduce this finding. Somatic 2016-06-28 00:27:56 UTC https://civicdb.org/links/evidence_items/1314 https://civicdb.org/links/variants/272 https://civicdb.org/links/genes/14 false MLH1 4292 METHYLATION Stomach Carcinoma 5517 Oxaliplatin Predictive Supports B Resistance The methylation status of MLH1 was analyzed in a study of 53 paraffin-embedded gastric cancer samples. No association was found between methylation status and clinical factors. The study showed that MLH1 methylation was associated with resistance to treatment with oxaliplatin. 24748501 PubMed Li et al., 2015, Gastric Cancer 2 accepted 1315 538 3532 Somatic 2016-06-23 22:05:07 UTC https://civicdb.org/links/evidence_items/1315 https://civicdb.org/links/variants/538 https://civicdb.org/links/genes/3532 false PTPN11 5781 Overexpression Laryngeal Carcinoma 2600 Prognostic Supports B Poor Outcome Study explored the expression of the PTPN11 protein (SHP2) and found that expression was increased in a cohort of 112 laryngeal cancer samples. Expression was also associated with poor survival (p=.02) and in vitro models showed SHP2 expression promoted tumor growth. 24297342 PubMed Gu et al., 2014, Int. J. Oncol. 2 accepted 1316 539 4685 12 112856718 112947717 ENST00000351677.2 75 GRCh37 Somatic 2016-06-23 22:07:12 UTC https://civicdb.org/links/evidence_items/1316 https://civicdb.org/links/variants/539 https://civicdb.org/links/genes/4685 false FLT3 2322 T227M Renal Cell Carcinoma 4450 Sunitinib Predictive Supports B Adverse Response In 219 patients with mostly Renal Cell Carcinoma and some Gastrointestinal Stromal tumors given sunitinib treatment, FLT3 T227M (rs1933437) was associated with the development of leukopenia. 95% confidence interval of hazard ratio of between .17 and .77. 19667267 PubMed van Erp et al., 2009, J. Clin. Oncol. 3 accepted 1317 540 24 13 28624294 28624294 G A ENST00000241453.7 75 GRCh37 FLT3 T227M (rs1933437) is a common polymorphism with a GMAF around .60 based on the Exome Aggregation Consortium (ExAC) data. Its role in cancer predisposition is still unknown, however it may be associated with the development of leukopenia in patients treated with sunitinib. Common Germline 2016-05-17 17:47:03 UTC https://civicdb.org/links/evidence_items/1317 https://civicdb.org/links/variants/540 https://civicdb.org/links/genes/24 false PALB2 79728 L531FS*30 Breast Cancer 1612 Diagnostic Supports B Positive Study explored the known PALB2 variant c.1592delT (p.L531C) in the context of breast cancer. The study found that among an augmented cohort of breast cancer patients with the variant, there was a hazard ratio of 6.1 (p=.01). Further there is weak evidence to conclude that breast cancer risk for this variant decreases with age (p=.06). 18628482 PubMed Erkko et al., 2008, Clin. Cancer Res. 3 accepted 1318 541 15013 16 23646276 23646276 ENST00000261584.4 75 GRCh37 Common Germline 2016-07-20 21:53:03 UTC https://civicdb.org/links/evidence_items/1318 https://civicdb.org/links/variants/541 https://civicdb.org/links/genes/15013 false MTOR 2475 S2215Y Endometrial Adenocarcinoma 2870 Sirolimus Predictive Supports D Sensitivity/Response Cell lines with various putative activating mutations were tested for sensitivity to rapamycin. The cell line JHUEM7 with the MTOR mutation S2215Y was hypersensitive to rapamycin treatment (IC50 of 0.23 nmol/L). 24631838 PubMed Grabiner et al., 2014, Cancer Discov 2 accepted 1319 542 2073 1 11184573 11184573 G T ENST00000361445.4 75 GRCh37 Somatic 2016-06-29 20:24:38 UTC https://civicdb.org/links/evidence_items/1319 https://civicdb.org/links/variants/542 https://civicdb.org/links/genes/2073 false MTOR 2475 C1483Y T-cell Acute Lymphoblastic Leukemia 5603 Sirolimus Predictive Supports D Sensitivity/Response Cell lines with various putative activating mutations were tested for sensitivity to rapamycin. The cell line MOLT16, with MTOR mutation C1483Y was hypersensitive to rapamycin treatment (IC50 of 0.75 nmol/L). 24631838 PubMed Grabiner et al., 2014, Cancer Discov 2 accepted 1320 543 2073 1 11217230 11217230 C T ENST00000361445.4 75 GRCh37 Somatic 2016-06-24 20:56:26 UTC https://civicdb.org/links/evidence_items/1320 https://civicdb.org/links/variants/543 https://civicdb.org/links/genes/2073 false MTOR 2475 E1799K Clear Cell Renal Cell Carcinoma 4467 Sirolimus Predictive Supports D Sensitivity/Response Cell lines with various putative activating mutations were tested for sensitivity to rapamycin. The cell line SNU349, with MTOR mutation E1799K was hypersensitive to rapamycin treatment (IC50 of 0.19 nmol/L). 24631838 PubMed Grabiner et al., 2014, Cancer Discov 2 accepted 1321 544 2073 1 11190804 11190804 C T ENST00000361445.4 75 GRCh37 Somatic 2016-06-27 15:24:35 UTC https://civicdb.org/links/evidence_items/1321 https://civicdb.org/links/variants/544 https://civicdb.org/links/genes/2073 false FGFR2 2263 N550K Endometrial Cancer 1380 PD173074 Predictive Supports D Sensitivity/Response The endometrial cancer cell lines, AN3CA and MFE296, which carry the N550K FGFR2 mutation, were found to be sensitive to FGFR inhibition with PD174074 (10 to 40x more sensitive than cell lines with wild type FGFR2.). 18757403 PubMed Byron et al., 2008, Cancer Res. 3 accepted 1322 545 22 10 123258034 123258034 A T ENST00000457416.2 75 GRCh37 Somatic 2016-06-29 20:23:46 UTC https://civicdb.org/links/evidence_items/1322 https://civicdb.org/links/variants/545 https://civicdb.org/links/genes/22 false RB1 5925 Overexpression Pancreatic Adenocarcinoma 4074 Mitomycin,Doxorubicin,Fluorouracil,Gemcitabine Substitutes Predictive Supports D Resistance In Capan-1 cell lines engineered to reduce pRB expression (by transfection with p16), resensitization to chemotherapy-induced apoptosis was observed. The effect was asserted to be specific to pRB depletion because, in two separate cell lines, also transfected with p16, that retained high pRB expression, chemotherapy resistance was still observed. 11792751 PubMed Plath et al., 2002, J. Natl. Cancer Inst. 2 accepted 1324 547 4795 13 48877911 49056122 ENST00000267163.4 75 GRCh37 Somatic 2016-06-27 15:26:45 UTC https://civicdb.org/links/evidence_items/1324 https://civicdb.org/links/variants/547 https://civicdb.org/links/genes/4795 false PPP1R15A 23645 RS557806 Colorectal Cancer 9256 FOLFIRI Regimen,Bevacizumab Combination Predictive Supports B Sensitivity/Response Exome and RNA sequencing was performed in tumor and matched normal tissue of 19 patients with metastatic colorectal cancer treated with chemotherapy and bevacizumab. The variant PPP1R15A (rs557806) showed the most significant association (P = 0.000401) with FOLFIRI-bevacizumab-driven tumor inhibition rate in exome sequencing data and the highest correlation (r = 0.74) with the drug responses in RNA sequencing data. Patients who were homozygous for the reference alleles (GG) of PPP1R15A rs557806 exhibited greater disease control rates and a tendency toward greater overall response rate than those with homozygous or heterozygous substitution alleles (GC and CC; P = 0.027 and 0.073) when treated with bevacizumab-containing regimens. PPP1R15A rs557806 nonsignificantly correlated with DCR in multivariate analysis (P = 0.054). In HCT116 xenograft tumors, tumor growth IR with FRB was 25 % in mock cells, 24 % in clones with reference alleles (G alleles) of PPP1R15A rs557806, and 17 % in clones with substitution alleles (C alleles) of PPP1R15A rs557806 (P = 0.004, day 13). FDG-PET imaging on day 7 showed FDG uptake (mean SUV max) of 0.219 and 0.500 in HCT116 xenografts expressing the reference allele (G) and substitution allele (C) of PPP1R15A rs557806, respectively (P = 0.032). 27177629 PubMed Roh et al., 2016, J. Cancer Res. Clin. Oncol. 1 accepted 1325 548 9722 19 49377242 49377242 G C ENST00000200453.5 75 GRCh37 Common Germline 2016-06-23 21:12:23 UTC https://civicdb.org/links/evidence_items/1325 https://civicdb.org/links/variants/548 https://civicdb.org/links/genes/9722 false KRAS 3845 Exon 2 Mutation Colorectal Cancer 9256 Irinotecan,Selumetinib Combination Predictive Supports B Sensitivity/Response 31 patients with KRAS exon 2 mutation (codons 12 and 13) were treated with selumetinib and irinotecan. All patients had ECOG status 0 or 1 and confirmed progression after first line therapy with oxaliplatin-based chemotherapy and bevacizumab. Patients with more than one line of therapy, MEK or B-RAF inhibitor treatment or prior irinotecan treatment were excluded. The study was terminated before full accrual due to non-protocol considerations. Three patients had a PR, 16 patients had SD >= 4 weeks. Median PFS for all patients was 105 days, median OS was 267 days. 25322874 PubMed Hochster et al., 2015, Cancer Chemother. Pharmacol. 1 accepted 1326 75 30 12 25398208 25398329 ENST00000256078.4 75 GRCh37 Exon 2 mutations have been associated with reduced response rates or resistance to EGFR inhibitors in non-small cell lung and colorectal cancer. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. Somatic 2016-06-28 15:28:54 UTC https://civicdb.org/links/evidence_items/1326 https://civicdb.org/links/variants/75 https://civicdb.org/links/genes/30 false ALK 238 F1174L Neuroblastoma 769 AZD3463 Predictive Supports D Sensitivity/Response The SH-SY5Y neuroblastoma cell line containing the F1174L ALK mutation was found to undergo cell death when treated with the ALK/IGF1R inhibitor AZD3463. These cells were more sensitive than other neuroblastoma cell lines containing wild-type ALK. Marked inhibition of soft agar colony formation of SH-SY5Y cells was also observed with drug treatment. AZD3463 inhibited Akt signaling in these cells within two hours of treatment, and activated apoptosis and autophagy pathways. Treatment of SH-SY5Y cells implanted into left kidneys of nude mice resulted in almost complete tumor regression. 26786851 PubMed Wang et al., 2016, Sci Rep 3 accepted 1327 8 1 2 29443695 29443695 G T ENST00000389048.3 75 GRCh37 ALK F1174L has been observed as recurrent in neuroblastoma, non-small cell lung cancer (NSCLC), and other cancer types. Neuroblastoma cells containing this mutation have shown resistance to low doses of criztonib. However, increased dosage can overcome this resistance in cell lines studies. TAE684 has also proven effective in both NSCLC and neuroblastoma F1174L containing cells. Somatic 2016-07-02 15:53:32 UTC https://civicdb.org/links/evidence_items/1327 https://civicdb.org/links/variants/8 https://civicdb.org/links/genes/1 false MYCN 4613 Amplification Neuroblastoma 769 Prognostic Supports A Poor Outcome In a cohort of 1596 diagnostic tumor samples taken from patients enrolled in the Children's oncology group (COG) neuroblastoma biology protocol ANBL00B1, 1579 samples were annotated with MYCN amplification status. 1239 (78%) were not MYCN amplified, and 349 (22%) were MYCN amplified. Five year event free survival was 74 +/- 1.6 months in non MYCN amplified cases and 39 +/- 4.1 months in amplified cases. Differences were significant with p<0.0001. Five year overall survival was 83 +/- 1.4 months and non MYCN amplified cases and 46 +/- 4.2 months in amplified cases, with p<0.0001, indicating poor prognosis for MYCN amplified cases. 25517749 PubMed Bresler et al., 2014, Cancer Cell 4 accepted 1328 298 3741 2 16080686 16087129 ENST00000281043.3 75 GRCh37 Somatic 2022-02-22 19:38:26 UTC https://civicdb.org/links/evidence_items/1328 https://civicdb.org/links/variants/298 https://civicdb.org/links/genes/3741 false ALK 238 F1174L Neuroblastoma 769 Lorlatinib Predictive Supports D Sensitivity/Response Efficacy of the second generation ALK inhibitor PF-06463922 was tested on ALK mutation F1174L containing neuroblastoma-derived cells. COG-N-453x and SH-SY5Y xenografts showed some inhibition when treated with crizotinib, but showed complete growth inhibition with PF-06463922 treatment. This corresponded to 0% event free survival (EFS) in these mice by 6 weeks with crizotinib treatment, but 100% EFS with PF-06463922 treatment. Comparison of crizotinib and PF-06463922 growth inhibition in F1174L cells SH-SY5Y, NBSD 415-IMDM and KELLY showed increased sensitivity to PF-06463922, as compared to crizotinib. Inhibition effects were not seen on neuroblastoma cells with wild type ALK (NB-EBc1, SK-N-BE(2)C). Decreased phosphorylation on ALK tyrosine 1278 was seen with PF-06463922 over crizotinib at 10 and 100 nM concentrations in SH-SY5Y cells. PF-06463922 was well tolerated in the in-vivo models. 26554404 PubMed Infarinato et al., 2016, Cancer Discov 4 accepted 1329 8 1 2 29443695 29443695 G T ENST00000389048.3 75 GRCh37 ALK F1174L has been observed as recurrent in neuroblastoma, non-small cell lung cancer (NSCLC), and other cancer types. Neuroblastoma cells containing this mutation have shown resistance to low doses of criztonib. However, increased dosage can overcome this resistance in cell lines studies. TAE684 has also proven effective in both NSCLC and neuroblastoma F1174L containing cells. Somatic 2016-06-28 03:03:04 UTC https://civicdb.org/links/evidence_items/1329 https://civicdb.org/links/variants/8 https://civicdb.org/links/genes/1 false ALK 238 F1245C Neuroblastoma 769 Lorlatinib Predictive Supports D Sensitivity/Response Patient derived xenografts of neuroblastoma Felix cells with F1245C ALK mutation in CB17 SCID mice showed growth inhibition with crizotinib treatment over control, and mice had improved duration of event-free survival (EFS) with crizotinib treatment over vehicle, but EFS with crizotinib went down to 0% by six weeks. In contrast, PF-06463922 treatment induced complete tumor regression and EFS rate of 100% at six weeks. PF-06463922 inhibited viability in Felix cells at 37x efficacy over crizotinib, with IC50 values of 21.8 +/- 0.4 and 814.0 +/- 119 respectively. PF-06463922 was well tolerated in the animal models. 26554404 PubMed Infarinato et al., 2016, Cancer Discov 3 accepted 1330 549 1 2 29436859 29436859 A C ENST00000389048.3 75 GRCh37 Somatic 2016-06-27 19:58:23 UTC https://civicdb.org/links/evidence_items/1330 https://civicdb.org/links/variants/549 https://civicdb.org/links/genes/1 false ALK 238 R1275Q Neuroblastoma 769 Lorlatinib Predictive Supports D Sensitivity/Response In NB-1643 and LAN-5 neuroblastoma cell lines containing R1275Q mutation, PF-06463922 showed 51 and 19 fold greater effect on cell viability over crizotinib treatment respectively. ALK wild-type neuroblastoma cell lines did not show differential sensitivity to the treatments within the sensitivity range of R1275Q cells, and had IC50 values above 3800 nM to the inhibitors. NB-1653 cells induced tumors in CB17 SCID mice and crizotinib treatment inhibited tumor growth over vehicle treatment, but PF-06463922 induced complete tumor regression. 26554404 PubMed Infarinato et al., 2016, Cancer Discov 4 accepted 1331 9 1 2 29432664 29432664 C T ENST00000389048.3 75 GRCh37 ALK R1275Q has been observed as a recurrent mutation in neuroblastoma, non-small cell lung cancer (NSCLC), as well as other cancer types. Neuroblastoma cells with this mutation have shown sensitivity to the ALK-inhibitor TAE684. This and the geldanamycin deriviative 17-DMAG have been shown to be effective in NSCLC cell lines. Somatic 2016-06-28 00:29:20 UTC https://civicdb.org/links/evidence_items/1331 https://civicdb.org/links/variants/9 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK Lung Non-small Cell Carcinoma 3908 Lorlatinib Predictive Supports D Sensitivity/Response EML4-ALK variant 1 containing H-3122 NSCLC cells were treated with second generation ALK inhibitor PF-06463922. PF-06463922 was 125x more potent at reducing cell viability than crizotinib. Control neuroblastoma cell lines with wild-type ALK did not show inhibition below 3800 nM with either drug. At values of 10 and 100 nM, PF-06463922 showed increased ability to inhibit ALK 1278 tyrosine phosphorylation in H3122 cells. 26554404 PubMed Infarinato et al., 2016, Cancer Discov 2 accepted 1332 5 1 2 42396490 42522656 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The EML4-ALK fusion variant 1 consisting of ALK kinase domain (exons 20-29) fused to EML4 exons 1-13 is the most common EML4-ALK variant, and was discovered in non-small cell lung cancer. Multiple EML4 breakpoint shave been described with differential sensitivity to inhibitors with variant 1 showing greater sensitivity than 3a in cell lines. EML4-ALK is crizotinib sensitive; however, several mutations that confer resistance mutations have been described in case studies. In the only clinical trial for crizotinib that included determination of EML4-ALK variant type in a subset of its participants, a very high response rate was observed, although the numbers were insufficient to validate correlation of variant type to outcome. Preclinical studies with this variant have indicated sensitivity to Hsp90 inhibitors. Somatic 2016-07-11 04:10:48 UTC https://civicdb.org/links/evidence_items/1332 https://civicdb.org/links/variants/5 https://civicdb.org/links/genes/1 false ALK 238 F1245C Neuroblastoma 769 Crizotinib Predictive Supports C Resistance A participant in Children's Oncology Group (COG) study AVDL0912 with measurable neuroblastoma mutated at ALK F1245C was administered crizotinib at 100mg twice daily. The patient showed progressive disease as best response after two 28-day cycles on crizotinib. 23598171 PubMed Mossé et al., 2013, Lancet Oncol. NCT00939770 3 accepted 1333 549 1 2 29436859 29436859 A C ENST00000389048.3 75 GRCh37 Somatic 2016-06-27 20:27:46 UTC https://civicdb.org/links/evidence_items/1333 https://civicdb.org/links/variants/549 https://civicdb.org/links/genes/1 false ALK 238 Fusion Colorectal Adenocarcinoma 0050861 Crizotinib Predictive Supports E Sensitivity/Response 26 colorectal adenocarcinoma samples were run on Affymetrix human Exon 1.0 arrays and a computational method that assessed differential 5' and 3' gene expression for each gene was used to find potential rearrangements. One sample showed potential rearrangement and RT-PCR demonstrated an EML4-ALK fusion where EML4 exon 21 was fused to ALK exon 13. This EML4-ALK variant is different from those commonly found in NSCLC. Genomic PCR verified the existence of the fusion breakpoint in intronic space, indicating that some colorectal adenocarcinoma may have targetable ALK-fusion driver mutations. 19737969 PubMed Lin et al., 2009, Mol. Cancer Res. 1 accepted 1334 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-07-02 02:56:50 UTC https://civicdb.org/links/evidence_items/1334 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ALK 238 Fusion Breast Cancer 1612 Crizotinib Predictive Supports E Sensitivity/Response 84 breast cancer samples acquired from commercial sources were assayed on Affymetrix human exon 1.0 arrays. A computational method was used to find potential gene fusions which assessed differential exon expression between the 3' and 5' ends of each gene. Two potential fusions were found and assessed using RNA ligase mediated rapid amplifiation of cDNA ends and RT-PCR. The fusions were EML4-ALK variants 1 and 2. Genomic PCR identified fusion breakpoints, and these differed from breakpoints for these EML4-ALK variants reported in NSCLC. 19737969 PubMed Lin et al., 2009, Mol. Cancer Res. 1 accepted 1335 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-07-02 15:33:39 UTC https://civicdb.org/links/evidence_items/1335 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ALK 238 Exon 4-11 Deletion Neuroblastoma 769 Brigatinib Predictive Supports D Sensitivity/Response The MYCN amplification positive relapsed neuroblastoma-derived cell line CLB-BAR contains the driver ALK DEL 11-14 mutation, which removes extracellular domain exons 4 through 11. Brigatinib treatment of CLB-BAR cells reduced MYCN protein levels and ALK phosphorylation (Y1604) similar to crizotnib. Brigatinib reduced CLB-BAR cellular proliferation more effectively than crizotinib (IC50 75.2 vs 186.4nM). CLB-BAR xenografts in BalbC/NUDE mice responded to brigatinib with reduced tumor volume and weight (N=8/group) as well as reduced ALK phosphorylation and MYCN levels compared to untreated controls. Release of brigatinib administration at day 15 resulted in tumor growth (N=2). 27049722 PubMed Siaw et al., 2016, Oncotarget 3 accepted 1336 550 1 2 29474528 29853656 ENST00000389048.3 75 GRCh37 Somatic 2016-07-17 21:41:23 UTC https://civicdb.org/links/evidence_items/1336 https://civicdb.org/links/variants/550 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion F1245C Cancer 162 Crizotinib Predictive Supports D Resistance A Ba/F3 cell line expressing EML4-ALK variant 1 was created, and then exposed to the DNA modifying agent ENU. Cells were subsequently cultured in 96 well plates at increasing concentrations of crizotinib (250, 500, 720, 1000, 1440 and 2000 nM). Cell growth occurred in all wells at 250 nM, and was absent at 2000 nM. From 500 through 1440 nM there were progressively fewer resistant clones present. 422 mutations representing 16 different sites were identified. EML4-ALK F1245C was found at 500 nM crizotinib, and was among the 10 most frequently observed mutations. Ba/F3 cells with unaltered EML4-ALK had crizotinib IC50 values for viability of 132 +/- 45 nM. EML4-ALK F1245C clones from the selection assay had IC50 viability value of 425 +/- 100 nM, while Ba/F3 cells expressing reintroduced EML4-ALK F1245C had IC50 value of 269 +/- 194 nM. 22034911 PubMed Zhang et al., 2011, Chem Biol Drug Des 2 accepted 1337 551 1 2 29436859 29436859 A C ENST00000389048.3 75 GRCh37 In neuroblastoma, F1245 is one of three hotspot ALK mutations found at a high frequency. In a case study, a pretreated non-small cell lung cancer (NSCLC) patient with EML4-ALK F1245C mutation responded well to ceritinib after slow disease progression during crizotinib treatment. Crizotinib resistance was attributed to the F1245C mutation, although the ALK-rearrangement was not sequenced prior to crizotinib treatment. The patient's slow onset of disease progression during crizotinib treatment mirrors preclinical findings that indicate ALK-fusion with F1245C has moderate resistance to crizotinib compared to the fusion alone. Somatic 2016-06-22 19:29:27 UTC https://civicdb.org/links/evidence_items/1337 https://civicdb.org/links/variants/551 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion F1245C Lung Non-small Cell Carcinoma 3908 Ceritinib Predictive Supports C Sensitivity/Response A 52 year old male never smoker was diagnosed with stage IV NSCLC adenocarcinoma and was treated with chemotherapy with eventual disease progression. He tested positive for ALK rearrangement via break apart FISH assay, and started crizotinib with near complete response for 27 months. Progression then occurred and biopsy of a pleural nodule was performed with hybrid-capture NGS. EML4-ALK variant 3 with F1245C mutation was found with allele frequency of 2% and tumor purity 13%. Due to slow progression and low tumor burden crizotinib was maintained for additional 8 months, and then he was transitioned onto ceritinib at 750 mg daily. After 3 months ceritinib, complete radiographic response was seen and the patient was without evidence of disease at 6 months. Dose was reduced to 600 mg ceritinib daily due to gastrointestinal side effects. 26775591 PubMed Kodityal et al., 2016, Lung Cancer 3 accepted 1338 551 1 2 29436859 29436859 A C ENST00000389048.3 75 GRCh37 In neuroblastoma, F1245 is one of three hotspot ALK mutations found at a high frequency. In a case study, a pretreated non-small cell lung cancer (NSCLC) patient with EML4-ALK F1245C mutation responded well to ceritinib after slow disease progression during crizotinib treatment. Crizotinib resistance was attributed to the F1245C mutation, although the ALK-rearrangement was not sequenced prior to crizotinib treatment. The patient's slow onset of disease progression during crizotinib treatment mirrors preclinical findings that indicate ALK-fusion with F1245C has moderate resistance to crizotinib compared to the fusion alone. Somatic 2016-06-07 03:29:00 UTC https://civicdb.org/links/evidence_items/1338 https://civicdb.org/links/variants/551 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion F1245C Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Resistance A 52 year old with a non-smoking history was diagnosed with stage IV NSCLC-adenocarcinoma and treated with chemotherapy. Upon disease progression, the initial diagnostic biopsy tested positive for ALK-rearrangement using break apart FISH, but the ALK fusion was not sequenced for mutations. Break-apart signal was positive in 66% of tumor cells. Crizotinib was initiated and a sustained near complete response for 27 months was observed, after which an FDG-avid cervical lymph node appeared along with pleural effusions and pleural nodules. A pleural nodule was biopsied and profiled using hybrid-capture next generation sequencing, and revealed EML4-ALK variant 3 with F1245C mutation at mutant allele frequency of 2% and tumor purity of 13%. Crizotinib was maintained for 8 additional months due to low tumor burden and slow progression. 26775591 PubMed Kodityal et al., 2016, Lung Cancer 2 accepted 1339 551 1 2 29436859 29436859 A C ENST00000389048.3 75 GRCh37 In neuroblastoma, F1245 is one of three hotspot ALK mutations found at a high frequency. In a case study, a pretreated non-small cell lung cancer (NSCLC) patient with EML4-ALK F1245C mutation responded well to ceritinib after slow disease progression during crizotinib treatment. Crizotinib resistance was attributed to the F1245C mutation, although the ALK-rearrangement was not sequenced prior to crizotinib treatment. The patient's slow onset of disease progression during crizotinib treatment mirrors preclinical findings that indicate ALK-fusion with F1245C has moderate resistance to crizotinib compared to the fusion alone. Somatic 2016-06-07 03:29:34 UTC https://civicdb.org/links/evidence_items/1339 https://civicdb.org/links/variants/551 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK e6-e20 Lung Non-small Cell Carcinoma 3908 Ceritinib Predictive Supports D Sensitivity/Response Ceritinib was 28x more potent (GI50 3.8nM) than crizotinib (GI50 107nM) at inhibiting growth of H2228, an NSCLC cell line which harbors the EML4-ALK variant 3a/3b. SCID mice xenografted with H2228 were treated for 14 days with crizotinib (100 mg/kg) or ceritinib (25 or 50 mg/kg). All treatments caused tumor regression, but tumors recurred within 11 days after crizotinib treatment withdrawal. 4/8 mice treated with 25 mg/kg ceritinib showed regrowth after 1 month treatment withdrawal. The remaining 4/8 mice treated at 25 mg/kg ceritinib, and all mice treated at 50 mg/kg ceritinib maintained complete remission for four months. While 100 mg/kg crizotinib in mice approximates levels 3-5 times the maximal tolerated dose in humans, the authors state 25 to 50 mg/kg ceritinib in mice is predicted to approximate tolerable doses in humans. 24675041 PubMed Friboulet et al., 2014, Cancer Discov 3 accepted 1340 503 1 2 42396490 42491871 ENST00000318522.5 2 29415640 29446394 ENST00000389048.3 75 GRCh37 The EML4-ALK variant 3a consists of the ALK kinase domain fused to EML4 exons 1-6, while the 3b variant has an additional 33bp of intronic EML4 sequence between EML4 and ALK regions. The two variants were found to originate from a single genomic rearrangement, and 3a/3b is found in ~ 30% of EML4-ALK positive NSCLC. Variant 3a has cytoplasmic and nuclear distribution. In vitro, these variants have shown sensitivity to ALK inhibitors TAE684 and crizotinib but less sensitive than other EML4-ALK variants. The H2228 cell line contains 3a and 3b variants and is described as having cyctostatic response to ALK inhibition as opposed to apoptotic. In a study of 31 NSCLC patients with EML4-ALK rearrangements, 4/5 patients with the 3a variant showed a partial response while 1 showed progressive disease (the only PD observed). In cells the 3a variant was reported to be more stable than other variants, less sensitive to crizotinib and not to respond to Hsp90 inhibition. Somatic 2016-06-28 22:21:43 UTC https://civicdb.org/links/evidence_items/1340 https://civicdb.org/links/variants/503 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK L1196M Lung Non-small Cell Carcinoma 3908 Ceritinib Predictive Supports D Sensitivity/Response The crizotinib-resistant MGH045 cell line with EML4-ALK L1196M was treated with crizotinib or ceritinib. In nude mice with MGH045 xenografts, tumor response to crizotinib did not differ appreciably from vehicle, while ceritinib controlled tumor growth. Ceritinib inhibited Ba/F3 cells expressing EML4-ALK L1196M slightly stronger than ALK wild-type, but approximately double the potency as crizotinib, indicating ceritinib sensitivity in Ba/F3 EML4-ALK L1196M cells. 24675041 PubMed Friboulet et al., 2014, Cancer Discov 4 accepted 1341 7 1 2 29443631 29443631 G T ENST00000389048.3 75 GRCh37 In patients with non-small cell lung cancer exhibiting EML4-ALK fusion, L1196M has been shown to confer resistance to crizotinib. This was also true in a patient with both EML4-ALK C1156Y & L1196M. Somatic 2016-07-26 16:04:35 UTC https://civicdb.org/links/evidence_items/1341 https://civicdb.org/links/variants/7 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion G1269A Lung Non-small Cell Carcinoma 3908 Ceritinib Predictive Supports D Sensitivity/Response The NSCLC cell line MGH021-4, harboring SQSTM1-ALK G1269A, was 6 times more sensitive to ceritinib (80nM GI50) than crizotinib (500 nM) in proliferation assays and caused notable reductions in phospho-ALK and phospho-AKT (detected by Western blot) at concentrations 10 fold lower than crizotinib. GI50 values were similar in Ba/F3 cells expressing either EML4-ALK wild-type or EML4-ALK G1269A (1.6nM and 2.2nM, respectively). In contrast, crizotinib treatment of Ba/F3 with EML4-ALK G1269A had survival GI50 of 130nM. 24675041 PubMed Friboulet et al., 2014, Cancer Discov 3 accepted 1342 552 1 2 29432682 29432682 C G ENST00000389048.3 75 GRCh37 Somatic 2016-11-06 01:00:20 UTC https://civicdb.org/links/evidence_items/1342 https://civicdb.org/links/variants/552 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK S1206Y Cancer 162 Ceritinib Predictive Supports D Sensitivity/Response Ba/F3 cells expressing the EML4-ALK S1206Y variant were treated with ceritinib, and survival GI50 value of 1.5 nM was obtained, which compares favorably with GI50 of 1.7 for the highly ceritinib sensitive EML4-ALK wild-type variant obtained in parallel experiments, as well as the GI50 value of 16 nM obtained for crizotinib treatment of EML4-ALK wild-type. 24675041 PubMed Friboulet et al., 2014, Cancer Discov 2 accepted 1343 172 1 2 29443600 29443600 G T ENST00000389048.3 75 GRCh37 Somatic 2016-07-13 18:40:04 UTC https://civicdb.org/links/evidence_items/1343 https://civicdb.org/links/variants/172 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion I1171 Lung Non-small Cell Carcinoma 3908 Ceritinib Predictive Supports D Sensitivity/Response Ba/F3 cells expressing EML4-ALK variant 3 with ALK I1171T mutation were treated with ceritinib, and survival IC50 of 2.6 nM was observed, which compares favorably with highly ceritinib sensitive EML4-ALK wild-type variant 1 survival IC50 of 1.7 nM reported from parallel experiments. Tumors from mice with EML4-ALK variant 3 H2228 NSCLC cell xenografts which had progressed after approximately 40 days of crizotinib treatment were sequenced for ALK mutations. I1171T was found as one of 6 ALK resistance mutations from 80 sequenced tumors. Treatment of these mouse xenograft models with ceritinib reduced tumor volume to zero, while in contrast tumor size increased with crizotinib treatment. 24675041 PubMed Friboulet et al., 2014, Cancer Discov 4 accepted 1344 527 1 2 29445213 29445213 A G ENST00000389048.3 75 GRCh37 Multiple case reports indicate that the I1171T missense mutation in ALK-rearranged non-small cell lung cancer (NSCLC) confers resistance to crizotinib and alectinib but is sensitive to ceritinib treatment. These results have been validated in vitro. In vitro evidence indicates this mutation interferes with alectinib binding the active site of ALK and may explain the sensitivity to the structurally distinct ALK inhibitor ceritinib. Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1344 https://civicdb.org/links/variants/527 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion G1202R Lung Non-small Cell Carcinoma 3908 Ceritinib Predictive Supports D Resistance Ba/F3 cells expressing EML4-ALK variant 1 with ALK G1202R mutation were assessed for ceritinib sensitivity. Crizotinib was shown to confer significantly more potency than ceritinib (43-fold decrease in IC50). EML4-ALK variant 3 NSCLC cell line H2228 was used in SCID mouse xenografts which were exposed to increasing crizotinib up to 100 mg/kg. Within 40 days tumors progressed, and progressed tumors were assayed for ALK mutation. Of 80 tumors, 6 had ALK mutation and 3 of these were G1202R. Treatment of crizotinib progressed tumors with ceritinib resulted in tumor growth which did not differ appreciably from crizotinib or vehicle treatment of these tumors. 24675041 PubMed Friboulet et al., 2014, Cancer Discov 4 accepted 1345 171 1 2 29443613 29443613 C T ENST00000389048.3 75 GRCh37 ALK fusion with G1202R mutation in the ALK kinase domain was first identified in a lung adenocarcinoma patient who had progressed after 10 months of responding to crizotinib. Further characterization of this variant verified crizotinib resistance and additionally demonstrated resistance to multiple next generation ALK inhibitors including ceritinib, alectinib and brigatinib. Experiments using the HSP90 inhibitor 17-AAG have indicated potential sensitivity of EML4-ALK G1202R to this drug, suggesting this variant may be an HSP90 client protein. Somatic 2016-06-27 23:53:33 UTC https://civicdb.org/links/evidence_items/1345 https://civicdb.org/links/variants/171 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK C1156Y Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports D Resistance EML4-ALK variant 3 containing NSCLC cell line H2228 xenografts in SCID beige mice were treated with increasing doses of crizotinib up to 100 mg/kg per day by oral gavage. At approximately 40 days tumors progressed. 80 progressed tumors were tested for ALK mutations, and 6 mutant ALK variants were found. Two of the mutations were at ALK C1156Y. In Ba/F3 cells, EML4-ALK variant 3 with C1156Y was introduced and tested for crizotinib sensitivity. Survival IC50 value of 177 nM was reported, which is 9.3 times the IC50 reported for crizotinib in EML4-ALK wild-type Ba/F3 cells. 24675041 PubMed Friboulet et al., 2014, Cancer Discov 4 accepted 1346 6 1 2 29445258 29445258 C T ENST00000389048.3 75 GRCh37 In patients with non-small cell lung cancer exhibiting EML4-ALK fusion, C1156Y has been shown to confer resistance to crizotinib. Case reports indicate that secondary mutations can modulate drug sensitivity. EML4-ALK C1156Y/L1196M maintained crizotinib resistance while the lorlatinib resistant combination EML4-ALK C1156Y/L1198F re-sensitized the tumor to crizotinib treatment. Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1346 https://civicdb.org/links/variants/6 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK T1151INST Lung Non-small Cell Carcinoma 3908 Alectinib Predictive Supports D Resistance Ba/F3 cells expressing EML4-ALK with 1151 Tins treated with alectinib had an IC50 of 165.7 nM, 16x higher than those expressing EML4-ALK wildtype variant 1. EML4-ALK variant 1 expressing H3122 NSCLC cell line was cultured in increasing levels of crizotinib to produce crizotinib resistant cell lines CR1, CR2 and CR3. H3122 CR2 was found to contain an 1151 insT ALK mutation and increased EML4-ALK levels. The H3122 CR2 cell line survival IC50 value for alectinib treatment was approximately 20x higher than that for H3122 cells. 22277784 PubMed Katayama et al., 2012, Sci Transl Med 3 accepted 1347 173 1 2 29445271 29445272 CGT ENST00000389048.3 75 GRCh37 The ALK fusion variant with insertion of T at amino acid 1151 was found in an ALK rearranged lung adenocarcinoma which had progressed after responding to crizotinib treatment. The mutation was absent in tumor sample taken before crizotinib treatment. Characterization of the variant using cell lines expressing EML4-ALK with 1151 T insert found the variant to be highly crizotinib resistant, and other work demonstrated resistance to next generation inhibitor alectinib, while resistance to tool compound TAE684 indicates potential resistance to the next generation ALK inhibitor ceritinib which is derived from TAE684. Other experiments suggest theraputic potential for HSP90 inhibitors, as EML4-ALK T1151 Tins sensitivity to 17-AAG has been observed. Somatic 2016-07-06 19:41:12 UTC https://civicdb.org/links/evidence_items/1347 https://civicdb.org/links/variants/173 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK T1151INST Lung Non-small Cell Carcinoma 3908 TAE684 Predictive Supports D Resistance Treatment of Ba/F3 cells expressing EML4-ALK 1151 insT with TAE684 produced an IC50 value (28.3 nM) 20x higher cells expressing EML4-ALK wildtype variant 1. The crizotinib resistant clones were produced from parental H3122 cells (CR1, CR2, CR3). H3122 CR2 was found to contain the 1151 Tins variant as well as elevated EML4-ALK expression. H3122 CR2 cells treated with TAE684 produced IC50 values 20-30 times that of the parental H3122 cells. These results suggest possible variant resistance to the TAE684-derived compound ceritinib. 22277784 PubMed Katayama et al., 2012, Sci Transl Med 3 accepted 1348 173 1 2 29445271 29445272 CGT ENST00000389048.3 75 GRCh37 The ALK fusion variant with insertion of T at amino acid 1151 was found in an ALK rearranged lung adenocarcinoma which had progressed after responding to crizotinib treatment. The mutation was absent in tumor sample taken before crizotinib treatment. Characterization of the variant using cell lines expressing EML4-ALK with 1151 T insert found the variant to be highly crizotinib resistant, and other work demonstrated resistance to next generation inhibitor alectinib, while resistance to tool compound TAE684 indicates potential resistance to the next generation ALK inhibitor ceritinib which is derived from TAE684. Other experiments suggest theraputic potential for HSP90 inhibitors, as EML4-ALK T1151 Tins sensitivity to 17-AAG has been observed. Somatic 2016-07-06 19:39:58 UTC https://civicdb.org/links/evidence_items/1348 https://civicdb.org/links/variants/173 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK T1151INST Lung Non-small Cell Carcinoma 3908 Tanespimycin Predictive Supports D Sensitivity/Response Ba/F3 cells transduced with EML4-ALK 1151 insT were treated with 17-AAG producing an IC50 value of 44.5 nM, which was 0.4 times that reported for EML4-ALK wildtype in Ba/F3, indicating possible increased dependence of EML4-ALK 1151 insT on HSP90. 17-AAG also reduced survival of the parental IL3-dependent Ba/F3 cells (183.7 nM), indicating increased nonspecific effects of 17_AAG treatment. Crizotinib resistant clones were produced from the parental EML4-ALK variant 1 containing cell line H3122 (CR1, CR2, CR3). H3122 CR2 was found to contain the EML4-ALK InsT variant. H3122 CR2 and H3122 cells were similarly sensitized to 17-AAG death with an IC50 value of approximately 5 nM, while control cells without EML4-ALK had IC50 values approximately 10x higher. 22277784 PubMed Katayama et al., 2012, Sci Transl Med 2 accepted 1349 173 1 2 29445271 29445272 CGT ENST00000389048.3 75 GRCh37 The ALK fusion variant with insertion of T at amino acid 1151 was found in an ALK rearranged lung adenocarcinoma which had progressed after responding to crizotinib treatment. The mutation was absent in tumor sample taken before crizotinib treatment. Characterization of the variant using cell lines expressing EML4-ALK with 1151 T insert found the variant to be highly crizotinib resistant, and other work demonstrated resistance to next generation inhibitor alectinib, while resistance to tool compound TAE684 indicates potential resistance to the next generation ALK inhibitor ceritinib which is derived from TAE684. Other experiments suggest theraputic potential for HSP90 inhibitors, as EML4-ALK T1151 Tins sensitivity to 17-AAG has been observed. Somatic 2016-07-06 19:40:53 UTC https://civicdb.org/links/evidence_items/1349 https://civicdb.org/links/variants/173 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion G1202R Cancer 162 Alectinib Predictive Supports D Resistance Ba/F3 cell line expressing EML4-ALK variant 3 with G1202R ALK mutation was assessed for alectinib sensitivity and IC50 for survival of 868 nM was reported, which was 64.4x higher than the IC50 reported for alectinib on Ba/F3 with EML4-ALK wild-type. Similar experiments using NPM-ALK instead of EML4-ALK yielded survival IC50 of 549 nM of NPM-ALK G1202R to alectinib, which was 27.9 times higher than IC50 for NPM-ALK wild-type. Western blots of Ba/F3 with NPM-ALK wild-type showed ablation of pALK levels above 100 nM alectinib, while pALK levels were essentially unchanged up to 1000 nM in NPM-ALK G1202R Ba/F3 cells. 25727400 PubMed Fontana et al., 2015, Cancer Med 3 accepted 1350 171 1 2 29443613 29443613 C T ENST00000389048.3 75 GRCh37 ALK fusion with G1202R mutation in the ALK kinase domain was first identified in a lung adenocarcinoma patient who had progressed after 10 months of responding to crizotinib. Further characterization of this variant verified crizotinib resistance and additionally demonstrated resistance to multiple next generation ALK inhibitors including ceritinib, alectinib and brigatinib. Experiments using the HSP90 inhibitor 17-AAG have indicated potential sensitivity of EML4-ALK G1202R to this drug, suggesting this variant may be an HSP90 client protein. Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1350 https://civicdb.org/links/variants/171 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion G1202R Cancer 162 Brigatinib Predictive Supports D Resistance This study compared drug responses in Ba/F3 cells expressing either EML4-ALK or NPM-ALK fusions, with or without G1202R ALK mutation. Cells expressing the EML4-ALK variant 3 with G1202R ALK mutation were more resistant to brigatinib treatment (IC50 325 nM) than cells expressing wildtype EML4-ALK variant 3 (IC50 6 nM). These same experiments performed with the NPM-ALK fusion resulted in IC50 of 149 nM for G1202R and 11nM for wild type, consistent with resistance. In Western blots, ablation of pALK with brigatinib treatment above 100 nM was seen in Ba/F3 cells expressing NPM-ALK wildtype, but remained apparent at 1000 nM brigatinib in NPM-ALK G1202R cells, despite dose-dependent reduction. 25727400 PubMed Fontana et al., 2015, Cancer Med 3 accepted 1351 171 1 2 29443613 29443613 C T ENST00000389048.3 75 GRCh37 ALK fusion with G1202R mutation in the ALK kinase domain was first identified in a lung adenocarcinoma patient who had progressed after 10 months of responding to crizotinib. Further characterization of this variant verified crizotinib resistance and additionally demonstrated resistance to multiple next generation ALK inhibitors including ceritinib, alectinib and brigatinib. Experiments using the HSP90 inhibitor 17-AAG have indicated potential sensitivity of EML4-ALK G1202R to this drug, suggesting this variant may be an HSP90 client protein. Somatic 2016-06-28 21:50:07 UTC https://civicdb.org/links/evidence_items/1351 https://civicdb.org/links/variants/171 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion G1202R Lung Non-small Cell Carcinoma 3908 Tanespimycin Predictive Supports D Sensitivity/Response The G1202R ALK mutation was found in a crizotinib-resistant ALK-rearranged NSCLC, and the mutant ALK fusion was further characterized in Ba/F3 cells. EML4-ALK variant 1 with G1202R mutation was expressed in Ba/F3 and subject to 17-AAG. IC50 for cell number in response to 17-AAG was 33.4 nM, in contrast to IC50 for EML4-ALK wild-type, which was 98.9 nM, suggesting sensitization of this variant to HSP90 inhibition. 22277784 PubMed Katayama et al., 2012, Sci Transl Med 2 accepted 1352 171 1 2 29443613 29443613 C T ENST00000389048.3 75 GRCh37 ALK fusion with G1202R mutation in the ALK kinase domain was first identified in a lung adenocarcinoma patient who had progressed after 10 months of responding to crizotinib. Further characterization of this variant verified crizotinib resistance and additionally demonstrated resistance to multiple next generation ALK inhibitors including ceritinib, alectinib and brigatinib. Experiments using the HSP90 inhibitor 17-AAG have indicated potential sensitivity of EML4-ALK G1202R to this drug, suggesting this variant may be an HSP90 client protein. Somatic 2016-07-10 21:43:14 UTC https://civicdb.org/links/evidence_items/1352 https://civicdb.org/links/variants/171 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion G1269A Cancer 162 Brigatinib Predictive Supports D Sensitivity/Response EML4-ALK with ALK G1269A has been seen in crizotinib resistant NSCLC, and this mutation was tested for Brigatinib sensitivity via ectopic expression in Ba/F3 cells, where half maximal inhibitory concentration of 9 nM was seen, which was 1.5 times the IC50 of EML4-ALK wild-type to brigatinib. NPM-ALK G1269A was also tested for brigatinib sensitivity, and IC50 values of 11 nM were reported for both NPM-ALK G1269A and NPM-ALK wild-type. In western blotting, brigatinib at and above 100 nM ablated pALK signal (Y 1604), indicating sensitivity of this variant to brigatinib together with the other results. 25727400 PubMed Fontana et al., 2015, Cancer Med 2 accepted 1353 552 1 2 29432682 29432682 C G ENST00000389048.3 75 GRCh37 Somatic 2016-07-10 21:38:02 UTC https://civicdb.org/links/evidence_items/1353 https://civicdb.org/links/variants/552 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion G1269A Cancer 162 Alectinib Predictive Supports D Resistance EML4-ALK with ALK G1269A mutation was tested for sensitivity to alectinib using Ba/F3 cells. In Ba/F3 cells with ectopic EML4-ALK variant 1 G1269A, IC50 of 84 nM was reported with alectinib, which was a 6 fold increase over IC50 for EML4-ALK wild-type. The authors considered a fold difference of 4 to 10 between the alectinib-sensitized wild-type and mutant variant to indicate a resistant mutant variant. In the background of the NPM-ALK fusion, IC50 for G1269A mutation was 104 nM, which was 5.3 fold that reported for NPM-ALK wild-type. Western blots of alectinib treated NPM-ALK G1269A were performed and reduced pALK Y1604 was seen at 300 nM alectinib, and no pALK at 1000 nM. In contrast pALK signal was ablated at and above 100 nM in NPM-ALK wild-type. 25727400 PubMed Fontana et al., 2015, Cancer Med 3 accepted 1354 552 1 2 29432682 29432682 C G ENST00000389048.3 75 GRCh37 Somatic 2016-07-10 21:40:43 UTC https://civicdb.org/links/evidence_items/1354 https://civicdb.org/links/variants/552 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion G1269A Cancer 162 Ceritinib Predictive Supports D Sensitivity/Response EML4-ALK with G1269A mutation was tested for sensitivity to ceritinib via transduction into Ba/F3 cells and generation of survival curves varying ceritinib concentration. IC50 of 33 nM was seen, which was 1.5 times the IC50 for EML4-ALK wild-type, indicating sensitivity of the G1269A mutation to ceritinib in the context of EML4-ALK. The mutation was also tested for ceritinib sensitivity in the context of NPM-ALK, where IC50 values were reported of 19 nM and 20 nM for mutant and wild-type versions, respectively, also indicating sensitivity. In western blots, Y1604 pALK levels for wild-type NPM-ALK were ablated at 100 nM, while at 100 nM residual pALK levels were seen in G1269A blotting, with ablation of signal at and above 300 nM, which differed somewhat from the equivalent IC50 values reported for mutant and wild-type in the NPM-ALK background, but still agrees with sensitivity to ceritinib for this mutation. 25727400 PubMed Fontana et al., 2015, Cancer Med 2 accepted 1355 552 1 2 29432682 29432682 C G ENST00000389048.3 75 GRCh37 Somatic 2016-11-04 22:14:21 UTC https://civicdb.org/links/evidence_items/1355 https://civicdb.org/links/variants/552 https://civicdb.org/links/genes/1 false ALK 238 NPM::ALK Cancer 162 Crizotinib Predictive Supports D Sensitivity/Response In Ba/F3 cells, crizotinib sensitivty of the NPM-ALK variant was compared to crizotinib sensitivity of EML4-ALK variant 3. 50% of maximal inhibitory concentration for NPM-ALK was 42 nM, which was approximately 4x greater than IC50 of 11 nM obtained for EML4-ALK. The IC50 for parental Ba/F3 supplemented with IL3 was 2299 nM, resulting in a fold difference of 209.2 for EML4-ALK and 55.1 for NPM-ALK, indicating some reduced sensitivity for NPM-ALK in direct comparison to EML4-ALK, but substantial sensitization to crizotinib for NPM-ALK in Ba/F3 cells. 25727400 PubMed Fontana et al., 2015, Cancer Med 2 accepted 1356 513 1 5 170814120 170818803 ENST00000517671.1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Somatic 2016-06-20 21:09:27 UTC https://civicdb.org/links/evidence_items/1356 https://civicdb.org/links/variants/513 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion G1202R Lung Adenocarcinoma 3910 Crizotinib Predictive Supports C Resistance A patient with ALK-rearranged lung adenocarcinoma responded to crizotinib treatment and then had relapse. Biopsy was taken within half a month and total DNA was extracted from the sample. Exons 20-28, which correspond to the tyrosine kinase domain of ALK, were sequenced, and ALK G1202A was found. CKIT focal amplification by FISH was also observed. Tumor sample before crizotinib treatment was not available in this case. 22277784 PubMed Katayama et al., 2012, Sci Transl Med 3 accepted 1357 171 1 2 29443613 29443613 C T ENST00000389048.3 75 GRCh37 ALK fusion with G1202R mutation in the ALK kinase domain was first identified in a lung adenocarcinoma patient who had progressed after 10 months of responding to crizotinib. Further characterization of this variant verified crizotinib resistance and additionally demonstrated resistance to multiple next generation ALK inhibitors including ceritinib, alectinib and brigatinib. Experiments using the HSP90 inhibitor 17-AAG have indicated potential sensitivity of EML4-ALK G1202R to this drug, suggesting this variant may be an HSP90 client protein. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1357 https://civicdb.org/links/variants/171 https://civicdb.org/links/genes/1 false PIK3CA 5290 Mutation Cancer 162 Tanespimycin,Pictilisib Substitutes Predictive Does Not Support D Sensitivity/Response Analysis of drug response data from the Sanger center cell line screen. Cell lines with either PI3K and/or PTEN mutations did not show a significant difference in response to class I PI3K inhibitor GDC-0941 (p =0.07 for combined PI3K/PTEN aberrations with a trend towards lower IC50 for mutated cell lines). IC50 values with HSP90 inhibitor 17-AAG were significantly lower in PI3K and/or PTEN mutated cell lines in the sanger cell line screening but these results could not be reproduced in the cancer cell line encyclopedia screening. 25855885 PubMed Wirtz et al., 2015, JAMA Otolaryngol Head Neck Surg 2 accepted 1358 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-06-27 23:36:39 UTC https://civicdb.org/links/evidence_items/1358 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PTEN 5728 Mutation Head And Neck Cancer 11934 Tanespimycin,Pictilisib Substitutes Predictive Does Not Support D Sensitivity/Response Analysis of drug response data from the Sanger center cell line screen. Cell lines with either PI3K and/or PTEN mutations did not show a significant difference in response to the class I PI3K inhibitor GDC-0941(p =0.07 for combined PI3K/PTEN aberrations with a trend towards lower IC50 for mutated cell lines). IC50 values with HSP90 inhibitor 17-AAG were significantly lower in PI3K and/or PTEN mutated cell lines in the Sanger cell line screening but these results could not be reproduced in the Broad cancer cell line encyclopedia screening. 25855885 PubMed Wirtz et al., 2015, JAMA Otolaryngol Head Neck Surg 2 accepted 1359 510 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-07-11 02:19:35 UTC https://civicdb.org/links/evidence_items/1359 https://civicdb.org/links/variants/510 https://civicdb.org/links/genes/41 false PIK3CA 5290 Mutation Head And Neck Cancer 11934 Dactolisib Predictive Supports D Sensitivity/Response Preclinical analysis of the predicitive value of PIK3CA mutations for mTOR/PI3K Inhibition with BEZ-235. Two cell lines with PIK3CA Mutation (H1047R) were more sensitive to BEZ-235 than two cell lines with wild-type PIK3CA (in-vitro, results from one cell line also confirmed in-vivo). Two patient-derived xenografts with PIK3CA mutations (E110K, E542K) showed sensitivity to BEZ-235. 23619167 PubMed Lui et al., 2013, Cancer Discov 3 accepted 1360 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1360 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Head And Neck Cancer 11934 Dactolisib Predictive Supports D Sensitivity/Response Lentiviral transduction of PIK3CA H1047R mutation into head and neck cancer cell line SCC25 led to increased sensitivity to PI3K/mTOR inhibition with BEZ235 compared to unmanipulated cells (IC50 values 6 nM and 31 nM). 25855885 PubMed Wirtz et al., 2015, JAMA Otolaryngol Head Neck Surg 1 accepted 1361 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2016-06-22 19:27:42 UTC https://civicdb.org/links/evidence_items/1361 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Head And Neck Cancer 11934 Dactolisib Predictive Supports D Sensitivity/Response Two head and neck cancer cell lines with PIK3CA H1047R mutation were more sensitive to PI3K/mTOR inhibition with BEZ-235 (NVP-BEZ235, Dactolisib) than two wild type cell lines in vitro. One cell line with H1047R mutation was also found to be sensitive to BEZ-235 in vivo. PIK3CA (H1047R) mutation positive cell lines used were "CAL-33" and "Detroit 562". Wild type cell lines used here were "SCC-9" and "PE/CA-PJ34(clone C12)". 23619167 PubMed Lui et al., 2013, Cancer Discov 2 accepted 1362 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2016-06-22 19:27:09 UTC https://civicdb.org/links/evidence_items/1362 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Head And Neck Cancer 11934 Cetuximab,Dactolisib Combination Predictive Supports D Sensitivity/Response Xenografts from one head and neck cancer cell line (CAL-33) with a PIK3CA H1047R mutation were more sensitive to the combined inhibition of PI3K/mTOR and EGFR with BEZ-235 and cetuximab (N=9) than cetuximab (N=9, P=0.0039) or BEZ-235 alone (N=9, P=0.0002) in-vivo. 23619167 PubMed Lui et al., 2013, Cancer Discov 2 accepted 1363 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2016-06-08 21:29:01 UTC https://civicdb.org/links/evidence_items/1363 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false PIK3CA 5290 Mutation Head And Neck Cancer 11934 Tanespimycin,Pictilisib,Trametinib Substitutes Predictive Does Not Support D Sensitivity/Response 6 head and neck cancer cell lines were tested for Response to 17-AAG, GDC-0941. Two of the cell lines did not carry PIK3CA mutations. No clear difference was shown between PIK3CA-mutant and wild-type cell lines and there was a trend towards increased resistance. SCC25 cell line was lentivirally transduced with PIK3CA E545K or H1047R mutation. Engineered cells, compared to the parental cell line, showed decreased sensitivity to 17-AAG, GDC-0941 or trametinib. 25855885 PubMed Wirtz et al., 2015, JAMA Otolaryngol Head Neck Surg 2 accepted 1364 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-06-27 23:34:16 UTC https://civicdb.org/links/evidence_items/1364 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false RET 5979 M918T Thyroid Gland Medullary Carcinoma 3973 Sorafenib Predictive Supports B Sensitivity/Response In a phase 2 clinical trial of sorafenib in patients with hereditary or sporadic advanced medullary thyroid cancer, 10 out of 12 patients genotyped in arm B (sporadic MTC) tested positive for RET mutations. In response to sorafenib, 8 patients with RET M918T mutations had stable disease, 1 RET M918T mutant had partial response, and 1 patient with a RET C634R mutation had stable disease. Prior to study entry, all patients with RET M918T mutations had progressive disease or were newly diagnosed. 20368568 PubMed Lam et al., 2010, J. Clin. Oncol. 3 accepted 1365 113 42 10 43617416 43617416 T C ENST00000355710.3 75 GRCh37 RET M819T is the most common somatically acquired mutation in medullary thyroid cancer (MTC). While there currently are no RET-specific inhibiting agents, promiscuous kinase inhibitors have seen some success in treating RET overactivity. Data suggests however, that the M918T mutation may lead to drug resistance, especially against the VEGFR-inhibitor motesanib. It has also been suggested that RET M819T leads to more aggressive MTC with a poorer prognosis. Somatic 2016-06-28 00:12:40 UTC https://civicdb.org/links/evidence_items/1365 https://civicdb.org/links/variants/113 https://civicdb.org/links/genes/42 false CDK4 1019 Amplification Liposarcoma 3382 Palbociclib Predictive Supports B Sensitivity/Response In a phase 2 clinical trial, NCT01209598, 30 patients with CDK4-amplified and RB-expressing well differentiated and dedifferentiated liposarcomas (WDLS/DDLS) were treated with a selective CDK 4/6 inhibitor, PD0332991. Treatment with PD0332991 was associated with favorable progression free survival rates (66% PFS rate, primary end point being greater than 40%) suggesting that CDK4 amplification is predictive of sensitivity to CDK4 inhibitor therapy. 23569312 PubMed Dickson et al., 2013, J. Clin. Oncol. NCT01209598 3 accepted 1366 553 13 12 58141510 58146304 ENST00000257904.6 75 GRCh37 Somatic 2016-06-18 04:03:43 UTC https://civicdb.org/links/evidence_items/1366 https://civicdb.org/links/variants/553 https://civicdb.org/links/genes/13 false ALK 238 ALK Fusion I1171 Lung Non-small Cell Carcinoma 3908 Alectinib Predictive Supports C Resistance A 51 year old female never-smoker was diagnosed with stage IV NSCLC with liver metastases. ALK rearrangement was verified via FISH. She was treated with crizotinib at 250 mg twice daily but discontinued due to adverse response. She then started alectinib at 600 mg twice daily with partial response, but new liver metastases then formed at 5 months. Liver tumor biopsy was performed and was estimated to be 15% tumor tissue. Next-generation sequencing discovered an ALK I1171N mutation. The tumor was not sequenced prior to alectinib resistance. 25736571 PubMed Ou et al., 2015, Lung Cancer 2 accepted 1367 527 1 2 29445213 29445213 A G ENST00000389048.3 75 GRCh37 Multiple case reports indicate that the I1171T missense mutation in ALK-rearranged non-small cell lung cancer (NSCLC) confers resistance to crizotinib and alectinib but is sensitive to ceritinib treatment. These results have been validated in vitro. In vitro evidence indicates this mutation interferes with alectinib binding the active site of ALK and may explain the sensitivity to the structurally distinct ALK inhibitor ceritinib. Somatic 2016-07-10 05:08:07 UTC https://civicdb.org/links/evidence_items/1367 https://civicdb.org/links/variants/527 https://civicdb.org/links/genes/1 false ALK 238 ALK Fusion I1171 Lung Non-small Cell Carcinoma 3908 Ceritinib Predictive Supports C Sensitivity/Response A 51 year old female never smoker was diagnosed with stage IV NSCLC with liver metastases, and had adverse response to crizotinib treatment, after which she responded to alectinib until disease progressed after 5 months with new liver metastases. Liver tumor biopsy was taken and estimated to be 15% tumor. Hybrid capture next generation sequencing was performed and an I1171N mutation was found in rearranged ALK, and estimated to be in 33% of the tumor cells. Ceritinib was given at 750 mg once daily but dose reduction to 600 mg once daily was required due to persistent nausea. CT showed regression of liver lesions and primary lung lesion and ongoing response was seen at 3 months. 25736571 PubMed Ou et al., 2015, Lung Cancer 3 accepted 1368 527 1 2 29445213 29445213 A G ENST00000389048.3 75 GRCh37 Multiple case reports indicate that the I1171T missense mutation in ALK-rearranged non-small cell lung cancer (NSCLC) confers resistance to crizotinib and alectinib but is sensitive to ceritinib treatment. These results have been validated in vitro. In vitro evidence indicates this mutation interferes with alectinib binding the active site of ALK and may explain the sensitivity to the structurally distinct ALK inhibitor ceritinib. Somatic 2016-07-06 19:44:34 UTC https://civicdb.org/links/evidence_items/1368 https://civicdb.org/links/variants/527 https://civicdb.org/links/genes/1 false NPM1 4869 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Does Not Support B Better Outcome In normal karyotype patients with AML (15-65 years old), complete remission rates and overall, event-free and relapse-free survival were not different for patients harboring NPM1 exon 12 mutations (N=50) than those wildtype for NPM1 (N=56). 16046528 PubMed Boissel et al., 2005, Blood 3 accepted 1369 86 35 5 170837531 170837569 ENST00000517671.1 75 GRCh37 NPM1 exon 12 mutations are frequently identified in patients with cytogenetically normal acute myeloid leukemia (AML) and often co-occur with FLT3-ITD. FLT3 status should also be evaluated as co-occurence with FLT3-ITD may impact prognosis. Exon 12 mutations have been identified as a predictor of good prognostic outcomes in the absence of FLT3-ITD. Due to their high frequency, NPM1 mutations have been retrospectively analyzed in the context of a number of therapies including variable results following ATRA treatment as well as improved response to high-dose daunorubicin or valproic acid. Additionally, multiple groups have shown increased surface expression of CD33 associated with NPM1 mutation, suggesting these patients may respond to anti-CD33 therapy. Cytoplasmic sequestration of NPM1 (NPM1c) is associated with a good response to induction therapy. Somatic 2016-06-10 20:23:04 UTC https://civicdb.org/links/evidence_items/1369 https://civicdb.org/links/variants/86 https://civicdb.org/links/genes/35 false BRCA1 672 Mutation Cancer 162 Olaparib Predictive Supports A Sensitivity/Response In this phase 1 trial, 60 patients with advanced solid tumors (ovarian, breast, colorectal, melanoma, sarcoma, prostate) were treated with PARP inhibitor olaparib. Durable antitumor activity was only observed in BRCA1/2 mutation carriers. 19 BRCA carriers had ovarian, breast, or prostate cancers; 12 of these (63%) had a clinical benefit from treatment with olaparib: radiologic or tumor-marker responses or meaningful disease stabilization (stable disease for a period of 4 months or more). Nine BRCA carriers had a response according to RECIST, with the response sustained for more than 76 weeks in one patient. No responses were seen in patients without BRCA mutation. 19553641 PubMed Fong et al., 2009, N. Engl. J. Med. NCT00516373 4 accepted 1370 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Rare Germline 2016-06-22 19:17:09 UTC https://civicdb.org/links/evidence_items/1370 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false BRCA2 675 Mutation Cancer 162 Olaparib Predictive Supports A Sensitivity/Response In this phase 1 trial 60 patients with advanced solid tumors (ovarian, breast, colorectal, melanoma, sarcoma, prostate) were treated with PARP inhibitor olaparib. Durable antitumor activity was only observed in BRCA1/2 mutation carriers.19 BRCA carriers had ovarian, breast, or prostate cancers; 12 of these (63%) had a clinical benefit from treatment with olaparib: radiologic or tumor-marker responses or meaningful disease stabilization (stable disease for a period of 4 months or more). Nine BRCA carriers had a response according to RECIST, with the response sustained for more than 76 weeks in one patient. No responses were seen in patients without BRCA mutation. 19553641 PubMed Fong et al., 2009, N. Engl. J. Med. NCT00516373 4 accepted 1371 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Rare Germline 2016-06-22 19:18:00 UTC https://civicdb.org/links/evidence_items/1371 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false CDKN2A 1029 Loss Skin Melanoma 8923 Alvocidib Predictive Supports D Sensitivity/Response Preclinical study in 9 melanoma cell lines. Three cell lines did not have CDKN2A (p16) mutations and showed expression of the protein on western blot analysis. Two of the other six cell lines had stop codons leading to a truncated protein, and three had missense mutations with evidence of protein expression on western blot (two cell lines with a P114L mutation and one with an E88K mutation). Mean IC50s of flavopiridol were significantly lower in cell lines with a mutated or non-expressed p16 (p16-) (mean 50% inhibitory concentration [IC(50)] = 12.5 nM), than in cell lines with intact p16 (p16+) (mean IC(50) = 25 nM). 12777976 PubMed Robinson et al., 2003, Melanoma Res. 2 accepted 1372 554 14 9 21967752 21994623 ENST00000579755.1 75 GRCh37 Somatic 2016-07-06 20:06:42 UTC https://civicdb.org/links/evidence_items/1372 https://civicdb.org/links/variants/554 https://civicdb.org/links/genes/14 false CDKN2A 1029 Loss Renal Cell Carcinoma 4450 Palbociclib Predictive Supports D Sensitivity/Response Preclinical study of CDK4/6 inhibitor PD-0332991 in 28 renal carcinoma cell lines (25 malignant RCC and three non-malignant, transformed cell lines derived from kidney epithelium). Both p15 and p16 loss (CGH) were tested for association with response to PD-0332991 using Fisher's exact test. Cell lines with p16 and p15 losses were significantly more likely to be classified as responders (defined by pharmacokinetic data-based concentration of <=400nM) to PD-0332991 (p=0.027, relative risk (RR)=2.06 and p=0.047, RR=1.71, respectively). Four cell lines had homozygous deletions of CDKN2A but not CDKN2B, and three of these lines were classified as being sensitive to PD-0332991. There were no cell lines with only CDKN2B deletion. 23898052 PubMed Logan et al., 2013, Anticancer Res. 3 accepted 1373 554 14 9 21967752 21994623 ENST00000579755.1 75 GRCh37 Somatic 2016-07-06 20:03:34 UTC https://civicdb.org/links/evidence_items/1373 https://civicdb.org/links/variants/554 https://civicdb.org/links/genes/14 false CDKN2B 1030 Loss Renal Cell Carcinoma 4450 Palbociclib Predictive Supports D Sensitivity/Response Preclinical study of CDK4/6 inhibitor PD-0332991 in 28 renal carcinoma cell lines (25 malignant RCC and three non-malignant, transformed cell lines derived from kidney epithelium). Both p15 and p16 loss (CGH) were tested for association with response to PD-0332991 using Fisher's exact test. Cell lines with p16 and p15 losses were significantly more likely to be classified as responders (defined by pharmacokinetic data-based concentration of <=400nM) to PD-0332991 (p=0.027, relative risk (RR)=2.06 and p=0.047, RR=1.71, respectively). Four cell lines had homozygous deletions of CDKN2A but not CDKN2B, and three of these lines were classified as being sensitive to PD-0332991. There were no cell lines with only CDKN2B deletion. 23898052 PubMed Logan et al., 2013, Anticancer Res. 3 accepted 1374 555 916 9 22002902 22009362 ENST00000276925.6 75 GRCh37 Somatic 2016-07-06 20:09:51 UTC https://civicdb.org/links/evidence_items/1374 https://civicdb.org/links/variants/555 https://civicdb.org/links/genes/916 false CDKN2A 1029 Loss Skin Melanoma 8923 Palbociclib Predictive Supports D Sensitivity/Response In a cohort of 143 patients with primary invasive melanoma hemizygous or homozygous loss of CDKN2A was observed (FISH) in 56% of cases. PD0332991 efficacy (proliferation assay) was assessed in a panel of 47 melanoma cell lines. Loss of functional p16INK4A (CDKN2A) due to gene deletion (49% of cells), methylation (4% of cells), or mutation (19% of cells) was the most prevalent alteration occurring in 71% of cell lines, and significantly correlated with PD0332991 sensitivity (Fisher's exact test P < 0.02). 24495407 PubMed Young et al., 2014, Pigment Cell Melanoma Res 3 accepted 1375 554 14 9 21967752 21994623 ENST00000579755.1 75 GRCh37 Somatic 2016-07-06 20:02:57 UTC https://civicdb.org/links/evidence_items/1375 https://civicdb.org/links/variants/554 https://civicdb.org/links/genes/14 false CDK4 1019 R24C Skin Melanoma 8923 Palbociclib Predictive Supports D Sensitivity/Response In a cohort of 143 patients with primary invasive melanoma, copy-number gain of CDK4 was observed (FISH) in 37% of cases. PD0332991 efficacy (proliferation assay) was assessed in a panel of 47 melanoma cell lines. Four cell lines had an R24C activating mutation in CDK4, three of these were sensitive to PD0332991 (palbociclib). 24495407 PubMed Young et al., 2014, Pigment Cell Melanoma Res 1 accepted 1376 556 13 12 58145431 58145431 G A ENST00000257904.6 75 GRCh37 Somatic 2016-06-27 21:10:46 UTC https://civicdb.org/links/evidence_items/1376 https://civicdb.org/links/variants/556 https://civicdb.org/links/genes/13 false CDKN2A 1029 Loss Ovarian Cancer 2394 Palbociclib Predictive Supports D Sensitivity/Response Preclinical study of the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation in a panel of 40 human ovarian cancer cell lines. Concentration-dependent antiproliferative effects of PD-0332991 were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb-proficient cell lines with low p16 expression were significantly more sensitive to PD-0332991 (as defined by IC50 < mean) in mRNA expression (Agilent), protein level (Western Blot) and copy number (Array CGH) analyses. 21278246 PubMed Konecny et al., 2011, Clin. Cancer Res. 3 accepted 1377 554 14 9 21967752 21994623 ENST00000579755.1 75 GRCh37 Somatic 2016-07-06 20:02:34 UTC https://civicdb.org/links/evidence_items/1377 https://civicdb.org/links/variants/554 https://civicdb.org/links/genes/14 false ASXL1 171023 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In older patients (>59 years) with cytogenetically normal acute myeloid leukemia classified as ELN favorable, multivariate analysis identified ASXL1 mutations (12/99 patients) were associated with lower complete remission rates (P = 0.03), disease-free survival (P < 0.001), overall survival (P < 0.001), and event-free survival (P < 0.001). This confirmed results from univariate analysis of patients not stratified by ELN category, but cytogenetically normal and older (38/220 patients). 22031865 PubMed Metzeler et al., 2011, Blood 3 accepted 1378 177 68 20 30946155 31027122 ENST00000375687.4 75 GRCh37 ASXL1 mutations are most frequently observed in the absence of FLT3-ITD and NPM1 mutations in acute myeloid leukemia (AML) patients and seem to be enriched in older patients (>60 years). These mutations are associated with poor prognosis with respect to both survival and compete remission rates. Somatic 2016-06-21 01:47:10 UTC https://civicdb.org/links/evidence_items/1378 https://civicdb.org/links/variants/177 https://civicdb.org/links/genes/68 false ASXL1 171023 EXON 12 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In patients with de novo AML who received intensive chemotherapy, ASXL1 mutations (N=51) were associated with shorter overall (P<0.001) and event free survival (P=0.012) compared to ASXL1 wild-type (N=430). Multivariate analysis identified ASXL1 mutations as an independent factor for adverse overall survival (P=0.032, relative risk: 1.70). 23018865 PubMed Schnittger et al., 2013, Leukemia 4 accepted 1379 557 68 20 31021087 31021720 ENST00000375687.4 75 GRCh37 Somatic 2016-06-20 20:48:50 UTC https://civicdb.org/links/evidence_items/1379 https://civicdb.org/links/variants/557 https://civicdb.org/links/genes/68 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Pictilisib Predictive Supports D Sensitivity/Response The HER2/Neu mammary tumor mouse model MMTV-NeuT was employed to demonstrate dependence of HER2 tumor formation on PIK3 p110alpha isoform. MMTV-NeuT mice were crossed with floxed p110alpha mice. Diassacociated tumors cells from these mice were treated with Cre adenovirus to delete p110alpha, or GFP adenovirus, and cells were transplanted into athymic mice. GFP treated cells formed new tumors, while p110alpha deletion blocked tumor formation indicating tumor dependence on PI3KA. Next, MMTV-NeuT tumors were dissociated and treated with pan-PI3K inhibitor GDC-0941. Reduced lipid kinase activity and reduced phospho-Akt levels were seen in these cells. Administration of 125 mg/kg GDC-0941 to athymic mice with transplantation of tumor cells caused marked reduction of tumor cell volume in comparison to control treatment. 22802530 PubMed Utermark et al., 2012, Genes Dev. 3 accepted 1380 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-07-06 20:19:24 UTC https://civicdb.org/links/evidence_items/1380 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 A66 Predictive Supports D Sensitivity/Response Pharmacologic (A66; p110alpha specific inhibitor) or genetic (cre-mediated knockout) ablation of the p110alpha PI3K isoform reduced tumor growth and tumor formation, respectively, in athymic mice transplanted with cells transduced by MMTV-NeuT (mammary specific overexpression of HER2 that effectively induces tumors). A66 treatment of cells from MMTV-NeuT mouse tumors resulted in decreased lipid kinase activity and phospho Akt levels. 22802530 PubMed Utermark et al., 2012, Genes Dev. 2 accepted 1381 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-11-03 19:22:32 UTC https://civicdb.org/links/evidence_items/1381 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Tgx 221 Predictive Does Not Support D Sensitivity/Response Treatment of cells obtained from MMTV-NeuT mouse mammary tumors with the p110beta selective inhibitor TGX-221 showed significant but minimal reductions in lipid kinase activity and negligible reductions in phospho Akt levels. In simmilar cells subjected to p110alpha isoform knockout, TGX-221 treatment fully blocked Akt activation, indicating that TGX-221 was fully inhibiting the p110beta isoform. Athymic mice recieved MMTV-NeuT tumor cell transplants and were treated with TGX-221, which resulted in significant but minimal reduction in tumor growth compared to controls. 22802530 PubMed Utermark et al., 2012, Genes Dev. 3 accepted 1382 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-07-05 19:47:27 UTC https://civicdb.org/links/evidence_items/1382 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false PTEN 5728 Loss Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Supports D Resistance A large-scale RNAi genetic sereen in HER2 overexpressing breast cancer cell line BT-474 was performed to discover genes whose loss induced trastuzumab resistance. The most prominently enriched gene in trastuzumab resistant populations was PTEN. Subsequent knockdown of PTEN in BT-474 cells increased cell survival when treated with trastuzumab, and growth curves showed partial restoration of proliferation in PTEN knockdown BT-474 cells treated with trastuzumab. 17936563 PubMed Berns et al., 2007, Cancer Cell 2 accepted 1383 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-06-27 21:04:12 UTC https://civicdb.org/links/evidence_items/1383 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PIK3CA 5290 Mutation Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Supports B Resistance The HER2 overexpressing breast cancer cell line BT-474 transduced with mutant PIK3CA H1047R demonstrated essentially normal proliferation under trastuzumab, while control cells showed negligible proliferation with trastuzumab. Sequencing of 55 HER2 breast cancer samples revealed 25% PIK3CA mutation rate and Kaplan Meier curves showed decreased time to progression for mutant PIK3CA at borderline statistical significance (p=0.052). This was potentially explained by presence of PTEN loss in wild-type PIK3CA sample and combining PTEN loss with PIK3CA mutation resulted in significant differences in time to progression (p=0.007). 17936563 PubMed Berns et al., 2007, Cancer Cell 2 accepted 1384 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1384 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PTEN 5728 Loss Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Supports B Resistance A subgroup of HER2-positive breast cancer patients that received first-line trastuzumab treatment were assessed for PTEN loss via IHC of FFPE samples. 46 samples showed PTEN loss while 41 did not, and PTEN loss alone was found to be significantly associated with resistance to trastuzumab (p=0.028) and shorter overall survival (p=0.008). 20813970 PubMed Esteva et al., 2010, Am. J. Pathol. 3 accepted 1385 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-06-27 21:05:22 UTC https://civicdb.org/links/evidence_items/1385 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PTEN 5728 Loss Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Does Not Support B Resistance While some reports indicate PTEN loss is associated with resistance to trastuzumab, in a subgroup of HER2 breast cancer FFPE samples from patients receiving trastuzumab as later line therapy (second or greater line therapy), with 25 PTEN loss and and 25 normal samples, no association was seen between trastuzumab response and PTEN status (p=1.000) or overall survival and PTEN status (p=0.863). 20813970 PubMed Esteva et al., 2010, Am. J. Pathol. 3 accepted 1386 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-06-27 18:50:51 UTC https://civicdb.org/links/evidence_items/1386 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false CALR 811 EXON 9 FRAMESHIFT Myelofibrosis 4971 Prognostic Supports A Better Outcome Study of 428 patients with primary Myelofibrosis found that those patients harboring CALR exon 9 mutations displayed significantly longer survival than those with JAK2 mutations (HR: 2.5, median survival yrs: CALR 15.9, JAK2 5.9) 25037629 PubMed Tefferi et al., 2014, Blood 4 accepted 1387 559 732 19 13054527 13054727 ENST00000316448.5 75 GRCh37 Exon 9 insertions and deletions have become part of the WHO diagnostic criteria for essential thrombocythemia (ET) and primary myelofibrosis (PMF) (Arber et al, 2016). These mutations are typically heterozygous and in the absence of JAK2 and MPL mutations. Approximately 80% of observed mutations are type 1 (p.L367fs*46), the result of a 52 bp deletion, or type 2 (p.K385fs*47), the result of a 5-bp TTGTC insertion, and studies have suggested phenotypic and prognostic differences between them. In PMF patients, CALR exon 9 mutations have been associated with improved median survival. Somatic 2016-09-12 12:51:26 UTC https://civicdb.org/links/evidence_items/1387 https://civicdb.org/links/variants/559 https://civicdb.org/links/genes/732 false CSF3R 1441 Mutation Chronic Neutrophilic Leukemia 0080187 Diagnostic Supports B Positive Study found that mutations in CSF3R are enriched in patients with Chronic Neutrophilic Leukemia (CNL) or Atypical Chronic Myeloid Leukemia (16/27, 59%) when compared to other blood disorders (AML=1/292, t-cell ALL=0/8, B-cell ALL=0/41) 23656643 PubMed Maxson et al., 2013, N. Engl. J. Med. 3 accepted 1388 560 1239 1 36932096 36933444 ENST00000373106.1 75 GRCh37 Somatic 2016-06-23 21:25:34 UTC https://civicdb.org/links/evidence_items/1388 https://civicdb.org/links/variants/560 https://civicdb.org/links/genes/1239 false CSF3R 1441 Mutation Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative 0060597 Diagnostic Supports B Positive Study found that mutations in CSF3R are enriched in patients with Chronic Neutrophilic Leukemia (CNL) or Atypical Chronic Myeloid Leukemia (16/27, 59%) when compared to other blood disorders (AML=1/292, t-cell ALL=0/8, B-cell ALL=0/41) 23656643 PubMed Maxson et al., 2013, N. Engl. J. Med. 3 accepted 1389 560 1239 1 36932096 36933444 ENST00000373106.1 75 GRCh37 Somatic 2016-06-23 21:28:10 UTC https://civicdb.org/links/evidence_items/1389 https://civicdb.org/links/variants/560 https://civicdb.org/links/genes/1239 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Ponatinib Predictive Supports B Sensitivity/Response Study describes a phase 1 clinical trial of ponatinib in treatment of 81 refractory Philadelphia chromosome-positive leukemias. 43 of these patients were considered to have chronic-phase CML. All 12 chronic-phase CML patients with a T315I mutation showed a complete hematologic response. Furthermore, 91% of these patients were estimated to remain in response at 1 year (95% CI, Kaplan-Meier analysis). 23190221 PubMed Cortes et al., 2012, N. Engl. J. Med. NCT00660920 4 accepted 1390 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2016-07-05 16:04:19 UTC https://civicdb.org/links/evidence_items/1390 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false EGFR 1956 T790M Lung Adenocarcinoma 3910 Gefitinib,Erlotinib Substitutes Predictive Supports B Resistance 155 patients with lung adenocarcinomas underwent rebiopsy and genotyping (EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS, PIK3CA and FISH for MET and HER2) after the development of acquired resistance to EGFR inhibitors (gefitinib or erlotinib). 98 patients were found to have developed EGFR T790M mutations. 23470965 PubMed Yu et al., 2013, Clin. Cancer Res. 3 accepted 1391 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1391 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false MET 4233 Amplification Lung Adenocarcinoma 3910 Erlotinib,Gefitinib Substitutes Predictive Supports C Resistance 155 patients with lung adenocarcinomas underwent rebiopsy and genotyping (EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS, PIK3CA and FISH for MET and HER2) after the development of acquired resistance to EGFR inhibitors (gefitinib or erlotinib). MET amplification was seen in 4 of 75 patients tested (no baseline samples available). One patient had small cell transformation and MET amplification, two patients had EGFR T790M mutation and MET amplification. 23470965 PubMed Yu et al., 2013, Clin. Cancer Res. 2 accepted 1392 270 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 N/A 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1392 https://civicdb.org/links/variants/270 https://civicdb.org/links/genes/52 false ERBB2 2064 Amplification Lung Adenocarcinoma 3910 Gefitinib,Erlotinib Substitutes Predictive Supports C Resistance 155 patients with lung adenocarcinomas underwent rebiopsy and genotyping (EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS, PIK3CA and FISH for MET and HER2) after the development of acquired resistance to EGFR inhibitors (gefitinib or erlotinib). 2 of 24 patients tested were found to have HER2 amplification (but no baseline samples available for analysis). One patient of which had a metastasis sample which was reported to have only HER2 amplification whereas another autopsy specimen from the same patient was HER2 negative but EGFR T790M positive. 23470965 PubMed Yu et al., 2013, Clin. Cancer Res. 1 accepted 1393 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. N/A 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1393 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false EGFR 1956 S768I Lung Adenocarcinoma 3910 Erlotinib Predictive Supports C Sensitivity/Response A patient with metastatic lung adenocarcinoma was found to harbor EGFR T790M and S768I mutations when acquired resistance developed after 8 years of erlotinib treatment. Analysis of original tumor samples from 2001 and 2003 were found to also harbor the S768I (but not T790M) mutation. Three-dimensional visualization showed the 768 position to be outside of the erlotinib binding position. 25521405 PubMed Hellmann et al., 2014, J Thorac Oncol 3 accepted 1394 562 19 7 55249005 55249005 G T ENST00000275493.2 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1394 https://civicdb.org/links/variants/562 https://civicdb.org/links/genes/19 false EGFR 1956 S768I Lung Adenocarcinoma 3910 Gefitinib Predictive Supports C Sensitivity/Response Case report of an 81-year old man with lung adenocarcinoma and EGFR S768I mutation. The patient then received chemotheraoy (vinorelbine) and showed stable disease. Gefitinib was administered when disease progression was noted 4 months later and the patient was followed-up without signs of disease progression for 461 days. 20522446 PubMed Masago et al., 2010, Jpn. J. Clin. Oncol. 2 accepted 1395 562 19 7 55249005 55249005 G T ENST00000275493.2 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1395 https://civicdb.org/links/variants/562 https://civicdb.org/links/genes/19 false EGFR 1956 C797S Lung Adenocarcinoma 3910 Osimertinib Predictive Supports C Resistance Case report of a patient with stage IV lung adenocarcinoma and a 15–base pair deletion in EGFR exon 19. Partial response with erlotinib was achieved for 15 months after initial chemotherapy. After further progression, rebiopsy additionally identified the EGFR T790M mutation and the patient received several cycles of chemotherapy and targeted therapy including afatinib, cetuximab, erlotinib, AZD9291. She was treated with AZD9291 for 9 months until disease progression. Repeat biopsy detected EGFRC797S mutation additionally to both aforementioned EGFR aberrations. In addition, PTEN Y27C and CTNNB1 S37F mutations were present in all 3 samples, and a TSC2 N486I was seen in the third biopsy sample only 26181354 PubMed Yu et al., 2015, JAMA Oncol NCT01802632 1 accepted 1396 415 19 7 55249091 55249091 T A ENST00000275493.2 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1396 https://civicdb.org/links/variants/415 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Adenocarcinoma 3910 Osimertinib Predictive Supports C Sensitivity/Response Case report of a patient with stage IV lung adenocarcinoma and a 15–base pair deletion in EGFR exon 19. Partial response with erlotinib was achieved for 15 months after initial chemotherapy. After further progression, rebiopsy additionally identified the EGFR T790M mutation and the patient received several cycles of chemotherapy and targeted therapy including afatinib, cetuximab, erlotinib, AZD9291. She was treated with AZD9291 for 9 months until disease progression. 26181354 PubMed Yu et al., 2015, JAMA Oncol NCT01802632 1 accepted 1397 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1397 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false BRAF 673 V600E Melanoma 1909 Vemurafenib Predictive Supports B Sensitivity/Response The BRIM-3 Phase III trial NCT01006980 assessed BRAF inhibitor vemurafenib versus dacarbazine in 598 patients with treatment naive metastatic melanoma and confirmed V600E mutation. Significant differences were seen in overall survival (13.3 months with vemurafenib vs. 10.0 months with dacarbazine) and median progression free survival (6.9 months with vemurafenib vs. 1.6 months with dacarbazine) 24508103 PubMed McArthur et al., 2014, Lancet Oncol. NCT01006980 5 accepted 1398 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-06-27 15:42:21 UTC https://civicdb.org/links/evidence_items/1398 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600K Melanoma 1909 Vemurafenib Predictive Supports B Sensitivity/Response In the Phase III study of vemurafenib versus dacarbazine BRIM-3 (NCT01006980) in metastatic melanoma, 57 patients were confirmed to have V600K mutation. In this subgroup of treatment-naive patients, significant differences were seen in overall survival (14.5 months with vemurafenib vs. 7.6 months with dacarbazine), as well as median progression free survival (5.9 months with vemurafenib vs. 1.7 months with dacarbazine). 24508103 PubMed McArthur et al., 2014, Lancet Oncol. NCT01006980 4 accepted 1399 563 5 7 140453136 140453137 AC TT ENST00000288602.6 75 GRCh37 Somatic 2016-06-27 23:40:52 UTC https://civicdb.org/links/evidence_items/1399 https://civicdb.org/links/variants/563 https://civicdb.org/links/genes/5 false BRAF 673 V600K Melanoma 1909 Vemurafenib Predictive Supports C Sensitivity/Response A 53 year old male presented with a scalp lesion which was incompletely excised. Metastases were seen in lymph node biopsy and subsequently in CT. BRAF inhibitor vemurafenib was then administered at 960 mg twice daily and later at 720 mg twice daily and reduction in metastases was observed. After 2 years complete radiological response was seen, while treatment was discontinued due to cardiomyopathy. 12 months after stopping vemurafenib patient did not show evidence of metastatic melanoma. 26989536 PubMed Sahadudheen et al., 2016, Case Rep Oncol Med 3 accepted 1400 563 5 7 140453136 140453137 AC TT ENST00000288602.6 75 GRCh37 Somatic 2016-06-27 23:29:52 UTC https://civicdb.org/links/evidence_items/1400 https://civicdb.org/links/variants/563 https://civicdb.org/links/genes/5 false PIK3CA 5290 H1047R Head And Neck Cancer 11934 Alpelisib Predictive Supports D Sensitivity/Response In a panel of head and neck cancer cell lines, 2 lines containing the PIK3CA mutation H1047R (Detroit562 and SNU-1076) were more sensitive to growth inhibition (IC50 1.10 and 6.82) by the PI3Kalpha specific inhibitor BYL719 (Alepelisib) than 3 of 4 lines with wild type PI3K (SNU-1066 IC50 1.13 μM; SNU-1041, 20.65 μM; FaDu, 19.67 μM; SCC25, 49.30 μM). In the H1047R mutant cell lines and the wildtype cell line tested, phospho-Akt and phospho-S6 levels were diminished with increasing BYL719 levels. 25550549 PubMed Keam et al., 2015, Anticancer Res. 1 accepted 1401 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2016-06-28 22:10:38 UTC https://civicdb.org/links/evidence_items/1401 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false PIK3CA 5290 Mutation Cancer 162 Alpelisib Predictive Supports D Sensitivity/Response A set of 474 cell lines from the Cancer Cell Line Encyclopedia was tested for responsiveness to the PI3Kalpha specific inhibitor BYL719 (Alpelisib). In the PIK3CA wild type subroup of cell lines, 22% were assessed as responsive, while in the subgroup of cell lines with PIK3CA mutations, 64% were labeled as responders. 7 patient derived xenografts with PIK3CA mutations (H1047R, E545K, M1043I, C420R, Q546K) were transplanted into mice and treated with BYL719. 6/7 mice responded with strong tumor growth inhibition or regression, while one (H1047R) responded with weak growth inhibition. 24608574 PubMed Fritsch et al., 2014, Mol. Cancer Ther. 4 accepted 1402 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-06-27 23:39:49 UTC https://civicdb.org/links/evidence_items/1402 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PIK3CA 5290 Amplification Stomach Carcinoma 5517 Alpelisib Predictive Supports D Sensitivity/Response 474 cancer cell lines from the cancer cell line encyclopedia were assessed for response to the PI3Kalpha inhibitor BYL719 (Alpelisib). PIK3CA amplification was significanly associated with BYL719 response. A gastric cancer patient derived xenograft (PDX) was transplanted into two athymic mice and one was treated with BYL719. The untreated PDX grew by over 100 percent while the BYL719 tumor was reduced by 86 percent. 24608574 PubMed Fritsch et al., 2014, Mol. Cancer Ther. 3 accepted 1403 212 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 Somatic 2016-07-10 21:20:50 UTC https://civicdb.org/links/evidence_items/1403 https://civicdb.org/links/variants/212 https://civicdb.org/links/genes/37 false BRAF 673 Mutation Colorectal Cancer 9256 Cetuximab,Panitumumab Substitutes Predictive Does Not Support B Sensitivity/Response A quantitative synthesis was performed on nine studies comparing treatment of metastatic colorectal cancer with cetuximab or panitumumab and chemotherapy, versus chemotherapy alone, or with other targeted inhibitors. It was found that in the patient subgroup with BRAF mutation (V600E in the majority of cases), there were no benefits to overall survival, progression free survival, or overall response rate with addition of cetuximab or panitumumab to treatment. This conclusion held in the first line treatment as well as general treatment setting. 25673558 PubMed Pietrantonio et al., 2015, Eur. J. Cancer 3 accepted 1404 399 5 7 140453136 140481403 ENST00000288602.6 75 GRCh37 Somatic 2016-06-28 02:27:21 UTC https://civicdb.org/links/evidence_items/1404 https://civicdb.org/links/variants/399 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Vemurafenib Predictive Does Not Support B Sensitivity/Response In this Phase II pilot study (NCT00405587) of BRAF V600 inhibitor vemurafenib in 21 metastatic colorectal cancer (CRC) patients with BRAF V600E, one patient had a durable 21 week partial response, and seven patients had 8 week stable disease as best response. Median progression free survival was 2.1 months and median overall survival was 7.7 months. The authors conclude that single agent vemurafenib did not show meaningful activity in V600E CRC, in contrast to the significant vemurafenib activity against V600 in melanoma. 26460303 PubMed Kopetz et al., 2015, J. Clin. Oncol. NCT00405587 4 accepted 1405 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-06-27 23:41:26 UTC https://civicdb.org/links/evidence_items/1405 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Dabrafenib Predictive Does Not Support B Sensitivity/Response In trial NCT00880321, dabrafenib was tested in various solid tumor types harboring mutant BRAF after establishing dosage of 150 mg twice daily. In nine colorectal cancer patients with established V600E mutation, 1 confirmed response, 7 instances of stable disease, and 1 case of progressive disease was seen, which contrasted strongly with a 56% confirmed response rate seen in metastatic V600E melanoma patients similarly treated in the same study. 22608338 PubMed Falchook et al., 2012, Lancet NCT00880321 3 accepted 1406 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-06-27 23:30:32 UTC https://civicdb.org/links/evidence_items/1406 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600 Melanoma 1909 Brain neoplasm Dabrafenib Predictive Supports B Sensitivity/Response In the NCT00880321 trial using mutant BRAF inhibitor dabrafenib in solid tumors, 10 cases of melanoma brain metastases were assessed for dabrafenib response. In nine patients a decrease in size of metastases was seen, and in four cases a complete resolution of brain lesions was observed. This subset of patients had median progression free survival of 4.2 months. 22608338 PubMed Falchook et al., 2012, Lancet NCT00880321 4 accepted 1407 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2016-06-27 15:47:51 UTC https://civicdb.org/links/evidence_items/1407 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Cetuximab,Gefitinib,Vemurafenib Combination Predictive Supports D Sensitivity/Response 5 of 7 colorectal cancer (CRC) cell lines with BRAF V600E mutation were resistant to treatment with the BRAF inhibitor vemurafenib. An RNAi screen in the WiDr cell line (a V600E CRC line) identified EGFR as an enhancer for survival when exposed to vemurafenib. Treatment with vemurafenib and EGFR inhibitor (cetuximab or gefitinib) in V600E CRC cells (WiDr, VACO432 and KM20) showed inhibited growth as well as induction of the cleaved PARP apoptotic marker. WiDr and VACO432 cells were injected into immunodeficient mice. Modest response was seen with vemurafenib treatment, while combination treatment showed considerable tumor growth inhibition as compared to control. 22281684 PubMed Prahallad et al., 2012, Nature 3 accepted 1408 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-06-29 20:22:51 UTC https://civicdb.org/links/evidence_items/1408 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Skin Melanoma 8923 Vemurafenib Predictive Supports A Sensitivity/Response Phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. A relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression was observed with vemurafenib as compared with dacarbazine (P<0.001 for both comparisons). 21639808 PubMed Chapman et al., 2011, N. Engl. J. Med. NCT01006980 5 accepted 1409 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-06-27 15:39:43 UTC https://civicdb.org/links/evidence_items/1409 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Skin Melanoma 8923 Vemurafenib Predictive Supports B Sensitivity/Response Phase 2 trial in 132 patients with previously treated metastatic melanoma with BRAF V600E mutation. Confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Median overall survival was 15.9 months (95% CI, 11.6 to 18.3). 22356324 PubMed Sosman et al., 2012, N. Engl. J. Med. NCT00949702 3 accepted 1410 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-06-27 18:13:09 UTC https://civicdb.org/links/evidence_items/1410 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600 Skin Melanoma 8923 Trametinib,Dabrafenib Combination Predictive Supports A Sensitivity/Response The Combi-v (NCT01597908) open-label, randomized phase 3 trial had 704 patients with metastatic melanoma with a BRAF V600 mutation. Patients were randomized to receive either a combination of dabrafenib and trametinib or vemurafenib orally as first-line therapy. At preplanned interim analysis the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). Cutaneous squamous-cell carcinoma and keratoacanthoma occurred at 1% with combination-therapy and 18% in the vemurafenib group. 25399551 PubMed Robert et al., 2015, N. Engl. J. Med. NCT01597908 5 accepted 1411 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2018-11-01 14:55:05 UTC https://civicdb.org/links/evidence_items/1411 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false SMAD4 4089 LOSS Pancreatic Cancer 1793 Prognostic Supports B Poor Outcome Study employed a rapid autopsy technique on a cohort of 76 patients with pancreatic cancer and explored the status of several genes. 63% (41/65) of carcinomas analyzed showed inactivation of SMAD4 (DPC4) via immunolabeling. Among the patterns of failure "metastatic and locally destructive", It was discovered that DPC4 loss was significantly associated with metastatic disease (p=.007). 19273710 PubMed Iacobuzio-Donahue et al., 2009, J. Clin. Oncol. 3 accepted 1412 564 77 18 48556583 48611409 ENST00000342988.3 75 GRCh37 Somatic 2016-06-28 16:46:02 UTC https://civicdb.org/links/evidence_items/1412 https://civicdb.org/links/variants/564 https://civicdb.org/links/genes/77 false BRAF 673 V600E Colorectal Cancer 9256 Vemurafenib,Panitumumab Combination Predictive Does Not Support B Sensitivity/Response Treatment response to mutant BRAF inhibitor vemurafenib and EGFR inhibitor panitumumab was assayed in 12 patients with metastatic colorectal cancer (CRC) who had progressed on chemotherapy. Two patients had confirmed partial responses, and 2 showed stable disease over 6 months. The authors conclude that although some efficacy is seen, only a small subset of patients respond to this treatment and the responses are not durable. 25589621 PubMed Yaeger et al., 2015, Clin. Cancer Res. 3 accepted 1413 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-06-28 20:20:59 UTC https://civicdb.org/links/evidence_items/1413 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Thyroid Gland Papillary Carcinoma 3969 Vemurafenib Predictive Supports C Sensitivity/Response A 73 year old patient with prior history of breast cancer presented with metastatic papillary thyroid carcinoma. After two treatments of I-131 a comprehensive tumor profile revealed BRAF V600E as the only genetic alteration on a near diploid genome with trisomy 1q. Vemurafenib treatment resulted in improvement of symptoms and considerable reductions in tumor mass, and after 23 months the patient remained on therapy with well controlled disease. 24987354 PubMed Ali et al., 2014, Case Rep Oncol 4 accepted 1414 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-06-28 19:21:56 UTC https://civicdb.org/links/evidence_items/1414 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600 Colorectal Cancer 9256 Dabrafenib,Trametinib Combination Predictive Supports B Sensitivity/Response In clinical trial NCT01072175, 43 patients with BRAF V600 metastatic colorectal cancer (CRC) received mutant BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Only 12% of patients showed partial response or better, with one complete response lasting 36 months and ongoing after data cutoff. 56% of patients achieved stable disease. The median progression free survival (PFS) was 3.5 months, longer than the median PFS (2.5 months) reported for metastatic CRC treated with standard chemotherapy. The authors conclude that MAPK targeting in CRC is a valid approach that can produce meaningful responses but additional work is required to more effectively inhibit the pathway. 26392102 PubMed Corcoran et al., 2015, J. Clin. Oncol. NCT01072175 2 accepted 1415 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2016-06-28 20:12:43 UTC https://civicdb.org/links/evidence_items/1415 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false BRAF 673 TRIM24::BRAF Skin Melanoma 8923 Vemurafenib Predictive Supports D Resistance Foundation One NGS assay and targeted RNAseq identified PAPSS1-BRAF fusion in a melanoma sample. Further BRAF fusions (TRIM24-BRAF) were identified in TCGA and additional samples. Ectopic expression of engineered cDNA in 293H cells showed that trametinib led to reduced ERK1/2 phosphorylation in fusion positive cells whereas vemurafenib was not effective. 24345920 PubMed Hutchinson et al., 2013, Clin. Cancer Res. 3 accepted 1416 287 5 7 138145079 138239711 ENST00000343526.4 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2020-09-23 06:00:08 UTC https://civicdb.org/links/evidence_items/1416 https://civicdb.org/links/variants/287 https://civicdb.org/links/genes/5 false SF3B1 23451 K700E Breast Cancer 1612 Spliceostatin A Predictive Supports D Sensitivity/Response Mutations in SF3B1 were identified in 21/936 ER positive vs. 1/289 ER negative breast cancers. Mutation was recurrent (K700E in 74% or K666Q or K666E in another 9% of tumors). Treatment of two SF3B1 mutant cell lines (pancreatic and endometrial with K700 and K666 mutation, respectively) and six wild-type controls showed that mutant cell lines were significantly more sensitive to spliceostatin A (SF3b complex inhibitor). 25424858 PubMed Maguire et al., 2015, J. Pathol. 2 accepted 1417 565 44 2 198266834 198266834 T C ENST00000335508.6 75 GRCh37 Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1417 https://civicdb.org/links/variants/565 https://civicdb.org/links/genes/44 false SF3B1 23451 K666N Breast Cancer 1612 Spliceostatin A Predictive Supports D Sensitivity/Response Mutations in SF3B1 were identified in 21/936 ER positive vs. 1/289 ER negative breast cancers. Mutation was recurrent (K700E in 74% or K666Q or K666E in another 9% of tumors). Treatment of two SF3B1 mutant cell lines (pancreatic and endometrial with K700 and K666 mutation, respectively) and six wild-type controls showed that mutant cell lines were significantly more sensitive to spliceostatin A (SF3b complex inhibitor). 25424858 PubMed Maguire et al., 2015, J. Pathol. 2 accepted 1418 114 44 2 198267359 198267359 C A ENST00000335508.6 75 GRCh37 SF3B1 K666N is a variant found in myelodysplastic syndromes, chronic leukemias, and more recently, breast cancer. This somatic mutation has been linked to better overall outcome and event-free survival in MDS patients. Somatic 2016-07-13 18:40:21 UTC https://civicdb.org/links/evidence_items/1418 https://civicdb.org/links/variants/114 https://civicdb.org/links/genes/44 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports B Sensitivity/Response In a retrospective study comparing survival outcomes in a subgroup of 82 ALK-positive crizotinib-treated patients enrolled in a phase 1 clinical trial (NCT00585195), crizotinib therapy was associated with improved survival. For the crizotinib-treated, ALK-positive patient group, 1 year survival was 74% and 2 year overall survival was 54%, compared with 72% and 36% for the control group (ALK-positive crizotinib naive patients). 21933749 PubMed Shaw et al., 2011, Lancet Oncol. NCT00585195 3 accepted 1419 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-06-28 20:26:49 UTC https://civicdb.org/links/evidence_items/1419 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false MAP2K7 5609 E116K Lung Cancer 1324 Prognostic Supports B Poor Outcome Study examined rare SNPs on MAP2K7 among a discovery and two validation cohorts. It was discovered that the E116K genotype was associated with a reduced median survival time of 4 and 7 months for E/K or K/K genotypes (P=2.61E-7) and an increased cancer death risk for heterozygous (HR=1.49) and homozygous (HR=1.94) genotypes for a pooled cohort. Further nude mice harboring this variant showed increased xenograft growth and metastasis. 27028764 PubMed Qiu et al., 2016, PLoS Genet. 5 accepted 1420 566 4546 19 7975157 7975157 G A ENST00000397979.3 75 GRCh37 Common Germline 2016-06-28 19:00:23 UTC https://civicdb.org/links/evidence_items/1420 https://civicdb.org/links/variants/566 https://civicdb.org/links/genes/4546 false BRAF 673 V600E Melanoma 1909 Vemurafenib,Cobimetinib Combination Predictive Supports B Sensitivity/Response In this Phase III trial (coBRIM, NCT01689519) of 495 V600 mutant melanoma patients, 344 had V600E mutation. 174 patients were treated with vemurafenib and placebo, and 170 were treated with vemurafenib and cobimetinib and tested for progression free survival. 88 of 174 monotherapy group patients had an event with median progression free survival of 6.5 months. In the combination group 58 of 174 patients had an event with median progression-free survival not met, however, when in combination with other V600 mutations median progression-free survival was 9.9 months with combination treatment. Median time to followup for the whole cohort was 7.3 months. Hazard Ratio for progression or death was 0.57 (0.41-0.80). 25265494 PubMed Larkin et al., 2014, N. Engl. J. Med. NCT01689519 4 accepted 1421 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-11-08 16:29:15 UTC https://civicdb.org/links/evidence_items/1421 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600 Melanoma 1909 Vemurafenib,Cobimetinib Combination Predictive Supports B Sensitivity/Response In a randomized phase 3 study, previously untreated advanced or metastatic BRAF V600 mutation-positive melanoma patients treated with combination vemurafenib and cobimetinib showed improved progression free survival (9.9 vs 6.2 months), increased rate of complete or partial response (68% vs 45%), and improved overall survival at 9 months ( 81% vs 73%) compared to the vemurafenib and placebo control group. 25265494 PubMed Larkin et al., 2014, N. Engl. J. Med. NCT01689519 4 accepted 1422 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2018-11-01 18:31:23 UTC https://civicdb.org/links/evidence_items/1422 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false KIT 3815 M541L Chronic Leukemia 1036 Imatinib Predictive Supports C Sensitivity/Response In 5 patients with KIT M541L mutation-positive chronic eosinophilic leukemia (4 somatic and 1 germline mutation), treatment with low dose imatinib resulted in complete and lasting remission with a median follow up of 74 months and 1 patient relapse at 50 months. 25015329 PubMed Iurlo et al., 2014, Oncotarget 2 accepted 1423 201 29 4 55593464 55593464 A C ENST00000288135.5 75 GRCh37 Somatic 2016-07-08 17:47:49 UTC https://civicdb.org/links/evidence_items/1423 https://civicdb.org/links/variants/201 https://civicdb.org/links/genes/29 false KIT 3815 Exon 9 Mutation Gastrointestinal Stromal Tumor 9253 Sunitinib Predictive Supports B Sensitivity/Response In a study of 78 patients with gastrointestinal stromal tumors treated with sunitinib, patients with Kit exon 9 mutations or wildtype (lacking KIT or PDGFRA mutations) showed increased progression free survival and overall survival compared to patients with Kit exon 11 mutations. 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 3 accepted 1424 509 29 4 55592023 55592216 ENST00000288135.5 75 GRCh37 In patients with gastrointestinal stromal tumors (GIST), imatinib has improved outcomes for patients with KIT mutations. However, acquired resistance to imatinib is common. Patients harboring exon 9 KIT mutations may benefit from higher imatinib doses (800mg/daily). Similarly, imatinib-refractory tumors showed sensitivity to sunitinib treatment. Improved responses to either treatment were not observed in patients with exon 11 mutations. Somatic 2016-07-26 14:54:28 UTC https://civicdb.org/links/evidence_items/1424 https://civicdb.org/links/variants/509 https://civicdb.org/links/genes/29 false PDGFRA 5156 Fusion Chronic Myelomonocytic Leukemia 0080188 Diagnostic Supports A Negative The 2016 World Health Organization guidelines for the classification of myeloid malignancies uses the detection of PCM1-JAK2 or rearrangements involving PDGFRA, PDGFRB, or FGFR1 as recommended exclusion criteria for a diagnosis of chronic myelomonocytic leukemia, particularly in patients with evidence of eosinophilia. 27069254 PubMed Arber et al., 2016, Blood 5 accepted 1425 567 38 Somatic 2016-06-29 18:35:31 UTC https://civicdb.org/links/evidence_items/1425 https://civicdb.org/links/variants/567 https://civicdb.org/links/genes/38 false PDGFRB 5159 Fusion Chronic Myelomonocytic Leukemia 0080188 Diagnostic Supports A Negative The 2016 World Health Organization guidelines for the classification of myeloid malignancies uses the detection of PCM1-JAK2 or rearrangements involving PDGFRA, PDGFRB, or FGFR1 as recommended exclusion criteria for a diagnosis of chronic myelomonocytic leukemia, particularly in patients with evidence of eosinophilia. 27069254 PubMed Arber et al., 2016, Blood 5 accepted 1426 568 4176 Somatic 2016-06-30 04:01:25 UTC https://civicdb.org/links/evidence_items/1426 https://civicdb.org/links/variants/568 https://civicdb.org/links/genes/4176 false FGFR1 2260 Fusion Chronic Myelomonocytic Leukemia 0080188 Diagnostic Supports A Negative The 2016 World Health Organization guidelines for the classification of myeloid malignancies uses the detection of PCM1-JAK2 or rearrangements involving PDGFRA, PDGFRB, or FGFR1 as recommended exclusion criteria for a diagnosis of chronic myelomonocytic leukemia, particularly in patients with evidence of eosinophilia. 27069254 PubMed Arber et al., 2016, Blood 5 accepted 1427 569 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 Somatic 2016-06-30 04:00:54 UTC https://civicdb.org/links/evidence_items/1427 https://civicdb.org/links/variants/569 https://civicdb.org/links/genes/1885 false BRAF 673 V600E Colorectal Cancer 9256 Dactolisib,GDC-0879 Combination Predictive Supports D Sensitivity/Response In a mouse model of BRAF V600E colorectal cancer, western blots from tumors in mice treated with BRAF inhibitor GDC-0879 and PI3K/mTOR inhibitor BEZ235 showed stronger reduction in phospho-Akt and phospho-S6 than PI3K/mTOR inhibitor alone, and combination inhibition also resulted in stronger phospho-ERK inhibition in tumors than did BRAF inhibition alone. Increased apoptosis in tumors was seen in dual treatment conditions with increased TUNEL-positive cells. In vehicle treated mice, area of colon covered by tumor increased, while treatment with single agent inhibitors caused growth inhibition resulting in no change in colon area covered by tumors. Administration of dual inhibitors induced tumor regression apparent in a decrease of colonic area covered by tumors over the course of treatment. 23549875 PubMed Coffee et al., 2013, Clin. Cancer Res. 3 accepted 1428 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-07-08 18:00:38 UTC https://civicdb.org/links/evidence_items/1428 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false NRAS 4893 Mutation Melanoma 1909 Trametinib,Omipalisib Combination Predictive Supports D Sensitivity/Response In six NRAS mutant melanoma cell lines, concomitant use of MEK inhibitor and PI3K/mTOR inhibitor resulted in greater decrease in cell viability than either alone, with the synergistic effect being marked in 4/6 cell lines. MEK inhibitor JTP-74057 and PI3K/mTOR inhibitor GSK2126458 together induced synergistic increase in apoptotic Annexin V+/PI+ cells in these cell lines. Tumor xenografts in nude mice were established with 5 of the 6 cell lines. Effects of single agent treatment with JTP-74057 or GSK2126458 ranged from minor inhibition to tumor stasis, while dual inhibitor treatment showed synergistic effects in each case, with marked tumor reductions in 2/5 cases and the authors report one compete response in a MaMel301 cell line xenograft mouse. 23431193 PubMed Posch et al., 2013, Proc. Natl. Acad. Sci. U.S.A. 4 accepted 1429 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2017-05-31 15:33:59 UTC https://civicdb.org/links/evidence_items/1429 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false BRAF 673 V600E Gastrointestinal Neuroendocrine Tumor 0050626 Dabrafenib,Vemurafenib,Trametinib Combination Predictive Supports C Sensitivity/Response BRAF mutations were identified in 9% of 108 cases of high-grade colorectal neuroendocrine tumors (80% V600E). Two patients were treated with a combination of BRAF and MEK inhibition and exhibited durable response (beyond 7 and 9 months, respectively). Urinary BRAF V600E tumor DNA correlated with disease response in one of the patients. BRAF and MEK inhibition was either dabrafenib+trametinib (case 1) or vemurafenib+trametinib (case 2). 27048246 PubMed Klempner et al., 2016, Cancer Discov 3 accepted 1430 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-07-01 16:10:32 UTC https://civicdb.org/links/evidence_items/1430 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Emtansine Predictive Supports B Sensitivity/Response In a randomized phase II study, first line treatment of HER2-positive metastatic breast cancer with trastuzumab emtansine (T-DM1) resulted in improved progression free survival and fewer serious adverse effects when compared to treatment with combination trastuzumab plus docetaxel (HT) (median follow up 14 months, median PFS with T-DM1 14.2 vs 9.2 with HT). 23382472 PubMed Hurvitz et al., 2013, J. Clin. Oncol. NCT00679341 3 accepted 1432 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-07-06 05:01:41 UTC https://civicdb.org/links/evidence_items/1432 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false PDGFRA 5156 Fusion Myeloid And Lymphoid Neoplasms With Eosinophilia And Abnormalities Of PDGFRA, PDGFRB, And FGFR1 0080164 Diagnostic Supports A Positive The 2016 World Health Organization guidelines for the classification of myeloid malignancies and acute leukemia describes a new class of disease defined by myeloid or lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2. 27069254 PubMed Arber et al., 2016, Blood 5 accepted 1433 567 38 Somatic 2017-04-13 16:16:25 UTC https://civicdb.org/links/evidence_items/1433 https://civicdb.org/links/variants/567 https://civicdb.org/links/genes/38 false PDGFRB 5159 Fusion Hematologic Cancer 2531 Diagnostic Supports A Positive The 2016 World Health Organization guidelines for the classification of myeloid malignancies and acute leukemia describes a new class of disease defined by myeloid or lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2. 27069254 PubMed Arber et al., 2016, Blood 5 accepted 1434 568 4176 Somatic 2016-06-30 16:04:53 UTC https://civicdb.org/links/evidence_items/1434 https://civicdb.org/links/variants/568 https://civicdb.org/links/genes/4176 false FGFR1 2260 Fusion Hematologic Cancer 2531 Diagnostic Supports A Positive The 2016 World Health Organization guidelines for the classification of myeloid malignancies and acute leukemia describes a new class of disease defined by myeloid or lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2. 27069254 PubMed Arber et al., 2016, Blood 5 accepted 1435 569 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 Somatic 2016-06-30 16:04:40 UTC https://civicdb.org/links/evidence_items/1435 https://civicdb.org/links/variants/569 https://civicdb.org/links/genes/1885 false JAK2 3717 PCM1::JAK2 Hematologic Cancer 2531 Diagnostic Supports A Positive The 2016 World Health Organization guidelines for the classification of myeloid malignancies and acute leukemia describes a new class of disease defined by myeloid or lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2. 27069254 PubMed Arber et al., 2016, Blood 5 accepted 1436 571 28 GRCh37 Somatic 2016-06-30 16:04:26 UTC https://civicdb.org/links/evidence_items/1436 https://civicdb.org/links/variants/571 https://civicdb.org/links/genes/28 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Docetaxel,Trastuzumab,Pertuzumab Combination Predictive Supports B Sensitivity/Response In a randomized phase 3 trial, HER2 positive metastatic breast cancer patients given first-line treatment of pertuzumab plus trastuzumb plus docetaxel experienced improved progression free survival (18.5 vs 12.4 months, P<0.001) and increased objective response rate (80.2% vs 69.3%, P=0.001) than the control group given placebo plus trastuzumab plus docetaxel. 22149875 PubMed Baselga et al., 2012, N. Engl. J. Med. NCT00567190 4 accepted 1437 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-02-18 04:13:00 UTC https://civicdb.org/links/evidence_items/1437 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false MTOR 2475 E2014K and E2419K Transitional Cell Carcinoma 2671 Everolimus,Pazopanib Combination Predictive Supports C Sensitivity/Response A phase 1 clinical trial identified a patient with chemotherapy-refractory urothelial carcinoma who had complete radiographic response lasting 14 months after combined everolimus and pazopanib treatment. This patient was exome sequenced and two mutations co-occurring in MTOR were identified. Expression of these mutations in HEK293T cells demonstrated these were activating mutations. The authors propose that these two activating mutations are the reason for the dramatic response to mTOR inhibition and considered them as "biologically plausible" to confer sensitivity to everolimus. 24625776 PubMed Wagle et al., 2014, Cancer Discov 2 accepted 1438 572 2073 1 11174420 11187857 ENST00000361445.4 75 GRCh37 Somatic 2020-11-20 15:48:06 UTC https://civicdb.org/links/evidence_items/1438 https://civicdb.org/links/variants/572 https://civicdb.org/links/genes/2073 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Trastuzumab,Lapatinib Combination Predictive Supports B Sensitivity/Response In a randomized open label phase 3 study (NCT00553358), women with HER2 positive primary breast cancer treated with lapatinib plus trasuzumab had higher rates of pathological complete responses than seen in control groups receiving either IV trastuzumab or oral lapatinib alone (combination treatment pCR rate of 51% vs 29.5% and 24.7% for trastuzumab and lapatinib alone, respectively). 22257673 PubMed Baselga et al., 2012, Lancet NCT00553358 4 accepted 1439 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2018-02-18 04:13:25 UTC https://civicdb.org/links/evidence_items/1439 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false RICTOR 253260 Amplification Lung Adenocarcinoma 3910 Onatasertib,Sapanisertib Substitutes Predictive Supports C Sensitivity/Response Study describes an 18 year old never smoker patient presenting with lung adenocarcinoma. A genomic profiling assay (FoundationOne) revealed a 7-copy amplification of RICTOR as the only somatic alteration. RICTOR amplification was confirmed via FISH and IHC. On two separate treatments with dual mTOR1/2 inhibitors patient exhibited stable disease for more than 18 months. 26370156 PubMed Cheng et al., 2015, Cancer Discov 2 accepted 1440 573 20480 5 38938021 39074510 ENST00000357387.3 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1440 https://civicdb.org/links/variants/573 https://civicdb.org/links/genes/20480 false PDGFRA 5156 FIP1L1::PDGFRA Myeloid And Lymphoid Neoplasms With Eosinophilia And Abnormalities Of PDGFRA, PDGFRB, And FGFR1 0080164 Imatinib Predictive Supports B Sensitivity/Response A cohort of seven male patients with myeloproliferative hypereosinophilic syndrome and elevated serum tryptase levels were enrolled in a study of imatinib mesylate therapy. All seven patients demonstrated improvement in clinical symptoms and resolution of laboratory abnormalities and bone marrow pathology in response to treatment. Complete molecular remission of FIP1L1-PDGFRA was observed in 5 of 6 patients tested post-therapy. 14504092 PubMed Klion et al., 2004, Blood 4 accepted 1441 574 38 4 54243812 54294350 ENST00000337488.6 4 55141008 55164414 ENST00000257290.5 75 GRCh37 Prospective trials of patients with hypereosinophilic syndrome harboring the FIP1L1-PDGFRA fusion identified marked response to imatinib treatment (Gotlib and Cool, Leukemia 2008). Imatinib is FDA approved for the treatment of "adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase" (NDA021588). Somatic 2017-04-11 20:55:00 UTC https://civicdb.org/links/evidence_items/1441 https://civicdb.org/links/variants/574 https://civicdb.org/links/genes/38 false ROS1 6098 Rearrangement Bronchiolo-alveolar Adenocarcinoma 4926 Crizotinib Predictive Supports C Sensitivity/Response Study describes a 31-year old male, never-smoker patient with advanced NSCLC with a ROS1 rearrangement. The patient was treated with crizotinib with marked response at 1 week and resolution of the tumor confirmed at 8 and 12 weeks via CT-scans. It was also demonstrated that crizotinib inhibits ROS1 phosphorylation in HEK 293 cells transfected with a CD14-ROS1 fusion gene, and crizotinib inhibited growth in the HCC78 cell line containing a ROS1 rearrangement to a similar degree as ALK-fusion positive cell lines. 22215748 PubMed Bergethon et al., 2012, J. Clin. Oncol. 3 accepted 1443 269 4941 6 117609463 117747018 ENST00000368508.3 75 GRCh37 ROS1 is a receptor tyrosine kinase that frequently forms gene fusions in several cancer types. Approximately 2% of NSCLC patients harbor a ROS1 gene fusion. Several fusion partners have been described with a constant ROS1-breakpoint, maintaining the kinase domain (Solomon B, 2015). Following case-studies and retrospective analyses, an expansion cohort of a phase-1 study showed clinical benefit of crizotinib in ROS1 rearranged NSCLC. The benefit was independent of the type of ROS1-rearrangement (Shaw et. al.,2014). Somatic 2016-11-04 18:20:47 UTC https://civicdb.org/links/evidence_items/1443 https://civicdb.org/links/variants/269 https://civicdb.org/links/genes/4941 false ROS1 6098 TFG::ROS1 Inflammatory Myofibroblastic Tumor 0050905 Crizotinib Predictive Supports C Sensitivity/Response Case report of a pediatric patient with treatment-refactory inflammatory myofibroblastic tumor negative for ALK expression and rearrangement. Next generation sequencing of the patient revealed a TFG-ROS1 fusion. CT scans after 3 cycles of crizotinib treatment showed a reduction of the tumor mass which continued to decrease at the time of publication after 4 months of crizonitib treatment. 24875859 PubMed Lovly et al., 2014, Cancer Discov 3 accepted 1444 576 4941 3 100428269 100447702 ENST00000240851.4 6 117609463 117642557 ENST00000368508.3 75 GRCh37 Somatic 2016-08-19 18:19:23 UTC https://civicdb.org/links/evidence_items/1444 https://civicdb.org/links/variants/576 https://civicdb.org/links/genes/4941 false PDGFRA 5156 FIP1L1::PDGFRA Myeloid And Lymphoid Neoplasms With Eosinophilia And Abnormalities Of PDGFRA, PDGFRB, And FGFR1 0080164 Imatinib Predictive Supports A Sensitivity/Response Of eleven patients prospectively accrued with hypereosinophilic syndrome, nine had favorable responses to imatinib that lasted >3 months post-treatment. Of these nine patients, five were found to have a FIP1L1-PDGFRA fusion. 12660384 PubMed Cools et al., 2003, N. Engl. J. Med. 3 accepted 1445 574 38 4 54243812 54294350 ENST00000337488.6 4 55141008 55164414 ENST00000257290.5 75 GRCh37 Prospective trials of patients with hypereosinophilic syndrome harboring the FIP1L1-PDGFRA fusion identified marked response to imatinib treatment (Gotlib and Cool, Leukemia 2008). Imatinib is FDA approved for the treatment of "adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase" (NDA021588). Somatic 2017-04-11 20:54:59 UTC https://civicdb.org/links/evidence_items/1445 https://civicdb.org/links/variants/574 https://civicdb.org/links/genes/38 false PDGFRA 5156 FIP1L1::PDGFRA T674I Myeloid And Lymphoid Neoplasms With Eosinophilia And Abnormalities Of PDGFRA, PDGFRB, And FGFR1 0080164 Imatinib Predictive Supports C Resistance A patient treated with imatinib for a FIP1L1-PDGFRA mutation relapsed during treatment. A T674I mutation in the PDGFRA split kinase domain was hypothesized to confer resistance, due to the strong evidence of this fusion in driving myeloproliferative hypereosinophilic syndrome and the contextual similarity to T315I mutations in BCR-ABL. 12660384 PubMed Cools et al., 2003, N. Engl. J. Med. 2 accepted 1446 577 38 4 55144547 55144547 C T ENST00000257290.5 75 GRCh37 A case study of relapsed myeloproliferative hypereosinophilic syndrome suggests that a T674I mutation in the PDGFRA split kinase domain of FIP1L1-PDGFRA fusions may confer resistance to imatinib. Somatic 2017-04-11 20:55:00 UTC https://civicdb.org/links/evidence_items/1446 https://civicdb.org/links/variants/577 https://civicdb.org/links/genes/38 false PIK3CA 5290 H1047R Lung Adenocarcinoma 3910 Dactolisib Predictive Supports D Sensitivity/Response Doxycycline dependent expression of the PIK3CA H1047R mutation in mouse type II alveolar epithelial cells drove lung cancer in a reversible fashion, indicating the driver properties of this p110alpha catalytic domain mutation. Administration of pan-p110 isoform and mTOR inhibitor BEZ235 to H1047R mice with established tumors resulted in reduced tumor phospho-Akt and phosoho-S6 levels, and significant regression of tumor volume. 19029981 PubMed Engelman et al., 2008, Nat. Med. 3 accepted 1447 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1447 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Pilaralisib,Trastuzumab Combination Predictive Supports D Sensitivity/Response In 5 trastuzumab resistant HER2 overexpressing breast cancer cell lines, combination of the pan-PI3K inhibitor XL147 (pilaralisib) and trastuzumab treatment induced cell death to similar or greater levels than XL147 alone. In three trastuzumab resistant cell lines tested, colony formation in matrigel was markedly inhibited by combination treatment. Apoptotic markers were apparent with combination treatment. In athymic mice, trastuzumab resistant cell line HR6 was used in tumor xenografts and tumors were allowed to form. Mice subsequently treated with trastuzumab or XL147 showed continued tumor growth without marked difference from control, while combination treatment essentially halted tumor growth rate. 23204226 PubMed Chakrabarty et al., 2013, Cancer Res. 4 accepted 1448 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2019-08-29 22:07:08 UTC https://civicdb.org/links/evidence_items/1448 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false BIRC5 332 Overexpression Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Supports B Resistance 13 HER2 breast cancer patients were treated with trastuzumab and then trastuzumab + docetaxel prior to surgery. Pretreatment biopsies and post-treatment surgical samples were obtained, and microarray performed. 5 of 13 patients responded to treatment, and pretreatment biopsies from non-responders showed significantly higher survivin (BIRC5) mRNA (p=0.026) levels than responders. In HER2 positive, trastuzumab-sensitive BT474 cells, overexpression of survivin blunted sensitivity to trastuzumab. In HER2 positive trastuzumab-resistant breast cancer cell lines, knockdown of survivin with RNAi or with YM155 induced growth inhibition and apoptosis. 23204226 PubMed Chakrabarty et al., 2013, Cancer Res. 4 accepted 1449 578 355 17 76210267 76221717 ENST00000301633.4 75 GRCh37 N/A 2020-11-24 07:10:37 UTC https://civicdb.org/links/evidence_items/1449 https://civicdb.org/links/variants/578 https://civicdb.org/links/genes/355 false TP53 7157 Mutation Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome A study of 53 patients with B-CLL found a significant resistance to chemotherapy and corresponding poor clinical outcomes among the 7 treated patients with p53 mutations compared to the 29 treated patients without. 8241511 PubMed el Rouby et al., 1993, Blood 3 accepted 1450 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2016-07-06 05:02:31 UTC https://civicdb.org/links/evidence_items/1450 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false TP53 7157 Mutation Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome In a study of 126 patients with long-term follow-up, TP53 mutations were significantly associated with shorter median survival in patients (P = 0.002) from time of diagnosis. The median survival from the time of first observation of a TP53 mutation was much more pronounced (P = <0.001). These findings were statistically independent of 17p deletions. 18689542 PubMed Zenz et al., 2008, Blood 4 accepted 1451 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2016-07-06 04:49:01 UTC https://civicdb.org/links/evidence_items/1451 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false TP53 7157 Mutation Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome The authors analyzed 328 patients with CLL, of which 28 were identified to have TP53 mutations. Patients with TP53 mutations were found to have significantly shorter progression-free (HR = 3.8; P < 0.001) and overall survival (HR = 7.2; P < 0.001). 20697090 PubMed Zenz et al., 2010, J. Clin. Oncol. 5 accepted 1452 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2016-07-06 04:48:45 UTC https://civicdb.org/links/evidence_items/1452 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false PIK3CA 5290 E545K Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Supports D Resistance PI3K mutant E545K was overexpressed in the trastuzumab sensitive HER2 BT474 breast cancer cell line, and significant resistance to trastuzumab was induced in comparison to control cells. 18829560 PubMed Serra et al., 2008, Cancer Res. 2 accepted 1453 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2016-07-21 17:22:49 UTC https://civicdb.org/links/evidence_items/1453 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false BRAF 673 D594A Skin Melanoma 8923 Mitogen-Activated Protein Kinase Kinase Inhibitor,Sorafenib Substitutes Predictive Supports E Sensitivity/Response Preclinical study in melanoma cell lines. Inactivity of BRAF as mediated by specific mutation (D594A, D594V or K483M) or selective pharmacological inhibition leads to MEK hyperactivation through CRAF binding in NRAS mutant D04 cells. Either pan-RAF (e.g. sorafenib in the abscence of CRAF T421N gatekeeper mutation) or MEK inhibitors (e.g., trametinib) could instead block ERK pathway hyperactivation in RAS mutated cancers. 20141835 PubMed Heidorn et al., 2010, Cell 3 accepted 1454 579 5 7 140453154 140453154 T G ENST00000288602.6 75 GRCh37 Somatic 2016-09-12 10:41:05 UTC https://civicdb.org/links/evidence_items/1454 https://civicdb.org/links/variants/579 https://civicdb.org/links/genes/5 false PTEN 5728 Loss Her2-receptor Positive Breast Cancer 0060079 Trastuzumab,PI3K/BET Inhibitor LY294002 Combination Predictive Supports D Sensitivity/Response Knockdown of PTEN in trastuzumab sensitive HER2 breast cancer BT474 cells induced trastuzumab resistance. PTEN null cells treated with PI3K inhibitor LY294002 also did not show substantial inhibition, but co-treatment with trastuzumab and LY294002 induced growth inhibition comparable to trastuzumab alone in normal BT474 cells. BT474 mouse xenograft tumors were injected with PTEN antisense (AS) oligonucleotides and this resulted in trastuzumab resitance. Co-treatment of PTEN AS tumor mice with LY294002 and trastuzumab inhibited tumor growth in comparison to PTEN AS tumors treated with trastuzumab or LY294002 alone. 15324695 PubMed Nagata et al., 2004, Cancer Cell 3 accepted 1455 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-07-05 16:49:23 UTC https://civicdb.org/links/evidence_items/1455 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false BRAF 673 D594V Skin Melanoma 8923 Trametinib,Sorafenib Substitutes Predictive Supports E Sensitivity/Response Preclinical study in melanoma cell lines. Inactivity of BRAF as mediated by specific mutation (D594A, D594V or K483M) or selective pharmacological inhibition leads to MEK hyperactivation through CRAF binding in NRAS mutant D04 cells. Either pan-RAF (e.g. sorafenib in the abscence of CRAF T421N gatekeeper mutation) or MEK inhibitors could instead block ERK pathway hyperactivation in RAS mutated cancers. 20141835 PubMed Heidorn et al., 2010, Cell 3 accepted 1456 580 5 7 140453154 140453154 T A ENST00000288602.6 75 GRCh37 Somatic 2016-11-07 22:42:59 UTC https://civicdb.org/links/evidence_items/1456 https://civicdb.org/links/variants/580 https://civicdb.org/links/genes/5 false BRAF 673 K483M Skin Melanoma 8923 Mitogen-Activated Protein Kinase Kinase Inhibitor,Sorafenib Substitutes Predictive Supports E Sensitivity/Response Preclinical study in melanoma cell lines. Inactivity of BRAF as mediated by specific mutation (D594A, D594V or K483M) or selective pharmacological inhibition leads to MEK hyperactivation through CRAF binding in NRAS mutant D04 cells. Either pan-RAF (e.g. sorafenib in the abscence of CRAF T421N gatekeeper mutation) or MEK inhibitors (e.g., trametinib) could instead block ERK pathway hyperactivation in RAS mutated cancers. 20141835 PubMed Heidorn et al., 2010, Cell 3 accepted 1457 581 5 7 140477859 140477860 TT CA ENST00000288602.6 75 GRCh37 The K483M variant is a kinase dead loss-of-function variant in the catalytic site of BRAF. This engineered variant is often used as a control when evaluating other BRAF variants. Somatic 2016-09-12 10:41:34 UTC https://civicdb.org/links/evidence_items/1457 https://civicdb.org/links/variants/581 https://civicdb.org/links/genes/5 false BRAF 673 L597R Skin Melanoma 8923 Trametinib,Vemurafenib Substitutes Predictive Supports D Sensitivity/Response Preclinical study in 293H cell line. Ectopic expression of V600E, L597R/Q/S, and K601E mutants elevated phospho-MEK and ERK levels. Vemurafenib treatment of all of the BRAF mutant–expressing cells led to a decrease in phospho-MEK and ERK protein levels. Treatment with MEK inhibitor GSK1120212 led to a more dramatic decrease in phospho-ERK signaling. 22798288 PubMed Dahlman et al., 2012, Cancer Discov 2 accepted 1458 288 5 7 140453145 140453145 A C ENST00000288602.6 75 GRCh37 Somatic 2016-10-20 04:02:20 UTC https://civicdb.org/links/evidence_items/1458 https://civicdb.org/links/variants/288 https://civicdb.org/links/genes/5 false BRAF 673 L597S Skin Melanoma 8923 Trametinib,Vemurafenib Substitutes Predictive Supports D Sensitivity/Response Preclinical study in 293H cell line. Ectopic expression of V600E, L597R/Q/S, and K601E mutants elevated phospho-MEK and ERK levels. Vemurafenib treatment of all of the BRAF mutant–expressing cells led to a decrease in phospho-MEK and ERK protein levels. Treatment with MEK inhibitor GSK1120212 led to a more dramatic decrease in phospho-ERK signaling. 22798288 PubMed Dahlman et al., 2012, Cancer Discov 2 accepted 1459 582 5 7 140453145 140453146 AG GA ENST00000288602.6 75 GRCh37 Somatic 2016-07-18 15:24:58 UTC https://civicdb.org/links/evidence_items/1459 https://civicdb.org/links/variants/582 https://civicdb.org/links/genes/5 false BRAF 673 L597S Skin Melanoma 8923 MEK Inhibitor TAK-733 Predictive Supports C Sensitivity/Response Case report of a 69 year old patient with metastatic melanoma treated with MEK inhibitor TAK-733 in a clinical trial. A partial radiographic response with a decrease of 31% in the sum of maximum diameters of target metastatic lesions in the liver and spleen was noted after 2 cycles of therapy and remained progression free at more than 24 weeks. Follow-up sequencing analysis of DNA from the patient's tumor revealed a somatic BRAF L597S mutation. 22798288 PubMed Dahlman et al., 2012, Cancer Discov 3 accepted 1460 582 5 7 140453145 140453146 AG GA ENST00000288602.6 75 GRCh37 Somatic 2017-02-14 21:47:48 UTC https://civicdb.org/links/evidence_items/1460 https://civicdb.org/links/variants/582 https://civicdb.org/links/genes/5 false BRAF 673 L597Q Skin Melanoma 8923 Vemurafenib,Trametinib Substitutes Predictive Supports D Sensitivity/Response Preclinical study in 293H cell line. Ectopic expression of V600E, L597R/Q/S, and K601E mutants elevated phospho-MEK and ERK levels. Vemurafenib treatment of all of the BRAF mutant–expressing cells led to a decrease in phospho-MEK and ERK protein levels. Treatment with MEK inhibitor GSK1120212 led to a more dramatic decrease in phospho-ERK signaling. 22798288 PubMed Dahlman et al., 2012, Cancer Discov 2 accepted 1461 583 5 7 140453145 140453145 A T ENST00000288602.6 75 GRCh37 Somatic 2016-10-20 04:03:12 UTC https://civicdb.org/links/evidence_items/1461 https://civicdb.org/links/variants/583 https://civicdb.org/links/genes/5 false BRAF 673 K601E Skin Melanoma 8923 Trametinib,Vemurafenib Substitutes Predictive Supports D Sensitivity/Response Preclinical study in 293H cell line. Ectopic expression of V600E, L597R/Q/S, and K601E mutants elevated phospho-MEK and ERK levels. Vemurafenib treatment of all of the BRAF mutant–expressing cells led to a decrease in phospho-MEK and ERK protein levels. Treatment with MEK inhibitor GSK1120212 led to a more dramatic decrease in phospho-ERK signaling. 22798288 PubMed Dahlman et al., 2012, Cancer Discov 3 accepted 1462 584 5 7 140453134 140453134 T C ENST00000288602.6 75 GRCh37 Somatic 2016-10-20 04:03:45 UTC https://civicdb.org/links/evidence_items/1462 https://civicdb.org/links/variants/584 https://civicdb.org/links/genes/5 false BRAF 673 L597V Skin Melanoma 8923 Trametinib Predictive Supports C Sensitivity/Response Case report of a phase 1 study in advanced melanoma patients. 97 patients with melanoma were enrolled and treated with trametinib. One patient with a BRAF Leu597Val had a confirmed partial response with 60% tumour reduction and received study treatment for more than 2 years. 22805292 PubMed Falchook et al., 2012, Lancet Oncol. NCT00687622 3 accepted 1463 585 5 7 140453146 140453146 G C ENST00000288602.6 75 GRCh37 Somatic 2016-07-19 19:34:04 UTC https://civicdb.org/links/evidence_items/1463 https://civicdb.org/links/variants/585 https://civicdb.org/links/genes/5 false PIK3CA 5290 Amplification Head And Neck Squamous Cell Carcinoma 5520 Taselisib Predictive Supports D Sensitivity/Response The HNSCC cell line LB771 with PIK3CA amplification was shown to have low antiproliferative IC50 for the p110beta-sparing PI3K inhibitor taselisib. Under increasing taselisib concentrations, reduction in phospho-Akt pro-survival signal was apparent, along with increased levels of pro-apoptotic marker cleaved PARP. A general tendency for taselisib sensitivity to PI3K activation (mutation/amplification) was also seen in a panel of 26 HNSCC cell lines 26589432 PubMed Zumsteg et al., 2016, Clin. Cancer Res. 1 accepted 1464 212 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 Somatic 2016-11-04 18:38:14 UTC https://civicdb.org/links/evidence_items/1464 https://civicdb.org/links/variants/212 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Head And Neck Squamous Cell Carcinoma 5520 Taselisib Predictive Supports D Sensitivity/Response The Cal-33 HNSCC cell line with H1047R mutation was found to have a low antiproliferative IC50 value for the alpha, gamma and delta isoform-specific PI3K inhibitor taselisib. Increasing taselisib concentration induced reduction of phospho-Akt levels in Call-33 cells, while upregulating the cleaved PARP apoptotic marker. Among a panel of 26 HNSCC cell lines, activating PI3K mutations were associated with taselisib sensitivity in comparison to wild-type PI3K or PTEN mutant cell lines. 26589432 PubMed Zumsteg et al., 2016, Clin. Cancer Res. 2 accepted 1465 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2016-07-21 20:54:23 UTC https://civicdb.org/links/evidence_items/1465 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false KIT 3815 Amplification Mucosal Melanoma 0050929 Imatinib Predictive Supports B Resistance Phase 2 trial in metastatic mucosal, acral or chronically sun-damaged melanoma. Twenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months. Best overall response rate was statistically significantly different by mutation status: 7 of 13 or 54% KIT mutated v 0% KIT amplified only. 23775962 PubMed Hodi et al., 2013, J. Clin. Oncol. NCT00424515 3 accepted 1466 586 29 4 55524085 55606881 ENST00000288135.5 75 GRCh37 N/A 2016-07-06 05:02:12 UTC https://civicdb.org/links/evidence_items/1466 https://civicdb.org/links/variants/586 https://civicdb.org/links/genes/29 false PTEN 5728 Mutation Head And Neck Squamous Cell Carcinoma 5520 Taselisib Predictive Supports D Resistance In a panel of 26 HNSCC cell lines tested for sensitivity to taselisib (an alpha, delta and gamma isoform-specific PI3K inhibitor) the UD-SCC-2 cell line with homozygous PTEN deletion had considerably higher antiproliferative IC50 than taselisib sensitized cell lines. Western blots of UD-SCC-3 cells with increasing taselisib concentration showed reduction of phospho-Akt only at micro-molar doses, in contrast to nano-molar range for sensitized cells. Slight induction of the apoptotic marker cleaved PARP was only apparent at 4 micro-molar dose. Similar results were reported with the PTEN mutant HNSCC cell line UPCI-SCC-90, and 4 of the 6 most taselisib resistant cell lines had PTEN mutation. 26589432 PubMed Zumsteg et al., 2016, Clin. Cancer Res. 3 accepted 1467 510 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-07-05 16:35:41 UTC https://civicdb.org/links/evidence_items/1467 https://civicdb.org/links/variants/510 https://civicdb.org/links/genes/41 false NF1 4763 Mutation Skin Melanoma 8923 Vemurafenib Predictive Supports D Resistance Preclinical study of mouse melanoma in-vitro and in-vivo. In-vitro treament of Braf-mutant melanomas were 10-fold more sensitive to vermurafenib (PLX4032) treatment than Braf/Nf1-mutant melanomas. In vivo treatment of mice with Braf/Nf1-mutant allografts showed less sensitivity to vemurafenib (PLX4032) than the MEK inhibitor, PD0325901. 23171796 PubMed Maertens et al., 2013, Cancer Discov 2 accepted 1468 587 3867 17 29421945 29704695 ENST00000358273.4 75 GRCh37 Somatic 2016-10-22 14:44:33 UTC https://civicdb.org/links/evidence_items/1468 https://civicdb.org/links/variants/587 https://civicdb.org/links/genes/3867 false NF1 4763 Mutation Skin Melanoma 8923 Mirdametinib,Sirolimus Combination Predictive Supports D Sensitivity/Response Preclinical study of mouse melanoma both in-vitro and in-vivo. Braf/Nf1-mutant melanomas were less sensitive to vemurafenib than the MEK inhibitor PD0325901. mTOR inhibition with rapamycin had a more pronounced effect than GDC-0941 on mouse melanoma, but synergized with PD0325901(but not vemurafenib) to promote tumor regression. 23171796 PubMed Maertens et al., 2013, Cancer Discov 3 accepted 1469 587 3867 17 29421945 29704695 ENST00000358273.4 75 GRCh37 Somatic 2016-11-07 18:39:45 UTC https://civicdb.org/links/evidence_items/1469 https://civicdb.org/links/variants/587 https://civicdb.org/links/genes/3867 false NF1 4763 Mutation Skin Melanoma 8923 Vemurafenib Predictive Supports C Resistance NF1 was identified in an unbiased RNAi screen as mediator of resistance to BRAF inhibition in BRAF mutant melanoma. Knockdown of NF1 led to PLX4720 resistance in-vitro. MEK inhibition with AZD6244 (selumetinib) had some efficacy but was also less active than in NF1 proficient cells. 4 patients with mutant alleles of NF1 were identified among patients relapsed after vemurafenib. Of these, one was a nonsense mutation (p.R2450*) present in both pretreatment and postrelapse biopsies. The patient had a progression-free survival (PFS) of about 10 weeks. The other NF1 mutations were silent events (patient 15, c.135T>C, patient 45 c.4023G>A, and patient 50 c3018C>T) located within candidate splicing motifs. Patients 15 and 50 exhibited response rates of relatively short duration (10 and 12 weeks, respectively) and the mutations were observed in both the pretreatment and postrelapse biopsies. Patient 45 experienced a PFS of 5 months, and the NF1 mutation was only present in the postrelapse biopsy indicative of acquired resistance. 23288408 PubMed Whittaker et al., 2013, Cancer Discov 4 accepted 1470 587 3867 17 29421945 29704695 ENST00000358273.4 75 GRCh37 Somatic 2016-07-17 20:57:03 UTC https://civicdb.org/links/evidence_items/1470 https://civicdb.org/links/variants/587 https://civicdb.org/links/genes/3867 false NF1 4763 Mutation Skin Melanoma 8923 VTX-11e,AZ628 Substitutes Predictive Supports D Sensitivity/Response NF1 was identified in an unbiased RNAi screen as mediator of resistance to BRAF inhibition in BRAF mutant melanoma. BRAF V600E/NF1 mutant cell lines were sensitive to ERK inhibition with VTX-11e, modest resistance was observed against RAF inhibitor AZ628. Combined PLX4720 and AZD6244 (selumetinib) achieved greater efficacy than either agent alone but NF1 knockdown was still associated with residual resistance to combined RAF/MEK inhibition in vitro. 23288408 PubMed Whittaker et al., 2013, Cancer Discov 2 accepted 1471 587 3867 17 29421945 29704695 ENST00000358273.4 75 GRCh37 Somatic 2016-07-26 15:02:43 UTC https://civicdb.org/links/evidence_items/1471 https://civicdb.org/links/variants/587 https://civicdb.org/links/genes/3867 false NRAS 4893 Mutation Skin Melanoma 8923 Binimetinib Predictive Supports B Sensitivity/Response Phase II study in 71 patients with NRAS or BRAF V600 mutant melanoma treated with MEK162. Six (20%) of 30 patients with NRAS-mutated melanoma had a partial response (three confirmed). 23414587 PubMed Ascierto et al., 2013, Lancet Oncol. NCT01320085 2 accepted 1472 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2016-07-06 05:03:11 UTC https://civicdb.org/links/evidence_items/1472 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false NRAS 4893 Q61 Skin Melanoma 8923 Selumetinib Predictive Supports C Sensitivity/Response Phase 1 trial in 57 patients with advanced cancers treated with selumetinib. 4 melanoma patients had NRAS Q61 mutations. One patient with NRAS mutation had 70% tumor shrinkage after three cycles of selumetinib (AZD6244) but developed symptomatic brain metastases before confirmatory scans could be performed. 18390968 PubMed Adjei et al., 2008, J. Clin. Oncol. 2 accepted 1473 94 36 1 115256528 115256530 ENST00000369535.4 75 GRCh37 NRAS Q61 mutations have been found in multiple myeloma, gastrointestinal stromal tumors, melanoma, and others. Two melanoma patients, each harboring mutations at this locus (Q61L and Q61R), responded to treatment with the akylating agent temozolomide. However, in colorectal cancer patients, mutations at this locus have been shown to confer resistance to cetuximab. The prognostic impact of mutations at this locus is currently under study. Somatic 2016-07-19 19:43:43 UTC https://civicdb.org/links/evidence_items/1473 https://civicdb.org/links/variants/94 https://civicdb.org/links/genes/36 false NRAS 4893 Q61K Skin Melanoma 8923 Vemurafenib Predictive Supports D Resistance Preclinical study in melanoma cell lines. NRAS Q61K, in addition to the BRAF V600E mutation was associated with resistance to vemurafenib but sensitivity to AZD6244 (selumetinib) in vitro in the acquired resistant cell line M249-AR4 and in the patient-derived acquired resistant cell line M376. 22194965 PubMed Atefi et al., 2011, PLoS ONE 2 accepted 1474 427 36 1 115256530 115256530 G T ENST00000369535.4 75 GRCh37 Somatic 2016-07-14 00:05:48 UTC https://civicdb.org/links/evidence_items/1474 https://civicdb.org/links/variants/427 https://civicdb.org/links/genes/36 false NRAS 4893 Q61K Skin Melanoma 8923 Selumetinib Predictive Supports D Sensitivity/Response Preclinical study in melanoma cell lines. NRAS Q61K, in addition to the BRAF V600E mutation was associated with resistance to vemurafenib but sensitivity to AZD6244 (selumetinib) in vitro in the acquired resistant cell line M249-AR4 and in the patient-derived acquired resistant cell line M376. 22194965 PubMed Atefi et al., 2011, PLoS ONE 2 accepted 1475 427 36 1 115256530 115256530 G T ENST00000369535.4 75 GRCh37 Somatic 2016-07-14 00:05:46 UTC https://civicdb.org/links/evidence_items/1475 https://civicdb.org/links/variants/427 https://civicdb.org/links/genes/36 false NRAS 4893 Mutation Skin Melanoma 8923 Amuvatinib Predictive Supports D Sensitivity/Response Preclinical study in melanoma cell lines. Cell lines (2-5/assay) with NRAS mutation were more sensitive to Amuvatinib (inhibitor targets multiple tyrosine kinases) than BRAF mutant cell lines in growth inhibition, tyrosine phosphorylation inhibition, cell cycle and apoptotic (Annexin V) assays. 24950457 PubMed Fedorenko et al., 2014, Melanoma Res. 1 accepted 1476 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2016-10-25 17:27:47 UTC https://civicdb.org/links/evidence_items/1476 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false SMO 6608 Mutation Basal Cell Carcinoma 2513 Vismodegib,Sonidegib Sequential Predictive Supports B Resistance Study explored the response to the SMO inhibitor sonidegib (LDE225) in a cohort of 9 patients with advanced basal cell carcinoma that exhibited treatment resistance with vismodegib (GDC0449). Sequencing revealed that 5 of these patients harbored SMO mutations known to confer resistance to the Smoothened inhibitors (D473G, D473H, Q477E, S533N, W535L) an additional patient harbored a SMO mutation of unknown consequence (R168H). Of these patients, 4 with a SMO mutation displayed progressive disease and 1 stable disease for 58 weeks according to RECIST v1.1 criteria. 26546616 PubMed Danial et al., 2016, Clin. Cancer Res. 2 accepted 1477 300 5365 7 128828713 128853386 ENST00000249373.3 75 GRCh37 Somatic 2016-07-06 05:05:28 UTC https://civicdb.org/links/evidence_items/1477 https://civicdb.org/links/variants/300 https://civicdb.org/links/genes/5365 false TP53 7157 Mutation Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome In the CLL4 trial assessing first line treatment with chlorambucil or fludarabine with or without cyclophosphamide, patients with TP53 mutations experienced poorer overall response rates (27% vs 83%), shorter progression free survival (5 year PFS 5% vs 17%), and overall survival (20% vs 59%) compared to patients without TP53 mutations. 21483000 PubMed Gonzalez et al., 2011, J. Clin. Oncol. 3 accepted 1478 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2016-07-06 05:02:22 UTC https://civicdb.org/links/evidence_items/1478 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false NOTCH1 4851 Mutation Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome In the randomized UK LRF CCL4 phase 3 trial comparing first-line treatment with chlorambucil, fludarabine, or fludarabine plus cyclophosphamide, univariate analysis of patients with NOTCH1 mutations (within amino acids 2405-2525, a 399bp region of the PEST domain) demonstrated poorer overall survival (54.8 vs 74.6 months, P=0.02) and progression free survival (22 vs 26.4 months, P=0.02) compared to patients with wild-type NOTCH1. Progression-free survival was not significant (P = 0.21), however, overall survival remained significant (P = 0.03) under multivariate analysis. 23086750 PubMed Oscier et al., 2013, Blood 2 accepted 1479 206 50 9 139388896 139440314 ENST00000277541.6 75 GRCh37 Unknown 2016-11-04 21:39:47 UTC https://civicdb.org/links/evidence_items/1479 https://civicdb.org/links/variants/206 https://civicdb.org/links/genes/50 false SF3B1 23451 Mutation Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome In the randomized phase 3 UK LRF CCL4 trial comparing first-line treatment with chlorambucil, fludarabine, or fludarabine plus cyclophosphamide, SF3B1 mutations (73/437 patients) were associated with poorer overall survival (median 54.3 vs 79 months, P <0.001), independent of treatment. Additionally, controlling for cases with TP53 deletions/mutations, SF3B1 mutations were associated with reduced progression free survival for patients in the fludarabine plus cyclophosphamide treatment arm when compared to wildtype SF3B1 (29.4 vs 46 months, P=0.002). 23086750 PubMed Oscier et al., 2013, Blood 4 accepted 1480 215 44 2 198254508 198299815 ENST00000335508.6 75 GRCh37 Somatic 2016-07-05 19:57:02 UTC https://civicdb.org/links/evidence_items/1480 https://civicdb.org/links/variants/215 https://civicdb.org/links/genes/44 false TP53 7157 Mutation Chronic Lymphocytic Leukemia 1040 Alemtuzumab Predictive Supports B Sensitivity/Response Thirty-six patients with CLL were treated with alemtuzumab. Partial or complete response was achieved in 6 of 15 patients with p53 mutations, compared to 4 of 21 without. These findings are not statistically significant, but the authors suggest that alemtuzumab is an effective therapy for patients with p53 mutations or deletions. 14726385 PubMed Lozanski et al., 2004, Blood 2 accepted 1481 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2016-07-06 05:02:49 UTC https://civicdb.org/links/evidence_items/1481 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false CALR 811 EXON 9 FRAMESHIFT Essential Thrombocythemia 2224 Peginterferon Alfa-2a Predictive Supports B Sensitivity/Response Study explored the hematologic and molecular responses in a cohort of 31 patients presenting with thrombocythemia and CALR exon 9 frameshift mutations. All 31 patients exhibited a hematologic response at the time of followup (European LeukemiaNet criteria). In regards to molecular response, before treatment the CALR mutant allele displayed a median frequency of 41% across the cohort, during treatment a significant decrease was observed in comparison to controls treated with hydroxyurea and aspirin. 26486786 PubMed Verger et al., 2015, Blood 4 accepted 1482 559 732 19 13054527 13054727 ENST00000316448.5 75 GRCh37 Exon 9 insertions and deletions have become part of the WHO diagnostic criteria for essential thrombocythemia (ET) and primary myelofibrosis (PMF) (Arber et al, 2016). These mutations are typically heterozygous and in the absence of JAK2 and MPL mutations. Approximately 80% of observed mutations are type 1 (p.L367fs*46), the result of a 52 bp deletion, or type 2 (p.K385fs*47), the result of a 5-bp TTGTC insertion, and studies have suggested phenotypic and prognostic differences between them. In PMF patients, CALR exon 9 mutations have been associated with improved median survival. Somatic 2022-03-22 20:31:20 UTC https://civicdb.org/links/evidence_items/1482 https://civicdb.org/links/variants/559 https://civicdb.org/links/genes/732 false ALK 238 HIP1::ALK I1171N Lung Non-small Cell Carcinoma 3908 Alectinib,Crizotinib Sequential Predictive Supports C Resistance Case study describes a female (age 58) never-smoker presenting with stage IV NSCLC with an ALK rearrangement (confirmed by fish). Patient was treated with crizotinib (partial response) and alectinib (complete response). Liver metastasis was noted after 12 months with sequencing revealing a HIP1-ALK fusion with a I1171N variant. 25393796 PubMed Ou et al., 2014, J Thorac Oncol 2 accepted 1483 588 1 2 29445213 29445213 A T ENST00000389048.3 75 GRCh37 Somatic 2017-05-31 15:32:23 UTC https://civicdb.org/links/evidence_items/1483 https://civicdb.org/links/variants/588 https://civicdb.org/links/genes/1 false ALK 238 EML4::ALK I1171S Lung Non-small Cell Carcinoma 3908 Crizotinib,Alectinib Sequential Predictive Supports C Resistance Case study describes a caucasian male (age 38) never smoker presenting with stage IV non-small cell lung cancer with an ALK rearrangement. Patient was given crizotinib and exhibited a partial response after 5 months with brain metastasis occurring at 21 months. Patient then received alectinib and exhibited partial response however liver metastasis presented after 12 months on alectinib. Sequencing of this liver metastasis revealed an EML4-ALK fusion with an I1171S variant at a variant frequency of 36% (tumor purity estimated as 70%). 25393796 PubMed Ou et al., 2014, J Thorac Oncol 2 accepted 1484 589 1 2 29445213 29445213 A C ENST00000389048.3 75 GRCh37 Somatic 2016-08-04 05:39:53 UTC https://civicdb.org/links/evidence_items/1484 https://civicdb.org/links/variants/589 https://civicdb.org/links/genes/1 false TP53 7157 Mutation Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome In a multivariate analysis of 774 CLL patients, TP53 aberrations were significantly correlated with shorter time to first treatment (HR=2.081; 95% CI=1.431-3.021). This finding was independent of IGHV mutation status. 24943832 PubMed Baliakas et al., 2015, Leukemia 5 accepted 1485 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2016-07-05 19:40:22 UTC https://civicdb.org/links/evidence_items/1485 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false NOTCH1 4851 Mutation Chronic Lymphocytic Leukemia 1040 Prognostic Does Not Support B Poor Outcome In a multivariate analysis of 774 CLL patients, NOTCH1 mutations were not significantly correlated with shorter time to first treatment (HR=1.305; 95% CI=0.923-1.847). 24943832 PubMed Baliakas et al., 2015, Leukemia 5 accepted 1486 206 50 9 139388896 139440314 ENST00000277541.6 75 GRCh37 Somatic 2021-04-15 19:54:31 UTC https://civicdb.org/links/evidence_items/1486 https://civicdb.org/links/variants/206 https://civicdb.org/links/genes/50 false SF3B1 23451 Mutation Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome In a multivariate analysis of 774 CLL patients, SF3B1 mutations were significantly correlated with shorter time to first treatment (HR=1.644; 95% CI=1.134-2.383). This finding was independent of IGHV mutation status. 24943832 PubMed Baliakas et al., 2015, Leukemia 5 accepted 1487 215 44 2 198254508 198299815 ENST00000335508.6 75 GRCh37 Somatic 2016-07-26 14:59:04 UTC https://civicdb.org/links/evidence_items/1487 https://civicdb.org/links/variants/215 https://civicdb.org/links/genes/44 false BIRC3 330 TRUNCATING MUTATION Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome BIRC3 mutations were identified in 23 of 919 screened CLLs. They are strongly linked to non-mutated IGHV genes (18/23, P = 0.0001), a widely recognized prognostic signature for poor outcome. 24943832 PubMed Baliakas et al., 2015, Leukemia 2 accepted 1488 590 353 11 102201730 102207833 ENST00000263464.3 75 GRCh37 Somatic 2016-07-06 05:27:17 UTC https://civicdb.org/links/evidence_items/1488 https://civicdb.org/links/variants/590 https://civicdb.org/links/genes/353 false MYD88 4615 L265P Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Better Outcome MYD88 mutations were identified in 24 of 1080 screened CLLs. They were exclusively seen in instances of mutated IGHV genes (18/23, P = 0.0001), a widely recognized prognostic signature for better outcome in CLL. 24943832 PubMed Baliakas et al., 2015, Leukemia 2 accepted 1489 424 3742 3 38182641 38182641 T C ENST00000396334.3 75 GRCh37 Somatic 2016-07-06 05:27:07 UTC https://civicdb.org/links/evidence_items/1489 https://civicdb.org/links/variants/424 https://civicdb.org/links/genes/3742 false PIK3CA 5290 Mutation Head And Neck Squamous Cell Carcinoma 5520 Taselisib,Radiation Therapy Combination Predictive Supports D Sensitivity/Response A panel of 26 HNSCC cell lines was tested for efficacy of the p110 alpha, delta and gamma isoform inhibitor taselisib (GDC-0032). Cell lines with PIK3CA mutation or amplification were the most sensitive. Four HNSCC cell lines with activating PIK3CA alterations showed synergistic cell death response to the combination of drug with radiation treatment. This synergism was not apparent in 4 tested HNSCC cell lines with wild-type PIK3CA or PTEN mutation. Nude mouse xenografts were established with Cal-33 PIK3CA H1047R cells. Radiation and taselisib treatments alone showed some growth inhibition in comparison to control, but only the combined treatment led durable tumor regressions. 26589432 PubMed Zumsteg et al., 2016, Clin. Cancer Res. 3 accepted 1490 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-11-08 02:27:22 UTC https://civicdb.org/links/evidence_items/1490 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PTEN 5728 Mutation Cancer 162 Ipatasertib Predictive Supports D Sensitivity/Response IC50 for the pan-Akt inhibitor ipatasertib (GDC-0068) was determined over a panel of 100 cancer cell lines. Loss or mutation of PTEN (e.g. PTEN deletion, T319fsX1/Y155C, etc.) was significantly associated with ipatasertib sensitivity (p=0.000071). Non-transformed human mammary epithelial MCF10A cells were compared to an isogenic line with PTEN knockout. With low or high EGF culture conditions, a 4x or 3.5x decrease in IC50 for ipatasertib was seen in PTEN knockout cells, respectively. 23287563 PubMed Lin et al., 2013, Clin. Cancer Res. 3 accepted 1491 510 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-07-11 02:20:42 UTC https://civicdb.org/links/evidence_items/1491 https://civicdb.org/links/variants/510 https://civicdb.org/links/genes/41 false PTEN 5728 Loss Ovarian Cancer 2394 Cisplatin Predictive Supports D Resistance A cisplatin resistant derivative of ovarian cancer cell line OVCAR-3 was generated by long term passage with increasing cisplatin levels. Western blot showed decreased PTEN level in the resistant cell line, and siRNA against PTEN in parent OVCAR-3 cells induced cisplatin resistance. 15790433 PubMed Lee et al., 2005, Gynecol. Oncol. 2 accepted 1492 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-07-05 16:51:19 UTC https://civicdb.org/links/evidence_items/1492 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PTEN 5728 Loss Stomach Carcinoma 5517 Chemotherapy Predictive Supports B Resistance Cancer and normal tissue samples were taken from 68 gastric cancer patients undergoing surgery without prior chemotherapy. Tissue samples were divided into high grade and low grade for phospho Akt (p-Akt) expression, and tested for PTEN LOH by sequencing. Patients with PTEN LOH were significantly more likely to have elevated p-Akt (p=0.0081), and high p-Akt samples were significantly less sensitive to chemotherapy agents 5-flourouracil, adriamycin, mitomycin and cis-platinum in MTT assay. 15900596 PubMed Oki et al., 2005, Int. J. Cancer 2 accepted 1493 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-07-05 16:44:39 UTC https://civicdb.org/links/evidence_items/1493 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false EZH2 2146 Y646 Skin Melanoma 8923 GSK126 Predictive Supports D Sensitivity/Response Preclinical study in melanoma cell lines. EZH2 expression was higher in EZH2 mutant (N=3) and wild-type melanoma cell lines (N=12) than untransformed cells (human epithelial melanocytes and human dermal fibroblasts). EZH2 mutant cell lines were the most sensitive to GSK126 compared to wild-type and untransformed. 26304929 PubMed Tiffen et al., 2015, Oncotarget 2 accepted 1494 165 63 7 148508726 148508728 ENST00000320356.2 75 GRCh37 Mutations of Y646 are associated with a diagnosis of Germinal Center B type DLBCL and Follicular non-Hodgkin Lymphoma. In vitro experimental findings suggest that this may be due to reduced methyltransferase activity of EZH2 on protein H3K27 (Morin et al., 2010). Somatic 2016-11-03 19:21:08 UTC https://civicdb.org/links/evidence_items/1494 https://civicdb.org/links/variants/165 https://civicdb.org/links/genes/63 false CCND1 595 Amplification Skin Melanoma 8923 Sorafenib,Carboplatin,Paclitaxel Combination Predictive Supports B Sensitivity/Response Retrospective analysis of somatic mutations and copy number changes in 119 patient treated with carboplatin, paclitaxel, ± sorafenib (CPS) in the E2603 trial. CPS therapy was associated with improved progression-free survival (PFS) compared with CP in patients with tumors with CCND1 gene copy gains (HR, 0.45; P = 0.035). 26307133 PubMed Wilson et al., 2016, Clin. Cancer Res. 2 accepted 1495 18 8 11 69455855 69469242 ENST00000227507.2 75 GRCh37 CCND1 amplification has been implicated in poorer prognosis in non-small cell lung cancer. Somatic 2016-07-06 05:05:56 UTC https://civicdb.org/links/evidence_items/1495 https://civicdb.org/links/variants/18 https://civicdb.org/links/genes/8 false RAF1 5894 Amplification Skin Melanoma 8923 Sorafenib,Carboplatin,Paclitaxel Combination Predictive Supports B Sensitivity/Response Retrospective analysis of somatic mutations and copy number changes in 119 patients treated with carboplatin, paclitaxel, ± sorafenib (CPS) in the E2603 trial. CPS therapy was associated with improved progression-free survival (PFS) compared with CP in patients with tumors that were positive for RAF1 gene copy gains (HR = 0.372; P = 0.025). 26307133 PubMed Wilson et al., 2016, Clin. Cancer Res. 2 accepted 1496 591 4767 3 12625100 12705725 ENST00000251849.4 75 GRCh37 Somatic 2016-07-10 21:44:36 UTC https://civicdb.org/links/evidence_items/1496 https://civicdb.org/links/variants/591 https://civicdb.org/links/genes/4767 false KRAS 3845 Amplification Skin Melanoma 8923 Docetaxel,Carboplatin,Sorafenib Combination Predictive Supports B Sensitivity/Response Retrospective analysis of somatic mutations and copy number changes in 119 patients treated with carboplatin, paclitaxel, ± sorafenib (CPS) in the E2603 trial. CPS therapy was associated with improved overall survival compared with CP in patients with tumors positive for KRAS gene copy gains (HR = 0.25; P = 0.035). 26307133 PubMed Wilson et al., 2016, Clin. Cancer Res. 2 accepted 1497 592 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 N/A 2016-07-10 21:42:10 UTC https://civicdb.org/links/evidence_items/1497 https://civicdb.org/links/variants/592 https://civicdb.org/links/genes/30 false PDGFRB 5159 Fusion Myeloproliferative Neoplasm 2226 Imatinib Predictive Supports A Sensitivity/Response Twelve patients with BCR-ABL-negative chronic myeloproliferative disease and reciprocal translocations involving PDGFRB received imatinib for a median of 47 months (range, 0.1-60 months). Eleven had prompt responses, 10 had complete resolution of cytogenetic abnormalities and decrease or disappearance of fusion transcripts as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Updates were sought from 8 further patients previously described in the literature; prompt responses were described in 7 and persist in 6. 16960151 PubMed David et al., 2007, Blood 4 accepted 1498 568 4176 Somatic 2017-01-05 19:09:21 UTC https://civicdb.org/links/evidence_items/1498 https://civicdb.org/links/variants/568 https://civicdb.org/links/genes/4176 false ERBB2 2064 Amplification Gastric Adenocarcinoma 3717 Trastuzumab Predictive Supports A Sensitivity/Response ToGA, a Phase III study (NCT01041404) addressed use of trastuzumab in HER2 positive (overexpression or amplification) advanced gastric cancer, where chemotherapy using fluoropyrimidine-based and platinum-based combinations had been common practice. Patients were given a chemotherapy regime containing capecitabine, flourouracil and cisplatin with (n=298) or without (n=296) trastuzumab, and had not been previously treated for metastatic cancer. Study endpoint was overall survival, which was significantly different in the two populations (13.8 months with chemotherapy + trastuzumab and 11.1 months for chemotherapy alone). The authors conclude that trastuzumab should be a standard option for HER2 positive advanced gastric cancer. 20728210 PubMed Bang et al., 2010, Lancet NCT01041404 4 accepted 1499 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. N/A 2016-10-06 18:38:51 UTC https://civicdb.org/links/evidence_items/1499 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false PTEN 5728 Loss Stomach Cancer 10534 Capivasertib,Docetaxel Combination Predictive Supports D Sensitivity/Response A patient derived mouse xenograft model was established with gastric cancer cells having PTEN loss. The xenograft was resistant to monotherapy with both the pan-Akt inhibitor AZD5363, and also to the commonly used gastric cancer chemotheraputic docetaxel. When used in combination, AZD5363 and docetaxel induced significant tumor growth inhibition in comparison to monotherapy and vehicle control. 24088382 PubMed Li et al., 2013, J Transl Med 1 accepted 1500 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-07-18 15:22:51 UTC https://civicdb.org/links/evidence_items/1500 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PIK3CA 5290 Mutation Stomach Cancer 10534 Capivasertib Predictive Supports D Sensitivity/Response In a panel of 22 gastric cancer cell lines, 4 of 6 cell lines having the highest sensitivity to AZD5363 contained a PIK3CA mutation (E542K, E453K, E545K). A patient derived gastric cancer xenograft mouse model was established with PIK3CA H1047R mutant cells, and treatment with AZD5363 induced significant tumor growth inhibition in comparison to vehicle control. 24088382 PubMed Li et al., 2013, J Transl Med 3 accepted 1501 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-07-11 02:45:19 UTC https://civicdb.org/links/evidence_items/1501 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PTEN 5728 Loss Cancer 162 Capivasertib Predictive Supports D Sensitivity/Response In a panel of 182 cell lines (162 with PIK3CA mutation status known) from solid and hematological tumors, significant correlation was found between AZD5363 (pan-Akt inhibitor) sensitivity and PIK3CA mutation status (N=33, p=0.0059). In the subpopulation free of RAS mutation (N=19) the correlation was increased. 22294718 PubMed Davies et al., 2012, Mol. Cancer Ther. 3 accepted 1502 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-11-07 21:14:25 UTC https://civicdb.org/links/evidence_items/1502 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PIK3CA 5290 Mutation Cancer 162 Capivasertib Predictive Supports D Sensitivity/Response Sensitivity to pan-Akt inhibitor AZD5363 was assessed in a panel of 182 cell lines (160 with PTEN evaluated) derived from solid and hematological tumors. PTEN loss of function due to loss or mutation (N=32) was found to be significantly correlated with AZD5363 sensitivity (p=0.0099), and correlation improved in the subpopulation free of RAS mutation. Mouse xenografts with 786-0 (PTEN-null renal cancer) cells were established. 75 mg/kg twice daily AZD5363 caused tumor growth inhibition while 150 mg/kg twice daily induced moderate tumor regression. 22294718 PubMed Davies et al., 2012, Mol. Cancer Ther. 3 accepted 1503 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-11-07 21:16:10 UTC https://civicdb.org/links/evidence_items/1503 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PIK3CA 5290 Mutation Her2-receptor Positive Breast Cancer 0060079 Capivasertib Predictive Supports D Sensitivity/Response HER2 overexpressing breast cancer cell lines with PIK3CA mutation BT474c (K111N) and HCC-1954 (H1047R) were used to establish mouse tumor xenografts. In BT474c xenografts, three dosing schedules of AZD5363 caused significant tumor inhibition (200 mg/kg twice daily > 200 mg/kg once daily > 100 mg/kg once daily). In HCC-1954 xenografts two doses of AZD5363 induced significant tumor inhibition (150 mg/kg twice daily > 75 mg/kg twice daily) while 30 mg/kg twice weekly trastuzumab was inactive. 22294718 PubMed Davies et al., 2012, Mol. Cancer Ther. 2 accepted 1504 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-11-07 21:12:08 UTC https://civicdb.org/links/evidence_items/1504 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Her2-receptor Positive Breast Cancer 0060079 Capivasertib,Trastuzumab Combination Predictive Supports D Sensitivity/Response Tumor xenografts in mice were established with the KPL4 HER2 positive breast cancer cell line with PIK3CA H1047R mutation. KPL4 has suboptimal responses to trastuzumab and lapatinib. Xengraft treatment with trastuzumab and AZD5363 monotherapy induced moderate growth inhibition which was significant for AZD5363, but co-treatment with trastuzumab and AZD5363 induced significant tumor regression and enhanced growth delay upon removal of treatment. 22294718 PubMed Davies et al., 2012, Mol. Cancer Ther. 3 accepted 1505 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2016-07-06 19:35:33 UTC https://civicdb.org/links/evidence_items/1505 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Her2-receptor Positive Breast Cancer 0060079 Capivasertib,Lapatinib Combination Predictive Supports D Sensitivity/Response The HER2 breast cancer cell line KPL4 with PIK3CA H1047R shows sub-optimal responses to trastuzumab and lapatinib, and was used to establish mouse xenografts. Treatment of mice with monotherapy of AZD5363 or lapatinib alone induced growth inhibition (37%, not significant; 65%, P = 0.004), but treatment with AZD5363 and lapatinib together induced significant tumor regression (109%, P < 0.0001) as well as delayed tumor regrowth after removal of therapy. 22294718 PubMed Davies et al., 2012, Mol. Cancer Ther. 3 accepted 1506 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2016-11-05 23:21:50 UTC https://civicdb.org/links/evidence_items/1506 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false TP53 7157 Mutation Chronic Lymphocytic Leukemia 1040 Prognostic Supports A Poor Outcome In a cohort of 406 patients with CLL, those patients with clonal or sub-clonal mutations in TP53 had significantly shorter overall survival (HR: 1.71; 95% CI: 1.28-2.26; P = .0001). 26837699 PubMed Nadeu et al., 2016, Blood 5 accepted 1507 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2016-07-14 02:46:33 UTC https://civicdb.org/links/evidence_items/1507 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false ASXL1 171023 Mutation Myelofibrosis 4971 Prognostic Supports B Poor Outcome An ASXL1 mutation, especially in conjunction with DNMT3A and EZH2 mutations, results in a fourfold increase in resistance to treatment with ruxolitinib and a reduced time to treatment discontinuation (TTD) for patients with myelofibrosis. 26124496 PubMed Patel et al., 2015, Blood 3 accepted 1508 177 68 20 30946155 31027122 ENST00000375687.4 75 GRCh37 ASXL1 mutations are most frequently observed in the absence of FLT3-ITD and NPM1 mutations in acute myeloid leukemia (AML) patients and seem to be enriched in older patients (>60 years). These mutations are associated with poor prognosis with respect to both survival and compete remission rates. Somatic 2016-07-07 14:22:25 UTC https://civicdb.org/links/evidence_items/1508 https://civicdb.org/links/variants/177 https://civicdb.org/links/genes/68 false NRAS 4893 Mutation Melanoma 1909 Binimetinib Predictive Supports D Sensitivity/Response In a panel of 7 NRAS mutant melanoma cell lines, all 7 were found to be sensitive to the MEK inhibitor MEK162, whereas 3 of 5 melanoma cell lines that were wild type for BRAF and NRAS were not sensitive to MEK162. In further tests using two of the seven NRAS mutant cell lines (YUDOSO Q16K/wt and YUKIM Q16R), colony forming capacity was reduced with increased MEK162 treatment, and MEK162 induced apoptotic markers in these cells. 24588908 PubMed Thumar et al., 2014, Mol. Cancer 3 accepted 1509 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2016-11-04 19:47:52 UTC https://civicdb.org/links/evidence_items/1509 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false IDH2 3418 R172 Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome In a study of 1,540 patients with Acute Myeloid Leukemia, 18 patients had a mutation in IDH2(R172). IDH2(R172) mutations rarely showed co-mutation with NPM1 (odds ratio= 0.06; P=4x10-5), whereas IDH2(R140) mutations showed strong co-mutation with NPM1 (odds ratio= 3.6; P=5x10-10). In an absence of gene fusion products, patients with IDH2(R172) mutations showed higher survival rates when compared to mutations in NPM1, chromatin-spliceosome mutations and TP53–aneuploidy. Patients with IDH2(R172) mutations showed worse prognosis when compared to CEBPA(biallelic) mutations. 27276561 PubMed Papaemmanuil et al., 2016, N. Engl. J. Med. NCT00146120 4 accepted 1511 199 27 15 90631837 90631839 ENST00000330062.3 75 GRCh37 IDH2 R172 is a gain-of-function mutation commonly observed in acute myeloid leukemia and is enriched in those patients which are cytogenetically normal. R172 is analogous to IDH1 R132 mutations and leads to neomorphic enzymatic activity. Specifically this mutation "catalyzes the conversion of alpha ketoglurarate to beta-hydrozyglutarate" leading to increased levels of beta-hydrozyglutarate. This in turn leads to hypermethylation of target genes and an inhibition of cellular differentiation. R172 mutations generally lead to worse overall survival and higher rates of relapse compared to the most common IDH2 mutations in AML (R140). Somatic 2016-07-07 23:32:10 UTC https://civicdb.org/links/evidence_items/1511 https://civicdb.org/links/variants/199 https://civicdb.org/links/genes/27 false CEBPA 1050 BIALLELIC INACTIVATION Acute Myeloid Leukemia 9119 Prognostic Supports B Better Outcome In a study of 1,540 patients with Acute Myeloid Leukemia, 66 patients (4%) had a CEBPA (biallelic) mutation. In the absence of gene fusion products, patients with biallelic CEBPA mutations showed the highest rate of survival (~78%) when compared to IDH2 (R172) mutations, NPM1(W288fs) mutations, chromatin-spliceosome mutations and TP53–aneuploidy. 27276561 PubMed Papaemmanuil et al., 2016, N. Engl. J. Med. NCT00146120 5 accepted 1512 594 15 19 33790840 33793470 ENST00000498907.2 75 GRCh37 Somatic 2016-07-10 21:21:46 UTC https://civicdb.org/links/evidence_items/1512 https://civicdb.org/links/variants/594 https://civicdb.org/links/genes/15 false ASXL1 171023 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Patients with Acute Myeloid Leukemia showed an synergistic mortality rate with ASXL1 and SRSF2 co-mutations such that individual mutations of either ASXL1 or SRSF2 resulted in ~20% probability of survival after 10 years, whereas co-mutations resulted in a 100% mortality rate after 4 years. 27276561 PubMed Papaemmanuil et al., 2016, N. Engl. J. Med. NCT00146120 5 accepted 1513 177 68 20 30946155 31027122 ENST00000375687.4 75 GRCh37 ASXL1 mutations are most frequently observed in the absence of FLT3-ITD and NPM1 mutations in acute myeloid leukemia (AML) patients and seem to be enriched in older patients (>60 years). These mutations are associated with poor prognosis with respect to both survival and compete remission rates. Somatic 2016-07-07 23:33:00 UTC https://civicdb.org/links/evidence_items/1513 https://civicdb.org/links/variants/177 https://civicdb.org/links/genes/68 false SRSF2 6427 MUTATION Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Patients with Acute Myeloid Leukemia showed an synergistic mortality rate with ASXL1 and SRSF2 co-mutations such that individual mutations of either ASXL1 or SRSF2 resulted in ~20% probability of survival after 10 years, whereas co-mutations resulted in a 100% mortality rate after 4 years. 27276561 PubMed Papaemmanuil et al., 2016, N. Engl. J. Med. NCT00146120 5 accepted 1514 595 5210 17 74732402 74733113 ENST00000392485.2 75 GRCh37 Somatic 2016-07-07 22:43:09 UTC https://civicdb.org/links/evidence_items/1514 https://civicdb.org/links/variants/595 https://civicdb.org/links/genes/5210 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In the absence of a FLT3 (ITD) mutation, a co-mutation of NPM1 and DNMT3A had a 50% 10-year survival rate, whereas triple-mutation of NPM1, DNMT3A, and FLT3 (ITD) had a 20% 10-year survival rate. 27276561 PubMed Papaemmanuil et al., 2016, N. Engl. J. Med. NCT00146120 5 accepted 1515 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-07-10 21:09:18 UTC https://civicdb.org/links/evidence_items/1515 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false NRAS 4893 G12/G13 Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome Patients with a triple mutation of NPM1, DNMT3A, and NRAS (G12/13) (three-way interaction p=0.04) showed a relatively benign prognosis with an 8-year survival rate of 75% and a 10-year survival rate of 55%. Conversely, patients with a concomitant NPM1/DNMT3A co-mutation, in the absence of an NRAS (G12/13) mutation, showed a clinically unfavorable 10-year survival rate of 30%. 27276561 PubMed Papaemmanuil et al., 2016, N. Engl. J. Med. NCT00146120 4 accepted 1516 596 36 1 115258744 115258748 ENST00000369535.4 75 GRCh37 Somatic 2017-08-24 15:55:23 UTC https://civicdb.org/links/evidence_items/1516 https://civicdb.org/links/variants/596 https://civicdb.org/links/genes/36 false CD274 29126 Expression Cancer 162 Nivolumab Predictive Supports B Sensitivity/Response Trial NCT00730639 tested monoclonal antibody nivolumab against the PD-1 immune checkpoint receptor in pretreated patients with various cancer types. PD-L1 expression was tested in 42 patients by ICH from tumor FFPE biopsies. (18 melanoma, 10 NSCLC, 7 colorectal cancer, 5 renal cell cancer, 2 prostate cancer). 9 of 25 PD-L1 expressing patients showed objective response, and zero of 17 PD-L1 negative patients showed objective response (p=0.006). Biopsies were optional, and therefore not fully randomized. 22658127 PubMed Topalian et al., 2012, N. Engl. J. Med. NCT00730639 2 accepted 1517 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2020-10-21 04:31:42 UTC https://civicdb.org/links/evidence_items/1517 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false RET 5979 Overexpression Papillary Adenocarcinoma 3112 Sunitinib Predictive Supports C Sensitivity/Response A 78-year-old man presented with oral papillary adenocarcinoma and lung metastases that were refractory to standard treatment. Tumor sequencing showed increased MAPK activity due to RET over-expression and PTEN deletion, therefore sunitinib (RET inhibitor) was initiated. After 28 days post-administration, the lung metastases decreased in size by 22% (28mm to 21mm) and no new metastatic lesions had appeared. After 4 months, the patient grew resistant to treatment. 20696054 PubMed Jones et al., 2010, Genome Biol. 3 accepted 1518 597 42 10 43572475 43625799 ENST00000355710.3 75 GRCh37 Somatic 2021-03-02 19:50:27 UTC https://civicdb.org/links/evidence_items/1518 https://civicdb.org/links/variants/597 https://civicdb.org/links/genes/42 false PML 5371 PML::RARA Acute Promyelocytic Leukemia 0060318 Tretinoin Predictive Supports C Sensitivity/Response A 39-year old woman who presented with acute myeloid leukemia revealed a complicated genetic profile using conventional metaphase cytogenetics and FISH analysis. Whole genome sequencing elucidated a PML-RARA fusion, which can be successfully treated with ATRA. Uncovering this mutation prevented an unnecessary allogeneic transplant and the patient remained in remission 15 months post-treatment (date of publication). 21505136 PubMed Welch et al., 2011, JAMA 3 accepted 1519 108 39 15 74287058 74325755 ENST00000268058.3 17 38504568 38513048 ENST00000254066.5 75 GRCh37 The PML-RARA fusion is seen as a diagnostic event in acute promyelocytic leukemia (APL). Both in vitro and in vivo studies have shown sensitivity to ATRA in APL patients harboring the PML-RARa fusion. Recent interest has been shown in combining ATRA and arsenic trioxide for treating these patients, and early results seem promising. Somatic 2016-09-15 16:53:31 UTC https://civicdb.org/links/evidence_items/1519 https://civicdb.org/links/variants/108 https://civicdb.org/links/genes/39 false CTLA4 1493 CTLA4::CD28 Sezary's Disease 8541 Ipilimumab Predictive Supports C Sensitivity/Response A 67-year-old Caucasian female with stage IVA Sezary syndrome presented refractory to traditional therapy and was enrolled in a whole genome study trial. Sequencing revealed a CTLA4-CD28 fusion protein such that the inhibitory CTLA4 receptor activated a stimulatory CD28 intracellular domain that promoted proliferation. The patient was treated with iplimumab, a CTLA4 receptor inhibitor, and after 10 days, there was a reduction in erythema and ulceration by 50%, a reduction in tumor size by 75%, and overall improved quality of life. However, during the sixth week of therapy, the patient rapidly developed skin tumors and died 3 months later. 25802883 PubMed Sekulic et al., 2015, Mol Genet Genomic Med 2 accepted 1520 599 1285 2 204732509 204736210 ENST00000302823.3 2 204599507 204603635 ENST00000324106.8 75 GRCh37 A survey of 115 T-cell lymphoma samples of diverse subtypes identified this fusion in 26 of 45 cases of angioimmunoblastic T-cell lymphomas (58%), nine of 39 peripheral T-cell lymphomas, not otherwise specified (23%), and nine of 31 extranodal NK/T cell lymphomas (29%). Somatic 2016-08-19 18:49:37 UTC https://civicdb.org/links/evidence_items/1520 https://civicdb.org/links/variants/599 https://civicdb.org/links/genes/1285 false AR 367 Mutation Prostate Cancer 10283 Nilutamide,Bicalutamide,Flutamide,Cyproterone Acetate Substitutes Predictive Supports B Resistance In a study of 150 patients with metastatic castration resistant prostate cancer (mCRPC), 71.3% of cases (n=107) harbored androgen receptor (AR) pathway aberrations. Within the AR mutation cohort, 78 patients had AR amplification mutations, 16 patients had AR missense mutations, and 13 patients had mutations in ZBTB16, NCOR1, FOXA1, and SPOP, which are all AR regulators or downstream effectors. All AR mutations were exclusive to mCRPC neoplasms and were not found in primary prostate cancer. 26000489 PubMed Robinson et al., 2015, Cell 4 accepted 1521 600 67 X 66764465 66950461 ENST00000374690.3 75 GRCh37 Somatic 2016-07-17 21:26:41 UTC https://civicdb.org/links/evidence_items/1521 https://civicdb.org/links/variants/600 https://civicdb.org/links/genes/67 false PTEN 5728 Mutation Prostate Cancer 10283 PI3Kbeta Inhibitor AZD8186,Alpelisib,Enzalutamide Combination Predictive Supports D Sensitivity/Response Castrated mice bearing androgen-sensitive human prostate adenocarcinomas (LNCaP tumors) were treated with PI3K inhibitors (AZD8186, BYL719) and an androgen receptor inhibitor (MDV3100). Mice treated with single therapy of either MDV3100, BYL719, or AZD8186 resulted in mild tumor growth inhibition of 90%, 36%, and 40% respectively (n=5 mice/group). However, triple therapy of MDV300, BYL719, and AZD8186 resulted in tumor regression of 113% (n=5 mice). 25544636 PubMed Schwartz et al., 2015, Cancer Cell 3 accepted 1522 510 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-10-25 14:50:00 UTC https://civicdb.org/links/evidence_items/1522 https://civicdb.org/links/variants/510 https://civicdb.org/links/genes/41 false BRCA1 672 Loss-of-function Prostate Cancer 10283 Prognostic Supports B Poor Outcome In a study of 2,019 patients with prostate cancer, 18 had germline BRCA1 mutations, 61 had germline BRCA2 mutations and 1,940 were non-carriers. Patients with BRCA1/2 mutations had a 2-fold higher incidence of poorly differentiated cancer (Gleason score >8), a higher incidence of advanced stage (37% vs. 28%; P=0.003), a higher incidence of nodal involvement (15% vs. 5%; P=0.0005), and a higher incidence of metastatic spread (18% vs. 9%; P=0.005). 23569316 PubMed Castro et al., 2013, J. Clin. Oncol. 3 accepted 1523 131 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 BRCA1 loss of function mutations have been shown to increase risk of breast and ovarian cancer in those carrying the allele in their germline. Treating BRCA mutant patients with PARP inhibitors such as Olaparib has led to significant response. Rare Germline 2016-07-16 15:09:20 UTC https://civicdb.org/links/evidence_items/1523 https://civicdb.org/links/variants/131 https://civicdb.org/links/genes/6 false BRCA2 675 Loss-of-function Prostate Cancer 10283 Prognostic Supports B Poor Outcome In a study of 2,019 patients with prostate cancer, 18 had germ-line BRCA1 mutations, 61 had germ-line BRCA2 mutations and 1,940 were non-carriers. Patients with BRCA1/2 mutations had a 2-fold higher incidence of poorly differentiated cancer (Gleason score >8), a higher incidence of advanced stage (37% vs. 28%; P=0.003), a higher incidence of nodal involvement (15% vs. 5%; P=0.0005), and a higher incidence of metastatic spread (18% vs. 9%; P=0.005). 23569316 PubMed Castro et al., 2013, J. Clin. Oncol. 3 accepted 1524 132 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 BRCA2 loss of function mutations have been shown to increase risk of breast and ovarian cancer in those carrying the allele in their germline. Treating BRCA mutant patients with PARP inhibitors such as Olaparib has led to significant response. Rare Germline 2016-07-16 15:09:37 UTC https://civicdb.org/links/evidence_items/1524 https://civicdb.org/links/variants/132 https://civicdb.org/links/genes/7 false NOTCH1 4851 Loss-of-function Head And Neck Squamous Cell Carcinoma 5520 Porcupine Inhibitor WNT974 Predictive Supports D Sensitivity/Response In an evaluation of 96 head and neck squamous cell carcinoma (HNSCC) cell lines, 31 were responsive to LGK974 (PORCN inhibitor). Of 40 cell lines (25 responsive, 15 non-responsive) that were exome sequenced, 6 cell lines had NOTCH1 loss-of-function mutations (N-terminal frameshift/nonsense) and 5/6 cell lines that had NOTCH1 mutations were susceptible to LGK974 (PORCN inhibitor). 24277854 PubMed Liu et al., 2013, Proc. Natl. Acad. Sci. U.S.A. 2 accepted 1525 601 50 9 139388896 139440314 ENST00000277541.6 75 GRCh37 Somatic 2016-11-07 21:15:28 UTC https://civicdb.org/links/evidence_items/1525 https://civicdb.org/links/variants/601 https://civicdb.org/links/genes/50 false CDK6 1021 Overexpression Estrogen-receptor Positive Breast Cancer 0060075 Fulvestrant Predictive Supports B Resistance In two cohorts (n=45 and n=46) of ER+ breast cancer patients who had received fulvestrant, CDK6 overexpression correlated with shorter median time to progression in both cohorts (2.5 vs. 8.2 months and 3.4 vs. 8.9 months for CDK6 overexpression vs. normal expression). CDK6 expression did not correlate with other lines of treatment (N=68, tamoxifen or endocrine therapy). Four fulvestrant-resistant cell lines were derived from estrogen responsive and fulvestrant sensitive parental breast cancer cell line MCF-7/SO.5. Gene expression profiling showed upregulation of CDK6 in the fulvestrant resistant derivatives. Knockdown of CDK6 in these derivative cells resulted in fulvestrant sensitivity. 27252418 PubMed Alves et al., 2016, Clin. Cancer Res. 4 accepted 1526 602 12 7 92234235 92463231 ENST00000265734.4 75 GRCh37 N/A 2016-08-22 22:39:18 UTC https://civicdb.org/links/evidence_items/1526 https://civicdb.org/links/variants/602 https://civicdb.org/links/genes/12 false CDK6 1021 Overexpression Estrogen-receptor Positive Breast Cancer 0060075 Fulvestrant,Palbociclib Combination Predictive Supports D Sensitivity/Response Four fulvestrant (estrogen receptor degrader) resistant cell lines were derived from parent fulvestrant sensitive ER+ MCF-7/SO.5 breast cancer cell line. Derivative cell lines showed some sensitivity to CDK4/6 inhibitor palbociclib, and increased growth inhibition when treated with fulvestrant and palbociclib together. 27252418 PubMed Alves et al., 2016, Clin. Cancer Res. 2 accepted 1527 602 12 7 92234235 92463231 ENST00000265734.4 75 GRCh37 Somatic 2016-07-12 15:17:53 UTC https://civicdb.org/links/evidence_items/1527 https://civicdb.org/links/variants/602 https://civicdb.org/links/genes/12 false FLT3 2322 Overexpression B-cell Adult Acute Lymphocytic Leukemia 0060592 Sunitinib Predictive Supports C Sensitivity/Response A 25-year-old Caucasian male presented with a second relapse of B-ALL. RNA sequencing revealed FLT3 overexpression (also confirmed by IHC). The patient was treated with 22 days of sunitinib, permitting the patient to undergo a bone marrow transplant. A bone marrow biopsy showed complete clearance by variant allele frequency and the patient remains in remission 4-years post matched-unrelated donor allograft. 27181063 PubMed Griffith et al., 2016, Exp. Hematol. 3 accepted 1528 603 24 13 28577411 28674729 ENST00000241453.7 75 GRCh37 Somatic 2021-03-02 19:53:17 UTC https://civicdb.org/links/evidence_items/1528 https://civicdb.org/links/variants/603 https://civicdb.org/links/genes/24 false BRCA1 672 Mutation Ovarian Carcinoma 4001 Platinum Compound Predictive Supports B Sensitivity/Response In a study of ovarian carcinomas, 81% of tumors with germline BRCA1/2 mutations were platinum sensitive, whereas only 60% of tumors with non-BRCA1/2 mutations were platinum sensitive (N=47; N=158; P=0.01). Sensitivity was defined by maintenance of complete response greater than 6 months post platinum-based therapy. 24240112 PubMed Pennington et al., 2014, Clin. Cancer Res. 3 accepted 1529 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Rare Germline 2016-07-16 15:14:02 UTC https://civicdb.org/links/evidence_items/1529 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false BRCA2 675 Mutation Ovarian Carcinoma 4001 Platinum Compound Predictive Supports B Sensitivity/Response In a study of ovarian carcinomas, 81% of tumors with germline BRCA1/2 mutations were platinum sensitive, whereas only 60% of tumors with non-BRCA1/2 mutations were platinum sensitive (N=47; N=158; P=0.01). Sensitivity was defined by maintenance of complete response greater than 6 months post platinum-based therapy. 24240112 PubMed Pennington et al., 2014, Clin. Cancer Res. 3 accepted 1530 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Rare Germline 2016-07-16 15:11:49 UTC https://civicdb.org/links/evidence_items/1530 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false BRCA1 672 Mutation Ovarian Carcinoma 4001 Platinum Compound Predictive Supports B Sensitivity/Response In a study of ovarian carcinomas, 87% of tumors with somatic BRCA1/2 mutations were platinum sensitive, whereas only 60% of tumors with non-BRCA1/2 mutations were platinum sensitive (N=38; N=158; P=0.002). Sensitivity to platinum was defined by maintenance of complete response greater than 6 months post platinum-based therapy. 24240112 PubMed Pennington et al., 2014, Clin. Cancer Res. 3 accepted 1531 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Somatic 2016-07-16 15:47:46 UTC https://civicdb.org/links/evidence_items/1531 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false BRCA2 675 Mutation Ovarian Carcinoma 4001 Platinum Compound Predictive Supports B Sensitivity/Response In a study of ovarian carcinomas, 87% of tumors with somatic BRCA1/2 mutations were platinum sensitive, whereas only 60% of tumors with non-BRCA1/2 mutations were platinum sensitive (N=38; N=158; P=0.002). Sensitivity to platinum was defined by maintenance of complete response greater than 6 months post platinum therapy. 24240112 PubMed Pennington et al., 2014, Clin. Cancer Res. 3 accepted 1532 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Somatic 2016-07-16 15:13:27 UTC https://civicdb.org/links/evidence_items/1532 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false GNAQ 2776 Q209P Skin Melanoma 8923 Vemurafenib Predictive Supports C Resistance A 26-year old patient presented with vemurafenib resistant BRAF-mutated (V600E) cutaneous melanoma. Five of his metastases were evaluated using whole genome sequencing. A GNAQ (Q209P) mutation was identified as unanimously present in all five tumors. 24504448 PubMed Turajlic et al., 2014, Ann. Oncol. 2 accepted 1533 604 2317 9 80409488 80409488 T G ENST00000286548.4 75 GRCh37 Somatic 2016-07-20 18:36:33 UTC https://civicdb.org/links/evidence_items/1533 https://civicdb.org/links/variants/604 https://civicdb.org/links/genes/2317 false PTEN 5728 V317FS Skin Melanoma 8923 MEK Inhibitor CI-1040,Akt Inhibitor MK2206 Combination Predictive Supports D Sensitivity/Response A 26-year old patient presented with vemurafenib resistant BRAF V600E-mutated cutaneous melanoma. Five metastases were evaluated using whole genome sequencing and a 4-bp deletion in PTEN (frameshift mutation at V317) was identified as unanimously present in all five tumors and a pre-treatment biopsy. The other copy of PTEN was lost with a chromosome-wide loss of chr 10. Subsequently, a patient-derived tumor cell line (designated 22 092) was suspended in a solution of PD184352/MK2206 combination therapy and cell growth inhibition confirmed tumor sensitivity to MEK/AKT inhibitors compared to the BRAF V600E-containing A375P cell line. ERK inhibitor resistance was demonstrated as a result of a GNAQ Q209P mutation also identified in the patient. This cell line showed overexpression of AKT and no expression of PTEN. 24504448 PubMed Turajlic et al., 2014, Ann. Oncol. 3 accepted 1534 605 41 10 89720799 89720802 TACT ENST00000371953.3 75 GRCh37 Somatic 2019-09-18 21:32:00 UTC https://civicdb.org/links/evidence_items/1534 https://civicdb.org/links/variants/605 https://civicdb.org/links/genes/41 false RB1 5925 Loss-of-function Breast Cancer 1612 Palbociclib Predictive Supports D Resistance In 3 ER positive and 2 ER negative breast cancer cell lines with intact Rb, significant growth inhibition, as measured by BrdU incorporation, was seen with incubation in CDK4/6 inhibitor palbociclib (PD-0332991). In contrast, two ER negative cell lines lacking detectable Rb were fully resistant to palbociclib. Knockdown of Rb in 3 of the tested Rb positive cell lines led to moderate palbociclib resistance in short term incubation experiments. In longer term (15 day) palbociclib incubations of ER negative MDA-MB-231 cells and ER positive MCF-7 cells, significant resistance to palbociclib was seen in Rb knockdown conditions while wild-type Rb cells maintained sensitivity. 20473330 PubMed Dean et al., 2010, Oncogene 3 accepted 1535 606 4795 13 48877911 49056122 ENST00000267163.4 75 GRCh37 Somatic 2016-08-23 06:58:08 UTC https://civicdb.org/links/evidence_items/1535 https://civicdb.org/links/variants/606 https://civicdb.org/links/genes/4795 false CCND1 595 Overexpression Mantle Cell Lymphoma 0050746 Palbociclib Predictive Does Not Support B Sensitivity/Response A pharmacodynamic study (NCT00420056) of 17 mantle cell lymphoma MCL patients was performed using the CDK4/6 inhibitor palbociclib (PD0332991). Patients were verified by IHC, FISH or molecular testing for the t(11:14) rearrangement causing Cyclin D overexpression in MCL. 1 patient demonstrated complete response, and 2 showed partial response for an 18% overall response rate. 7 patients showed stable disease. Patient population was heavily pretreated. 22383795 PubMed Leonard et al., 2012, Blood NCT00420056 2 accepted 1536 20 8 11 69455855 69469242 ENST00000227507.2 75 GRCh37 Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK's) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, and range from genomic amplification to promoter methylation changes. While Cyclin D2 has only been found to be significantly misregulated in glioma, Cyclin D1 in particular seems to be a pan-cancer actor. Cyclin D misregulation has been shown to lead to poorer outcomes in a number of studies, and currently there are no FDA-approved targeted therapies. N/A 2020-10-22 01:53:12 UTC https://civicdb.org/links/evidence_items/1536 https://civicdb.org/links/variants/20 https://civicdb.org/links/genes/8 false GNAQ 2776 Q209P Skin Melanoma 8923 PLX4720 Predictive Supports D Resistance Cells were derived from a 26-year old patient with vemurafenib resistant BRAF-mutated (V600E) cutaneous melanoma (designated 20 092 cells). Five of his metastases evaluated using whole genome sequencing contained a GNAQ (Q209P) mutation. 20 092 cells were insensitive to BRAF inhibition (PLX4720) in both proliferation assays and evaluation of pERK compared to BRAF V600E mutated, GNAQ wild-type A375P cells. Using GNAQ (Q209P) siRNA in 22 092 cells, ERK activity was suppressed and cell sensitivity to PLX4720 was increased. 24504448 PubMed Turajlic et al., 2014, Ann. Oncol. 3 accepted 1537 604 2317 9 80409488 80409488 T G ENST00000286548.4 75 GRCh37 Somatic 2016-11-04 16:22:14 UTC https://civicdb.org/links/evidence_items/1537 https://civicdb.org/links/variants/604 https://civicdb.org/links/genes/2317 false NOTCH1 4851 Mutation Chronic Lymphocytic Leukemia 1040 Prognostic Supports A Poor Outcome In a study of 406 previously untreated CLL cases, a multivariate analysis indicated clonal NOTCH1 mutations (N=55) were significantly associated with reduced overall survival (HR: 1.5; 95%CI: 1.13-1.99; P = 0.0049). Subclonal mutations (VAF <12%) were not associated with reduced OS (N=29, P=0.94, univariate analysis). 26837699 PubMed Nadeu et al., 2016, Blood 5 accepted 1538 206 50 9 139388896 139440314 ENST00000277541.6 75 GRCh37 Somatic 2016-07-14 18:24:42 UTC https://civicdb.org/links/evidence_items/1538 https://civicdb.org/links/variants/206 https://civicdb.org/links/genes/50 false ATM 472 Mutation Chronic Lymphocytic Leukemia 1040 Prognostic Supports A Poor Outcome In a study of 406 previously untreated CLL cases, a multivariate analysis indicated that aberrations (N=44; mixed pathogenic germline and somatic) in exons 2-63 of ATM were significantly associated with shorter time to first treatment (HR: 1.36; 95% CI: 1.05-1.76; P = 0.021). These mutations were not significantly associated with overall survival. 26837699 PubMed Nadeu et al., 2016, Blood 5 accepted 1539 178 69 11 108093559 108239826 ENST00000278616.4 75 GRCh37 N/A 2016-07-16 14:33:48 UTC https://civicdb.org/links/evidence_items/1539 https://civicdb.org/links/variants/178 https://civicdb.org/links/genes/69 false SF3B1 23451 Mutation Chronic Lymphocytic Leukemia 1040 Prognostic Supports A Poor Outcome In a study of 406 previously untreated CLL cases, a multivariate analysis indicated SF3B1 mutations (N=51) were significantly associated with reduced time to first treatment (HR: 1.73; 95%CI: 1.05-2.86; P = 0.031). While clonal mutations (VAF >= 12%) were associated with reduced time to first treatment by univariate analysis (N=28, P<0.0001), subclonal mutations were not (N=21, P=0.22). 26837699 PubMed Nadeu et al., 2016, Blood 5 accepted 1540 215 44 2 198254508 198299815 ENST00000335508.6 75 GRCh37 Somatic 2016-07-16 14:32:51 UTC https://civicdb.org/links/evidence_items/1540 https://civicdb.org/links/variants/215 https://civicdb.org/links/genes/44 false ESR1 2099 Overexpression Breast Cancer 1612 Palbociclib,Letrozole Combination Predictive Supports B Sensitivity/Response A phase 2 clinical trial evaluated 165 patients with oestrogen receptor positive and HER2-negative breast cancer such that 84 patients received combination therapy of palbociclib plus letrozole and 81 patients received letrozole alone. The combination therapy arm had higher median duration of progression-free survival when compared to the letrozole only group (20.2 months vs. 10.2 months; p<0.0004). A subcategory of patients taking combination therapy, who lacked mutations in p16 or CCND1 (n=34), had an even higher median free survival of 26.1 months. Noticeable side effects in the combination therapy group included neutropenia (54%) leucopenia (19%), fatigue (4%) back pain (2%), diarrhea (2%) and pulmonary embolism (4%). 25524798 PubMed Finn et al., 2015, Lancet Oncol. NCT00721409 4 accepted 1541 607 21 6 152128686 152424406 ENST00000206249.3 75 GRCh37 N/A 2020-12-10 20:01:31 UTC https://civicdb.org/links/evidence_items/1541 https://civicdb.org/links/variants/607 https://civicdb.org/links/genes/21 false IDH2 3418 R140 Acute Myeloid Leukemia 9119 Prognostic Does Not Support B N/A In patients with acute myeloid leukemia, the presence of IDH2 R140Q (n = 7), IDH2 R172K (n = 3) or IDH1 R132 (N=4) mutations did not confer prognostic value (overall survival) compared to wild-type IDH1/2 patients overall (N=102; P=0.177). IDH1/2 mutations were significantly more common in cytogenetically normal AML (P=0.004). IDH1/2 mutations did also not confer an overall survival benefit in patients with an intermediate risk karyotype (N=68, P=0.484). 21997850 PubMed Lin et al., 2012, Ann. Hematol. 2 accepted 1542 62 27 15 90631934 90631934 ENST00000330062.3 75 GRCh37 IDH2 mutations have been observed in a number of hematologic malignancies. In acute myeloid leukemia, the R140 mutants show mixed results affecting overall survival as compared to their wild-type counterparts. In myelodysplastic syndromes, however, no prognostic link was discovered between IDH2 mutation status and overall survival. Somatic 2016-08-04 04:55:49 UTC https://civicdb.org/links/evidence_items/1542 https://civicdb.org/links/variants/62 https://civicdb.org/links/genes/27 false MTOR 2475 F2108L Breast Cancer 1612 Sirolimus Predictive Supports D Resistance MCF-7 breast cancer cell line was exposed to mTOR inhibitors AZD8055 or rapamycin until resistance developed. Deep sequencing revealed an MTOR F2108L mutation in rapamycin-resistant clones (RR2 cells). Downstream signalling was independent of inhibitor presence in these clones and expression of the mutations in MDA-MB-468 cells led to resistance. 27279227 PubMed Rodrik-Outmezguine et al., 2016, Nature 4 accepted 1543 470 2073 1 11187094 11187094 G T ENST00000361445.4 75 GRCh37 Somatic 2016-11-02 19:44:15 UTC https://civicdb.org/links/evidence_items/1543 https://civicdb.org/links/variants/470 https://civicdb.org/links/genes/2073 false MTOR 2475 M2327I Breast Cancer 1612 MTOR Kinase Inhibitor AZD8055 Predictive Supports D Resistance MCF-7 breast cancer cell line was exposed to mTOR inhibitor AZD8055 until resistance developed. Deep sequencing revealed an MTOR M2327I mutation in the AZD8055-resistant clone. Downstream signalling was independent of inhibitor presence in these clones and expression of the mutation in MDA-MB-468 cells led to resistance. Tumor volume grew more rapidly in mice with xenografts of M2327I mTOR mutant MCF7 cells treated with AZD8055 than rapamycin or RapaLink-1 treatment. 27279227 PubMed Rodrik-Outmezguine et al., 2016, Nature 4 accepted 1544 609 2073 1 11177096 11177096 C A ENST00000361445.4 75 GRCh37 Somatic 2016-11-02 19:44:46 UTC https://civicdb.org/links/evidence_items/1544 https://civicdb.org/links/variants/609 https://civicdb.org/links/genes/2073 false MTOR 2475 M2327I Breast Cancer 1612 RapaLink-1,Sirolimus Substitutes Predictive Does Not Support D Resistance MCF-7 breast cancer cell line was exposed to mTOR inhibitor AZD8055 until resistance developed. Deep sequencing revealed an MTOR M2327I mutation in the AZD8055-resistant clone. These cells remained sensitive to rapamycin and RapaLink-1 in vitro and in mouse xenografts. Expression of the mutation in MDA-MB-468 cells led to AZD8055 resistance and these cells were also rapamycin and RapaLink-1 sensitive. 27279227 PubMed Rodrik-Outmezguine et al., 2016, Nature 3 accepted 1545 609 2073 1 11177096 11177096 C A ENST00000361445.4 75 GRCh37 Somatic 2016-11-05 21:55:17 UTC https://civicdb.org/links/evidence_items/1545 https://civicdb.org/links/variants/609 https://civicdb.org/links/genes/2073 false MTOR 2475 A2034V Breast Cancer 1612 Sirolimus Predictive Supports D Resistance MCF-7 breast cancer cell line was exposed to mTOR inhibitor rapamycin until resistance developed. Deep sequencing revealed an MTOR A2034V mutation in the resistant clone. Downstream signalling was independent of inhibitor presence in these clones and expression of the mutation in MDA-MB-468 cells led to resistance. Xenografts of these cells were more resistant to rapamycin than AZD8055 or RapaLink-1 treatment. 27279227 PubMed Rodrik-Outmezguine et al., 2016, Nature 4 accepted 1547 610 2073 1 11187796 11187796 G A ENST00000361445.4 75 GRCh37 Somatic 2016-11-02 19:45:10 UTC https://civicdb.org/links/evidence_items/1547 https://civicdb.org/links/variants/610 https://civicdb.org/links/genes/2073 false MTOR 2475 A2034V Breast Cancer 1612 MTOR Kinase Inhibitor AZD8055,RapaLink-1 Substitutes Predictive Does Not Support D Resistance MCF-7 breast cancer cell line was exposed to mTOR inhibitor rapamycin until resistance developed. Deep sequencing revealed an MTOR A2034V mutation in the resistant clone (RR1). Downstream signalling was independent of inhibitor presence in these clones and expression of the mutation in MDA-MB-468 cells led to resistance to rapamycin but maintained sensistivity to AZD8055. A novel mTOR inhibitor RapaLink-1 was designed and showed efficacy in A2034V mTOR mutant cell lines in-vivo and in-vitro. AZD8055 also retained efficacy in these clones in xenograft. 27279227 PubMed Rodrik-Outmezguine et al., 2016, Nature 4 accepted 1548 610 2073 1 11187796 11187796 G A ENST00000361445.4 75 GRCh37 Somatic 2016-11-07 18:42:27 UTC https://civicdb.org/links/evidence_items/1548 https://civicdb.org/links/variants/610 https://civicdb.org/links/genes/2073 false PIK3CA 5290 E542K Head And Neck Squamous Cell Carcinoma 5520 Apitolisib Predictive Supports C Sensitivity/Response Phase 1 study with the dual PI3K/mTOR inhibitor apitolisib. 120 patients were treated at doses between 2 and 70mg. Of the 14 evaluable patients with PIK3CA mutations total, there were 3 PRs (1 confirmed), 8 SD, and 3 PD as best radiological responses. One of the partial responses harbored a PIK3CA E542K mutation. 26787751 PubMed Dolly et al., 2016, Clin. Cancer Res. 2 accepted 1549 103 37 3 178936082 178936082 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K variants are the second most recurrent PIK3CA mutations in breast cancer and are highly recurrent mutations in many other cancer types. Colorectal cancer patients with the PIK3CA E545K variant, and possibly other variants in the E545 region, may indicate poor prognosis relative to patients with other PIK3CA variants or wild-type PIK3CA. The literature also suggests that E545/E542 variants may confer resistance to EGFR inhibitors (e.g., cetuximab). An FDA approved treatment regimen including a targeted PIK3CA inhibitor is available for specific subtypes of breast cancer. While PIK3CA variants are highly prevalent in many other cancer types, targeted therapies for PIK3CA variants are still in early clinical trial phases in other cancer types. Somatic 2016-08-05 06:54:49 UTC https://civicdb.org/links/evidence_items/1549 https://civicdb.org/links/variants/103 https://civicdb.org/links/genes/37 false PIK3CA 5290 E545K Cancer 162 Apitolisib Predictive Supports C Sensitivity/Response Phase 1 study with the dual PI3K/mTOR inhibitor apitolisib. 120 patients were treated at doses between 2 and 70mg. Of 45 evaluable patients receiving 40mg, two patients with E545K PIK3CA mutation (one head and neck squamous cell carcinoma patient and a patient with ovarian cancer) had unconfirmed partial responses. Of the 14 evaluable patients with PIK3CA mutations total, there were 3 PRs (1 confirmed), 8 SD, and 3 PD as best radiological responses. 26787751 PubMed Dolly et al., 2016, Clin. Cancer Res. 1 accepted 1550 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2016-11-09 20:09:44 UTC https://civicdb.org/links/evidence_items/1550 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false BRAF 673 D594G Colorectal Cancer 9256 Prognostic Supports B Poor Outcome In a study of 908 patients with colorectal cancer, 7 patients had BRAF (D594G) mutations and 45 patients had BRAF (V600E) mutations. Overall clinicopathological implications of BRAF V600E and D594G mutant tumors were similar but BRAF D594G mutations were more likely to be left-sided tumors (85.7% vs. 31.1%; p<0.0098) and they were more likely to present as metastatic tumors (71.4% vs. 28.9%; p<0.04) than BRAF V600E mutant tumors. The overall log-rank was p < 0.001 when all three groups were calculated simultaneously; p < 0.0001 comparing BRAF wild-type and BRAF V600E survival, p = 0.015 comparing BRAF wild-type and BRAF D594G survival, and p = 0.98 comparing BRAF V600E and BRAF D594G. There was no statistically significant difference in OS between BRAF D594G and BRAF wt but BRAF V600E mutant patients had significantly worse survival when only stage IV patients (BRAF D594G N=5) were analyzed. 27404270 PubMed Amaki-Takao et al., 2016, Oncology 1 accepted 1551 611 5 7 140453154 140453154 T C ENST00000288602.6 75 GRCh37 This BRAF mutation has a markedly reduced kinase activity and leads to paradoxical MEK-pathway activation via CRAF binding. Somatic 2016-07-16 15:41:35 UTC https://civicdb.org/links/evidence_items/1551 https://civicdb.org/links/variants/611 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Prognostic Supports B Poor Outcome In a study of 908 patients with colorectal cancer, 45 patients had BRAF V600E mutations and 589 patients were BRAF wild type. BRAF V600E mutations were more likely to be proximal tumors (68.9%, 20.7%; p<0.0001), they were more likely to be poorly differentiated (17.7%, 1.9%; p<0.0001), they were more likely to be mucinous carcinoma type (20.0%, 4.2%; p=0.0003), they were more likely to have lymphatic invasion (77.6%, 49.9%; p=0.0003), and they had a shorter survival time (31.1 mo, 41.6 mo; p=0.001). The 3-year survival rate was significantly poorer in the V600E group when compared to the wild type group (63.8%, 87.9%; p<0.0001). 27404270 PubMed Amaki-Takao et al., 2016, Oncology 3 accepted 1552 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-07-19 12:00:47 UTC https://civicdb.org/links/evidence_items/1552 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 D594G Colorectal Cancer 9256 Prognostic Supports B Poor Outcome In a study of 908 patients with colorectal cancer (CRC), 7 patients had BRAF D595G mutations and 589 patients were BRAF wild type. The survival rate of CRC patients at 3 years was significantly poorer in the BRAF D595G mutations when compared to the wild type group (50%, 87.9%; p<0.00152). 27404270 PubMed Amaki-Takao et al., 2016, Oncology 2 accepted 1553 611 5 7 140453154 140453154 T C ENST00000288602.6 75 GRCh37 This BRAF mutation has a markedly reduced kinase activity and leads to paradoxical MEK-pathway activation via CRAF binding. Somatic 2016-08-04 04:58:31 UTC https://civicdb.org/links/evidence_items/1553 https://civicdb.org/links/variants/611 https://civicdb.org/links/genes/5 false BRAF 673 D594G Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Does Not Support C Resistance Two patients with stage IV BRAF (D594G) mutations received anti-EGFR antibody therapy (cetuximab and panitumumab). The first patient was on FOLFOX plus bevacizumab and showed no signs of progression for 10 months. No response was observed after cetuximab was given as a third line therapy. The second patient received panitumumab with FOLFOX and showed no signs of progression for 8 months with reduction of the size of metastases. 27404270 PubMed Amaki-Takao et al., 2016, Oncology 1 accepted 1554 611 5 7 140453154 140453154 T C ENST00000288602.6 75 GRCh37 This BRAF mutation has a markedly reduced kinase activity and leads to paradoxical MEK-pathway activation via CRAF binding. Somatic 2016-07-16 21:26:48 UTC https://civicdb.org/links/evidence_items/1554 https://civicdb.org/links/variants/611 https://civicdb.org/links/genes/5 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Sorafenib Predictive Supports C Sensitivity/Response Six children with relapsed or refractory FLT3-ITD-positive AML received initial therapy with sorafenib (alone or in combination with clofarabine and cytarabine). Four of the patients initially achieved morphological complete remission (bone marrow blasts <5%), however, 3 patients developed resistance within 14-37 weeks and and 1 required a bone marrow transplant. Two patients did not have any clinical response to sorafenib upon initial treatment. 23969938 PubMed Baker et al., 2013, Clin. Cancer Res. 1 accepted 1555 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2016-08-28 22:03:58 UTC https://civicdb.org/links/evidence_items/1555 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false FLT3 2322 D835H Acute Myeloid Leukemia 9119 Sorafenib Predictive Supports C Resistance Three children with relapsed or refractory FLT3-ITD-positive AML were treated with sorafenib. FLT3 mutations were assessed before treatment and at the time of resistance. During the initiation of the treatment, all three patients had undetectable levels of FLT3 (D835H) mutations, however, after resistance developed, the mutation frequency rose to 33.1%, 35.7%, and 11.0% in the three patients. Ba/F3 cells expressing FLT3 mutants were resistant to sorafenib-dependent inhibition of cell viability 23969938 PubMed Baker et al., 2013, Clin. Cancer Res. 3 accepted 1556 612 24 13 28592642 28592642 C G ENST00000241453.7 75 GRCh37 Somatic 2016-08-28 04:50:34 UTC https://civicdb.org/links/evidence_items/1556 https://civicdb.org/links/variants/612 https://civicdb.org/links/genes/24 false FLT3 2322 D835H/Y Acute Myeloid Leukemia 9119 Sorafenib Predictive Supports D Resistance Mouse Ba/F3 cells with FLT3 mutations were evaluated for sorafenib resistance. Cells with single FLT3 (D835H/Y) mutants were resistant to sorafenib (IC50 81 nm/210 nM) whereas cells with FLT3 (ITD) mutants were not resistant to sorafenib (IC50 1.1 nM). Cells with double mutants (ITD-D835H/Y or ITD F691L) were highly resistant to sorafenib (IC50 460-3300 nM). 23969938 PubMed Baker et al., 2013, Clin. Cancer Res. 1 accepted 1557 613 24 13 28592642 28592642 C G/A ENST00000241453.7 75 GRCh37 Somatic 2016-07-21 19:57:41 UTC https://civicdb.org/links/evidence_items/1557 https://civicdb.org/links/variants/613 https://civicdb.org/links/genes/24 false RUNX1 861 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In patients with acute myeloid leukemia, those with RUNX1 mutations (n=245) had significantly worse outcomes when compared to those with RUNX1 wild-type alleles (n=2,194). The complete remission rate for patients with RUNX1 mutations was significantly lower (48.4% vs. 68.1%; p <0.0001), the refractory disease rate was significantly higher (40.6% 23.4%; p=0.03), the 5-year event free survival rate was significantly lower (9%, 24%; p<0.0001), the 5-year relapse free survival rate was significantly lower (22%, 36%; p=0.0007), and the 5-year overall survival rate was significantly lower (22%, 37%; p=0.0001). 27137476 PubMed Gaidzik et al., 2016, Leukemia 3 accepted 1558 155 43 21 36160098 36421641 ENST00000300305.3 75 GRCh37 RUNX1 mutations are associated with poor prognosis in patients with acute myeloid leukemia or adult T-cell acute lymphocytic leukemia. In younger (<60 years old) AML patients, allogeneic stem cell transplant at complete remission led to much better relapse-free survival than repetitive cycles of high-dose cytarabine. Somatic 2016-07-19 19:33:16 UTC https://civicdb.org/links/evidence_items/1558 https://civicdb.org/links/variants/155 https://civicdb.org/links/genes/43 false CCND1 595 Amplification Renal Cell Carcinoma 4450 Palbociclib Predictive Does Not Support D Sensitivity/Response 28 renal cell carcinoma cell lines were tested for sensitivity to CDK4/6 inhibitor Palbociclib (PD0332991). 19 were reported sensitive, and 9 resistant. 15 of the 28 cell lines had high levels of Cyclin D1 (CCND1) expression which did not correlate significantly with palbociclib sensitivity (p=0.348). 23898052 PubMed Logan et al., 2013, Anticancer Res. 2 accepted 1560 18 8 11 69455855 69469242 ENST00000227507.2 75 GRCh37 CCND1 amplification has been implicated in poorer prognosis in non-small cell lung cancer. Somatic 2016-10-11 17:32:30 UTC https://civicdb.org/links/evidence_items/1560 https://civicdb.org/links/variants/18 https://civicdb.org/links/genes/8 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Trastuzumab,Palbociclib Combination Predictive Supports D Sensitivity/Response In a panel of 47 breast cancer cell lines, HER2 overexpressing cells were among those more sensitive to CDK4/6 inhibitor Palbociclib (PD0332991). In the trastuzumab sensitive cell line Bt474, palbociclib synergized with trastuzumab in growth inhibition, while in 2 trastuzumab resistant cell lines, addition of trastuzumab to palbociclib treatment resulted in increased growth inhibition over palbociclib alone. 19874578 PubMed Finn et al., 2009, Breast Cancer Res. 2 accepted 1561 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-10-06 18:38:51 UTC https://civicdb.org/links/evidence_items/1561 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false CCND1 595 Amplification Breast Cancer 1612 Palbociclib Predictive Supports D Sensitivity/Response A panel of 47 breast cancer cell lines was tested for sensitivty/resistance to CDK4/6 inhibitor Palbociclib (PD0332991), where IC50 below 150nM was sensitive, and above 1000nM resistant. Cyclin D1 had higher expression levels in sensitive cell lines. 19874578 PubMed Finn et al., 2009, Breast Cancer Res. 2 accepted 1562 18 8 11 69455855 69469242 ENST00000227507.2 75 GRCh37 CCND1 amplification has been implicated in poorer prognosis in non-small cell lung cancer. Somatic 2016-11-07 18:54:46 UTC https://civicdb.org/links/evidence_items/1562 https://civicdb.org/links/variants/18 https://civicdb.org/links/genes/8 false CCND1 595 Overexpression Mantle Cell Lymphoma 0050746 Palbociclib Predictive Supports D Sensitivity/Response In Mantle Cell Lymphoma (MCL), t(11:14)-induced overexpression of cyclin D1 was targeted by CDK4/6 inhibitor Palbociclib (PD0332991). Palbociclib caused Rb dephosphorylation in MCL cell lines and patient derived tumor cells. MCL cell lines overexpressing cyclin D1 showed growth inhibition with Palbociclib. The VAL DLBCL cell line was used as control to verify cyclin D1 overexpression but was not used as a control in Palbociclib inhibitor experiments. Instead, the investigators report that other publications report cell lines without cyclin D1 overexpression had higher IC50 values for palbociclib, suggesting overexpresssed cyclin D1 targetability in MCL. 16690963 PubMed Marzec et al., 2006, Blood 1 accepted 1563 20 8 11 69455855 69469242 ENST00000227507.2 75 GRCh37 Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK's) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, and range from genomic amplification to promoter methylation changes. While Cyclin D2 has only been found to be significantly misregulated in glioma, Cyclin D1 in particular seems to be a pan-cancer actor. Cyclin D misregulation has been shown to lead to poorer outcomes in a number of studies, and currently there are no FDA-approved targeted therapies. N/A 2020-10-22 01:51:39 UTC https://civicdb.org/links/evidence_items/1563 https://civicdb.org/links/variants/20 https://civicdb.org/links/genes/8 false ATM 472 Underexpression Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome 43 B-CLL patients with LoH or reduced protein levels (<50% normal expression, radioimmunoassay, western blot) of ATM were found to have significantly shorter overall survival (35.6 vs. 97.3 months; P=0.003) when compared to 108 patients with normal expression levels. 9788599 PubMed Starostik et al., 1998, Cancer Res. 3 accepted 1564 179 69 11 108093559 108239826 ENST00000278616.4 75 GRCh37 N/A 2016-08-17 20:43:35 UTC https://civicdb.org/links/evidence_items/1564 https://civicdb.org/links/variants/179 https://civicdb.org/links/genes/69 false MET 4233 Amplification Glioblastoma 3068 Crizotinib Predictive Supports C Sensitivity/Response A 62 year old female was diagnosed with glioblastoma (GBM) WHO grade 4. Treatment included radiation, temozolomide and cediranib. MET amplification was found by FISH, and ALK and MET inhibitor crizotinib treatment was started. A 40% reduction in size of contrast enhancing lesion was seen. After 6 months, progressive disease was seen and crizotinib withdrawn. The authors state this is a first report of response to prospective MET targeted therapy in GBM. 22162573 PubMed Chi et al., 2012, J. Clin. Oncol. 3 accepted 1565 270 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 Somatic 2016-08-04 15:17:11 UTC https://civicdb.org/links/evidence_items/1565 https://civicdb.org/links/variants/270 https://civicdb.org/links/genes/52 false MET 4233 Amplification Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports D Sensitivity/Response 2 MET amplified NSCLC cell lines (EBC-1 and H1993), as well as 2 EGFR mutant and 2 MET and EGFR wild type cell lines were treated with ALK and MET inhibitor crizotinib, and the MET amplified cells had IC50 100 fold lower than the non MET amplified cell lines. Both crizotinib treatment and siRNA against MET increased apoptotic markers in MET amplified cells but not controls, indicating that crizotinib targeting of amplified MET was inducing the apoptotic effects. Tumors caused by MET amplified EBC-1 cells injected into mice were significantly inhibited with crizotinib treatment, while tumors from non-MET amplified cells showed no substantial effect. 21716144 PubMed Tanizaki et al., 2011, J Thorac Oncol 4 accepted 1566 270 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 Somatic 2016-11-05 21:56:33 UTC https://civicdb.org/links/evidence_items/1566 https://civicdb.org/links/variants/270 https://civicdb.org/links/genes/52 false JAK1 3716 Q503* Skin Melanoma 8923 Pembrolizumab Predictive Supports C Resistance Paired tumor samples were analyzed from four patients with metastatic melanoma and initial response with a subsequent relapse under pembrolizumab (PD-1 checkpoint inhibitor) therapy. Baseline biopsies were obtained before therapy initiation with pembrolizumab (before prior vemurafenib treatment in patient 1). A JAK1 Q503* mutation was observed at the time of relapse in patient 1. This mutation was one of 3 new homozygous mutations in this patient (53 new mutations total) and the tumor was described to be genetically similar to the pre-treatment tumor. CRIPR-Cas9 mediated modelling of the JAK1 mutation in a melanoma cell line led to a loss of response to interferon alpha, beta and gamma. 27433843 PubMed Zaretsky et al., 2016, N. Engl. J. Med. 4 accepted 1567 614 3090 1 65321333 65321333 G A ENST00000342505.4 75 GRCh37 Somatic 2016-11-05 21:27:04 UTC https://civicdb.org/links/evidence_items/1567 https://civicdb.org/links/variants/614 https://civicdb.org/links/genes/3090 false JAK2 3717 c.1641+1dup Skin Melanoma 8923 Pembrolizumab Predictive Supports C Resistance Paired tumor samples were analyzed from four patients with metastatic melanoma and initial response with a subsequent relapse under pembrolizumab (PD-1 checkpoint inhibitor) therapy. Baseline biopsies were obtained before therapy initiation with pembrolizumab. A JAK2 F547 splice site mutation was observed at the time of relapse in patient 2. RNA sequencing revealed an in-frame stop codon after exon 12. The JAK2 mutation was the only homozygous mutation (allele frequency >85%) of 76 new nonsynonymous mutations in patient 2. Cell line modelling of baseline and relapse JAK2 mutational status revealed a loss of response to interferon gamma and loss of JAK2 protein. This loss of response was also modeled in another cell line. 27433843 PubMed Zaretsky et al., 2016, N. Engl. J. Med. 4 accepted 1568 615 28 9 5070053 5070054 G ENST00000381652.3 75 GRCh37 Somatic 2016-11-05 21:31:29 UTC https://civicdb.org/links/evidence_items/1568 https://civicdb.org/links/variants/615 https://civicdb.org/links/genes/28 false B2M 567 S14FS Skin Melanoma 8923 Pembrolizumab Predictive Supports C Resistance Paired tumor samples were analyzed from four patients with metastatic melanoma and initial response with a subsequent relapse under pembrolizumab (PD-1 checkpoint inhibitor) therapy. Baseline biopsies were obtained before therapy initiation with pembrolizumab. A B2M frame-shift deletion in exon 1 was identified as the only new homozygous mutation among 24 new relapse-specific mutations. Immunohistochemistry revealed loss of MHC1 outer-membrane localization. 27433843 PubMed Zaretsky et al., 2016, N. Engl. J. Med. 3 accepted 1569 616 537 15 45003786 45003789 TCTT ENST00000558401.1 75 GRCh37 Somatic 2016-11-05 22:04:01 UTC https://civicdb.org/links/evidence_items/1569 https://civicdb.org/links/variants/616 https://civicdb.org/links/genes/537 false BRAF 673 PPFIBP2::BRAF Skin Melanoma 8923 Trametinib Predictive Supports C Sensitivity/Response Case report of a 47year old female patient with metastatic melanoma (BRAF, NRAS, KIT negative). A PPFIBP2-BRAF fusion was identified from DNA from a brain metastasis (inton 3 of PPFIBP2 fused to intron 10 of BRAF). Trametinib was introduced and anemia and ECOG status improved. Imaging revealed a 90% decrease in extracranial and 19% decrease in intracranial metastases with no new metastases and no progressing sites at 6 weeks. Trametinib was stopped and pembrolizumab introduced at this time. Progressive disease was noted after 5 cycles of pembrolizumab but re-introduction of trametinib did not show an effect. 26072686 PubMed Menzies et al., 2015, Pigment Cell Melanoma Res 2 accepted 1570 617 5 11 7535001 7586998 ENST00000299492.4 7 140434279 140481493 ENST00000288602.6 75 GRCh37 Somatic 2016-11-04 18:35:03 UTC https://civicdb.org/links/evidence_items/1570 https://civicdb.org/links/variants/617 https://civicdb.org/links/genes/5 false BRAF 673 KIAA1549::BRAF Skin Melanoma 8923 Trametinib Predictive Supports C Sensitivity/Response A 65 yr old male patient with metastatic acral lentiginous melanoma (BRAF, NRAS, KIT negative) was found to harbor a KIAA1549-BRAF (intron 15-intron 8) fusion in a subcutaneous metastasis sample after disease progression. Trametinib was started and fatigue and ECOG status improved but imaging revealed slight disease progression after 2 weeks (15 sites measurable, 9 stable, 6 progressive). No new metastases were identified. The patient was switched to pembrolizumab and major disease progression was noted. 26072686 PubMed Menzies et al., 2015, Pigment Cell Melanoma Res 1 accepted 1571 618 5 7 138545885 138666064 ENST00000440172.1 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2016-11-03 19:19:12 UTC https://civicdb.org/links/evidence_items/1571 https://civicdb.org/links/variants/618 https://civicdb.org/links/genes/5 false EGFR 1956 Expression Colorectal Cancer 9256 Cetuximab Predictive Supports B Sensitivity/Response Patients with refractory colorectal cancer expressing immunohistochemically detectable EGFR were randomly assigned to receive treatment with cetuximab (n=287) or receive supportive care alone (n=285). Patients receiving cetuximab had increased overall survival (HR=0.77, 95%CI 0.64-0.92; p=0.005), increased progression-free survival (HR=0.68, 95%CI 0.57-0.80; p<0.001), and improved quality of life at 4 months measured by survey on physical deterioration (-5.9 vs -12.5; p=0.03) and global health status (-3.6 vs. -15.2; p<0.001). 18003960 PubMed Jonker et al., 2007, N. Engl. J. Med. NCT00079066 4 accepted 1572 354 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 N/A 2016-08-12 13:18:58 UTC https://civicdb.org/links/evidence_items/1572 https://civicdb.org/links/variants/354 https://civicdb.org/links/genes/19 false BRAF 673 V600 Lung Non-small Cell Carcinoma 3908 Vemurafenib Predictive Supports B Sensitivity/Response Patients with BRAF-V600 mutated cancers were identified (n=122) and clinical response to vemurafenib was evaluated. Of the 20 patients with non-small-cell-lung cancer (17 with BRAF V600E, one with BRAF V600G and one with BRAF V600 unknown status), 19 were evaluable and the response rate to vemurafenib was 42%, tumor regression was observed in 14/19 patients, progression-free survival was 7.3 months, and 12-month overall survival was 66%. 26287849 PubMed Hyman et al., 2015, N. Engl. J. Med. NCT01524978 3 accepted 1574 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2016-08-22 22:35:27 UTC https://civicdb.org/links/evidence_items/1574 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false BRAF 673 V600 Langerhans-cell Histiocytosis 2571 Vemurafenib Predictive Supports B Sensitivity/Response Patients with BRAF-V600 mutated cancers were identified (n=122) and clinical response to vemurafenib was evaluated. Of the 14 patients with Langerhans’-cell histiocytosis, 43% of patients had a response to vemurafenib (1 complete and 5 partial responses), disease regression was observed in 12/14 patients, all patients detailed improvement in disease-related symptoms, 0 patients had progressive disease during treatment, 12-month progression free survival was 91%, and overall survival rate was 100%. Among all 18 patients with Erdheim-Chester disease or Langerhans histiocytosis, 94% had BRAF V600E mutations and the remaining 6 percent (1 patient) had an unknown V600 mutation. 26287849 PubMed Hyman et al., 2015, N. Engl. J. Med. NCT01524978 3 accepted 1575 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2016-08-22 22:35:54 UTC https://civicdb.org/links/evidence_items/1575 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false BRAF 673 V600 Colorectal Cancer 9256 Vemurafenib Predictive Supports B Resistance Patients with BRAF-V600 mutated cancers were identified (n=122) and clinical response to vemurafenib was evaluated. Of the 10 patients with colorectal cancer (80% BRAF V600E, 20% V600 unknown status), no responses were observed and overall survival was 9.3 months with a median progression-free survival of 4.5 months. 26287849 PubMed Hyman et al., 2015, N. Engl. J. Med. NCT01524978 3 accepted 1576 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2016-08-22 22:33:26 UTC https://civicdb.org/links/evidence_items/1576 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports B Sensitivity/Response A phase-3 clinical trial evaluated 347 patients with ALK-positive lung cancer. The study compared crizotinib treatment (n=173) with chemotherapy treatment of either pemetrexed or docetaxel (n=174). In the crizotinib arm, the response rate was significantly higher (65% vs 20%; P<0.001), the progression-free survival was increased (7.7 months vs. 3.0 months; HR=0.49, 95%CI:14 months-26 months; p<0.001), however, there was no significant improvement in overall survival (HR=1.02; 95%CI:0.68-1.54; P=0.54). Of the patients on crizotinib treatment, global quality of life was improved relative to baseline when compared to chemotherapy patients (+5 mean change, -5 mean change; P<0.001). 26466010 PubMed 2015, N Engl J Med 3 accepted 1577 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-10-20 06:25:20 UTC https://civicdb.org/links/evidence_items/1577 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false CD274 29126 Expression Merkel Cell Carcinoma 3965 Pembrolizumab Predictive Does Not Support B Sensitivity/Response Patients with Merkel Cell Carcinoma (n=26) were enrolled to receive pembrolizumab. Of these patients, 25 were evaluated for response rate to pembrolizumab and PD-L1 (CD274) expression. The response rate to pembrolizumab was 56% (95%CI: 35-76%), however, there was no correlation between PD-L1 expression (cutoff >1%) on tumor cells or on infiltrating immune cells and clinical response to pembrolizumab (P=0.61). 27093365 PubMed Nghiem et al., 2016, N. Engl. J. Med. NCT02267603 2 accepted 1578 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2020-10-21 04:31:18 UTC https://civicdb.org/links/evidence_items/1578 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false BRAF 673 V600E Hairy Cell Leukemia 285 Vemurafenib Predictive Supports B Sensitivity/Response Two clinical trials evaluated the effects of vemurafenib in 54 patients with BRAF (V600E) positive hairy-cell leukemia. The overall response rate was 98% with 19/54 having a complete response and 34/54 having a partial response. In the Italian study (n=25), the median relapse-free survival was 9 months and in the U.S. study (n=24), rate of progression-free survival was 73% with overall survival rate of 91%. 26352686 PubMed Tiacci et al., 2015, N. Engl. J. Med. NCT01711632 2 accepted 1579 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-08-15 19:25:01 UTC https://civicdb.org/links/evidence_items/1579 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false KRAS 3845 G12D Hairy Cell Leukemia 285 Vemurafenib Predictive Supports C Resistance One patient enrolled in a clinical study to evaluate vemurafenib treatment of BRAF V600E mutant hairy-cell leukemia developed resistance to vemurafenib retreatment. 300-gene targeted sequencing of the patient’s genome revealed activating subclonal KRAS mutations (KRAS G12D, 15.2% allele frequency; KRAS K117N, 1.2%), as well as a RUNX1 A55E mutation (5.9%) that had not been seen prior to vemurafenib treatment or at remission. BRAF V600E allele frequency was detectable (2.4%) at the time of remission but dramatically increased at relapse (64.9%). 26352686 PubMed Tiacci et al., 2015, N. Engl. J. Med. NCT01711632 2 accepted 1580 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2016-09-04 22:34:24 UTC https://civicdb.org/links/evidence_items/1580 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false MET 4233 Overexpression Skin Melanoma 8923 Vemurafenib Predictive Supports B Resistance Whole exome sequencing, transcriptome and methylome alterations in 48 melanoma samples with acquired resistance to BRAFi +/- MEKi therapy compared to patient-matched baseline melanoma tissues were analyzed. 39% of resistant melanomas were not accounted for by any validated mutational mechanism. c-MET was overexpressed in 21 of 48 (44%) resistant samples. Methylome analysis revealed three CpG clusters (C1–3) with differential methylation to be negatively correlated with differential c-MET mRNA expression. In nearly all (90%) pairwise comparisons of tumors and cell lines, differential c-MET mRNA expression could be accounted for by at least one differential CpG cluster methylation (Δβ ≥ 10% and FDR adjusted p ≤ 0.05). In contrast, only 48% displayed a concordant differential expression pattern of at least one c-MET transcription factor. In an independent study, c-MET was overexpressed in 8 of 35 (23%) MAPKi-resistant tumors from 7 of 26 (27%) patients. In two human BRAF V600E mutant cell lines, BRAFi treatment led to progressive methylation-expression changes akin to observations across MAPKi-sensitive versus resistant tumors. 26359985 PubMed Hugo et al., 2015, Cell 4 accepted 1581 621 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 N/A 2016-08-18 11:15:43 UTC https://civicdb.org/links/evidence_items/1581 https://civicdb.org/links/variants/621 https://civicdb.org/links/genes/52 false MET 4233 Overexpression Uveal Melanoma 6039 Crizotinib Predictive Supports D Sensitivity/Response c-MET and ligand HGF were expressed by 6 uveal melanoma cell lines in-vitro. GNA-mutant cell lines (n=3) showed stronger expression of ligand and receptor as well as more receptor phosphorylation. SiRNA mediated MET-knockdown reduced cell migration but not cell growth. Crizotinib treatment led to a decrease in cell growth and migration. At 25 nmol/L of crizotinib, only the migration of G-protein mutant cells lines and not G-protein wild type cell lines was decreased. Crizotinib did not lead to a reduction in tumor volume of two cell lines in vivo but reduced the formation of macrometastases (luciferase activity, p=0.03). 24140933 PubMed Surriga et al., 2013, Mol. Cancer Ther. 1 accepted 1583 621 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 N/A 2016-11-11 17:08:49 UTC https://civicdb.org/links/evidence_items/1583 https://civicdb.org/links/variants/621 https://civicdb.org/links/genes/52 false MET 4233 Overexpression Skin Melanoma 8923 Vemurafenib Predictive Does Not Support B Resistance FFPE tumours from patients enrolled in the BRIM2 (n = 59) and BRIM3 (n = 150) trials of vemurafenib in advanced BRAF mutant (V600E/K) melanoma were analyzed for MET expression (IHC). Pretreatment MET expression was frequent at the ≥1 + cutoff (BRIM3, 31%; BRIM2, 49%), but relatively infrequent at the ≥2 + cutoff (BRIM3, 9%; BRIM2, 19%). Retrospective subset analyses showed that, irrespective of the cutoff used or the treatment arm, MET expression did not show prognostic significance, in terms of objective response rate, progression-free survival, or overall survival. 23802768 PubMed Jubb et al., 2013, Histopathology 3 accepted 1584 621 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 N/A 2016-08-17 18:51:06 UTC https://civicdb.org/links/evidence_items/1584 https://civicdb.org/links/variants/621 https://civicdb.org/links/genes/52 false DNMT3A 1788 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome In AML patients aged <60years, presence of a DNMT3A mutation associated with inferior CR rate (HR, 0.54; P=.05) and shorter OS (HR, 1.84; P<.001) in multivariate analyses. Mutated DNMT3A associated with shorter RFS (HR 1.38; P=.034) irrespective of patient age. 27288520 PubMed Metzeler et al., 2016, Blood 4 accepted 1585 189 18 2 25455845 25565459 ENST00000264709.3 75 GRCh37 DNMT3A mutations occur in a variety of myeloid malignancies. These mutations are associated with adverse prognosis in acute myeloid leukemia (AML), particularly in the context of NPM1 and FLT3-ITD mutations, which often co-occur. Early results indicate AML patients with DNMT3A mutations may respond better to decitabine than those with wild-type. Shorter survival has been indicated in patients with T-cell acute lymphoblastic leukemia and myelodysplastic syndrome, however, larger cohorts are required to verify this finding. DNMT3A mutations have been suggested as a pre-leukemic lesion and found in older individuals with clonal hematopoiesis but no overt malignancy. Somatic 2016-08-02 15:38:57 UTC https://civicdb.org/links/evidence_items/1585 https://civicdb.org/links/variants/189 https://civicdb.org/links/genes/18 false DNMT3A 1788 Mutation Acute Myeloid Leukemia 9119 Prognostic Supports B Poor Outcome DNMT3A mutations associate with adverse overall survival in acute myeloid leukemia patients if they occur in the context of mutated NPM1 and FLT3-ITD (NPM1-FLT3ITD-DNMT3A phenotype), and in the context of IDH2 codon R140 mutations. 27276561 PubMed Papaemmanuil et al., 2016, N. Engl. J. Med. NCT00146120 4 accepted 1586 189 18 2 25455845 25565459 ENST00000264709.3 75 GRCh37 DNMT3A mutations occur in a variety of myeloid malignancies. These mutations are associated with adverse prognosis in acute myeloid leukemia (AML), particularly in the context of NPM1 and FLT3-ITD mutations, which often co-occur. Early results indicate AML patients with DNMT3A mutations may respond better to decitabine than those with wild-type. Shorter survival has been indicated in patients with T-cell acute lymphoblastic leukemia and myelodysplastic syndrome, however, larger cohorts are required to verify this finding. DNMT3A mutations have been suggested as a pre-leukemic lesion and found in older individuals with clonal hematopoiesis but no overt malignancy. Somatic 2016-08-15 15:30:34 UTC https://civicdb.org/links/evidence_items/1586 https://civicdb.org/links/variants/189 https://civicdb.org/links/genes/18 false DNMT3A 1788 Mutation Acute Myeloid Leukemia 9119 Decitabine Predictive Supports B Sensitivity/Response Among 46 AML patients treated with decitabine, the response rate was 75% (6/8) among DNMT3A mutated and 34% (13/38) among DNMT3A wild-type patients (P=.008) 22124213 PubMed Metzeler et al., 2012, Leukemia 3 accepted 1587 189 18 2 25455845 25565459 ENST00000264709.3 75 GRCh37 DNMT3A mutations occur in a variety of myeloid malignancies. These mutations are associated with adverse prognosis in acute myeloid leukemia (AML), particularly in the context of NPM1 and FLT3-ITD mutations, which often co-occur. Early results indicate AML patients with DNMT3A mutations may respond better to decitabine than those with wild-type. Shorter survival has been indicated in patients with T-cell acute lymphoblastic leukemia and myelodysplastic syndrome, however, larger cohorts are required to verify this finding. DNMT3A mutations have been suggested as a pre-leukemic lesion and found in older individuals with clonal hematopoiesis but no overt malignancy. Somatic 2016-08-02 15:38:42 UTC https://civicdb.org/links/evidence_items/1587 https://civicdb.org/links/variants/189 https://civicdb.org/links/genes/18 false MET 4233 Amplification Colorectal Cancer 9256 Crizotinib,Vemurafenib Combination Predictive Supports C Sensitivity/Response Case report of a patient with BRAF V600E mutant metastatic colorectal cancer. Combined EGFR and BRAF inhibition (panitumumab and vemurafenib) showed an initial partial response for 4 months. Re-biopsy at the time of progression showed a MET amplification and overexpression (IHC, ISH) but no secondary mutations in candidate resistance genes (EGFR, KRAS, NRAS, MAP2K1). MET amplification was also present in a subset of tumor cells in the pretreatment sample. MET amplification was also identified in 3/17 (18%) chemonaive BRAF V600E colorectal cancer tumor tissues. Overexpression of MET in a BRAF mutant CRC cell line (WiDr) confered resistance to combined vemurafenib and panitumumab. The addition of crizotinib to this combination restored sensitivity in vitro. The patient was started on combined vemurafenib and crizotinib in January 2016 and had a metabolic, clinical and tumor marker response that was ongoing at the time of publication (06/16) without significant toxicity. 27325282 PubMed Pietrantonio et al., 2016, Cancer Discov 4 accepted 1588 270 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 N/A 2016-08-04 15:16:55 UTC https://civicdb.org/links/evidence_items/1588 https://civicdb.org/links/variants/270 https://civicdb.org/links/genes/52 false BRAF 673 V600E Colorectal Cancer 9256 Panitumumab,Vemurafenib Combination Predictive Supports C Sensitivity/Response Case report of a patient with BRAF V600E mutant metastatic colorectal cancer. Combined EGFR and BRAF inhibition (panitumumab and vemurafenib) showed an initial partial response for 4 months with subsequent disease progression. 27325282 PubMed Pietrantonio et al., 2016, Cancer Discov 2 accepted 1589 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-08-04 14:55:55 UTC https://civicdb.org/links/evidence_items/1589 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false POT1 25913 MUTATION Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome In previously untreated patients with chronic lymphocytic leukemia, POT1 mutations (N=13) were associated with shorter overall survival than wildtype POT1 (N=148) in univariate and multivariate analysis (HR, 4.0; 95% CI, 1.6-10.1; P = .003) independent of IGHV mutation status, Binet stage, and serum beta-2-microglobulin. 27226433 PubMed Herling et al., 2016, Blood 3 accepted 1590 623 9935 7 124462440 124570035 ENST00000357628.3 75 GRCh37 Somatic 2016-09-11 13:04:03 UTC https://civicdb.org/links/evidence_items/1590 https://civicdb.org/links/variants/623 https://civicdb.org/links/genes/9935 false BRAF 673 V600E Thyroid Gland Papillary Carcinoma 3969 Vemurafenib Predictive Supports B Sensitivity/Response Open-label non-randomised phase 2 trial in patients with recurrent or metastatic BRAF V600E mutant papillary thyroid cancer refractory to radioactive iodine. Patients had (cohort 2) or had not (cohort 1) previously been treated with VEGFR inhibitors. 51 patients were enrolled (26 cohort 1, 25 cohort 2). In cohort 1, partial response was achieved in ten (38.5%) patients. Nine patients achieved stable disease for at least 6 months (35%). Median PFS was 18.2 months and median OS not reached after a median follow-up pf 18.8 months. In cohort 2, six patients (27.3%) achieved a partial response and another six patients achieved stable disease for at least six months. Median PFS was 8.9 months and median OS was 14.4. months. 27460442 PubMed Brose et al., 2016, Lancet Oncol. NCT01286753 3 accepted 1591 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-08-16 07:40:06 UTC https://civicdb.org/links/evidence_items/1591 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Osimertinib Predictive Supports A Sensitivity/Response Osimertinib has been approved for the treatment of EGFR T790M mutant NSCLC. 26729184 PubMed Greig, 2016, Drugs 5 accepted 1592 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2016-08-17 16:58:18 UTC https://civicdb.org/links/evidence_items/1592 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false MKI67 4288 EXPRESSION Breast Cancer 1612 Prognostic Supports B Poor Outcome A quantitative meta-analysis was performed to assess optimal IHC-calculated cutoff values for the prognostic use of proliferative biomarker Ki67 in breast cancer. The studies included ER positive and negative cases, and the MIB-1 antibody was used in the large majority of studies. 25 studies that employed multivariate analysis were used, and a hazard ratio of 2.05 for overall survival was obtained when Ki67 cutoff value was set at greater or equal to 25%. 26341751 PubMed Petrelli et al., 2015, Breast Cancer Res. Treat. 4 accepted 1593 624 3529 10 129894923 129924649 ENST00000368654.3 75 GRCh37 N/A 2016-08-17 18:48:03 UTC https://civicdb.org/links/evidence_items/1593 https://civicdb.org/links/variants/624 https://civicdb.org/links/genes/3529 false MKI67 4288 EXPRESSION Prostate Cancer 10283 Prognostic Supports B Poor Outcome 293 cases of clinically localized prostate cancer were analyzed on needle-biopsy FFPE tissue microarray, using the MIB-1 antibody against the Ki67 marker of proliferation. IHC staining was used to generate a Ki67 score, and cases were divided into 2 groups with Ki67 score greater or less than 10%. Primary endpoint was death due to prostate cancer. A hazard ratio for high Ki67 values of 3.42 was seen in univariate analysis, and Ki67 score also added significant predictive value in multivariate analysis, with a hazard ratio of 2.78. 23329234 PubMed Fisher et al., 2013, Br. J. Cancer 3 accepted 1594 624 3529 10 129894923 129924649 ENST00000368654.3 75 GRCh37 N/A 2016-08-17 18:48:09 UTC https://civicdb.org/links/evidence_items/1594 https://civicdb.org/links/variants/624 https://civicdb.org/links/genes/3529 false RB1 5925 Loss-of-function Glioblastoma 3068 Palbociclib Predictive Supports D Resistance A panel of 21 glioblastoma cell lines harboring various mutations was treated with palbociclib. 16 of the cell lines with intact Rb showed decreased proliferation (bromodeoxyuridine incorporation, BrdU flow cytometry) and growth arrest characteristic of senescence, while the 5 cell lines that did not show a palbociclib response had homozygous deletion of Rb. Rb positive and palbociclib responsive GBM cell line U87MG was treated with shRNA against Rb. shRb treated cells showed restoration of cell proliferation (BrdU incorporation) under palbociclib treatment, indicating resistance. 20354191 PubMed Michaud et al., 2010, Cancer Res. 3 accepted 1595 606 4795 13 48877911 49056122 ENST00000267163.4 75 GRCh37 Somatic 2016-08-23 06:58:47 UTC https://civicdb.org/links/evidence_items/1595 https://civicdb.org/links/variants/606 https://civicdb.org/links/genes/4795 false KRAS 3845 Mutation Pseudomyxoma Peritonei 3559 Prognostic Supports B Poor Outcome 40 patients with pseudomyxoma peritonei underwent panel sequencing after cytoreductive surgery and hypertermic intraperitoneal chemotherapy (HIPEC). KRAS mutations were found in 72% of samples and KRAS mutations were independently associated with PFS (p=0.012) after multivariate analysis. 27502722 PubMed Pietrantonio et al., 2016, Ann. Oncol. 3 accepted 1596 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-09-11 13:10:25 UTC https://civicdb.org/links/evidence_items/1596 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false RAD23B 5887 EXPRESSION Sarcoma 1115 Vorinostat Predictive Supports D Sensitivity/Response Western blot analyses were performed for HR23b (RAD23B) expression sarcoma cell lines after treatment with vorinostat, belinostat, mocetinostat and entinostat. All HDACi were able to regulate proliferation and apoptosis in vitro. Sensitivity to vorinostat correlated significantly with HR23b protein expression. IHC in 523 patient samples revealed high HR23b expression in 12.5% of sarcomas (among them malignant peripheral nerve sheath tumours, pleomorphic liposarcomas, leiomyosarcomas, dedifferentiated liposarcomas, synovial sarcomas and angiosarcomas) and 23.2% of GIST. 27499916 PubMed Angelika Ihle et al., 2016, J Pathol Clin Res 2 accepted 1597 625 4760 9 110045560 110094475 ENST00000358015.3 75 GRCh37 N/A 2016-11-11 17:17:35 UTC https://civicdb.org/links/evidence_items/1597 https://civicdb.org/links/variants/625 https://civicdb.org/links/genes/4760 false BRAF 673 V600 Colorectal Cancer 9256 Cetuximab,Vemurafenib Combination Predictive Does Not Support B Sensitivity/Response Patients with BRAF-V600 mutated cancers were identified (n=122) and subsequently underwent targeted therapy. 27 patients with colorectal cancer were treated with vemurafenib and cetuximab (N=24 with BRAF V600E mutation, N=3 with V600 unknown status). One response was observed; however, approximately half the patients had tumor regression that did not meet the standard criteria for a partial response. Median progression-free survival and overall survival for patients receiving combination therapy were 3.7 months (95% CI, 1.8 to 5.1) and 7.1 months (95% CI, 4.4 to not reached), respectively. Patients were heavily pretreated, with a median of two lines of previous therapy (range, one to six). 26287849 PubMed Hyman et al., 2015, N. Engl. J. Med. NCT01524978 2 accepted 1598 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2016-09-11 13:14:59 UTC https://civicdb.org/links/evidence_items/1598 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false CCND1 595 Amplification Ovarian Cancer 2394 Palbociclib Predictive Does Not Support D Sensitivity/Response A panel of 40 ovarian cancer cell lines with varied mutation profiles was assayed for sensitivity to the cdk4/6 inhibitor palbociclib (PD0332991) via measurement of IC50 values for inhibition of proliferation. Large variation in palbociclib sensitivity was observed and cell lines (N=40) were classified as above (resistant) or below (sensitive) the mean log of all IC50 values. 6/18 (33%) of the resistant lines and in only 1/22 (5%) of the sensitive lines (P = 0.017) had CCND1 copy number gain. Increased CCND1 expression was not correlated with sensitivity to palbociclib (p=0.671). 21278246 PubMed Konecny et al., 2011, Clin. Cancer Res. 3 accepted 1599 18 8 11 69455855 69469242 ENST00000227507.2 75 GRCh37 CCND1 amplification has been implicated in poorer prognosis in non-small cell lung cancer. Somatic 2016-11-07 18:53:50 UTC https://civicdb.org/links/evidence_items/1599 https://civicdb.org/links/variants/18 https://civicdb.org/links/genes/8 false PIK3CA 5290 Mutation Breast Cancer 1612 Phosphatidylinositide 3-Kinase Inhibitor,Ribociclib Combination Predictive Supports D Sensitivity/Response Three PI3K mutant breast cancer cell lines were rendered resistant to PI3K inhibitors (BYL719 or GDC-0941), and a panel of 42 inhibitor compounds was tested on the cells for ability to resensitize the cells to PI3K inhibition. The CDK4/6 inhibitor ribociclib (LEE011) acted synergistically with PI3K inhibitor to reduce viability in all three resistant cell lines. In a panel of 12 PIK3CA mutant and 10 wild type cell lines, synergistic effects between P110alpha inhibitor BYL719 and ribociclib were significantly stronger (weighted synergy score calculation, ANOVA, p=0.012) in PIK3CA mutant cells, indicating variant specific sensitization. Mouse xenografts of 4 different PIK3CA mutant breast cancer cells resistant to PI3K inhibitor showed stronger regression under dual PI3K inhibitor and ribociclib treatment than with either treatment alone. 25002028 PubMed Vora et al., 2014, Cancer Cell NCT01219699 4 accepted 1600 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-11-03 18:35:21 UTC https://civicdb.org/links/evidence_items/1600 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false RET 5979 CCDC6::RET Lung Non-small Cell Carcinoma 3908 Nintedanib Predictive Supports C Sensitivity/Response Case report of a 60-year old woman with lung adenocarcinoma. After negative testing for EGFR mutations and ALK translocations and failure of platinum-based chemotherapy she was enrolled on a nintedanib-docetaxel trial. Docetaxel was discontinued after 22 cycles because of edema and fatigue. A total of 48 treatment cycles (26 cycles of nintedanib alone) was administered over 33 months before documentation of disease progression in March 2013. Genomic testing revealed a CCDC6-RET fusion but no other actionable mutations (confirmed by FISH). 26787234 PubMed Takeda et al., 2016, Ann. Oncol. 2 accepted 1601 626 42 Somatic 2016-11-06 00:34:02 UTC https://civicdb.org/links/evidence_items/1601 https://civicdb.org/links/variants/626 https://civicdb.org/links/genes/42 false MAP2K1 5604 C121S Melanoma 1909 Vemurafenib Predictive Supports C Resistance A patient with BRAF-mutant melanoma relapsed after treatment with PLX4032 (vemurafenib). The MAP2K1 C121S mutation was identified as a relapse-specific variant and was undetectable in the pre-treatment tumor. In vitro experiments showed that the C121S mutation increased kinase activity and conferred resistance to PLX4032. 21383288 PubMed Wagle et al., 2011, J. Clin. Oncol. 4 accepted 1602 627 31 15 66729154 66729154 G C ENST00000307102.5 75 GRCh37 Somatic 2016-08-19 18:25:06 UTC https://civicdb.org/links/evidence_items/1602 https://civicdb.org/links/variants/627 https://civicdb.org/links/genes/31 false FGFR3 2261 S249C Transitional Cell Carcinoma 2671 Pazopanib Predictive Supports C Sensitivity/Response Case report of a 67 year old woman with high-grade papillary urothelial carcinoma. The patient underwent chemotherapy and palliative cystectomy followed by tumor progression and pulmonary lesion enlargement. Genomic profiling of the cystectomy specimen identified FGFR3, CCND1 and FGF19 amplification as well as an FGFR3 S249C mutation (allele frequency 58%). Pazopanib was initiated on the basis of these findings and a partial response was achieved for >6 months. 25766722 PubMed Palma et al., 2015, Eur. Urol. 2 accepted 1603 628 23 4 1803568 1803568 C G ENST00000340107.4 75 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. Somatic 2020-11-20 15:48:06 UTC https://civicdb.org/links/evidence_items/1603 https://civicdb.org/links/variants/628 https://civicdb.org/links/genes/23 false FGFR1 2260 Amplification Breast Cancer 1612 Dovitinib Predictive Supports B Sensitivity/Response Dovitinib was evaluated in-vitro, in xenograft and in a phase 2 study. Dovitinib inhibited proliferation in one FGFR1- and one FGFR2-amplified breast cancer cell lines at higher IC50 values than in 11 nonamplified cell lines. Dovitinib inhibited tumor growth and caused regression in both a FGFR1- and FGFR2-amplified xenograft model. 81 patients were enrolled in the trial and treated with dovitinib. Unconfirmed response or stable disease >6 months was observed in 25% of FGFR1-amplified/HR-positive vs. 3% FGFR1-nonamplified/HR-positive breast cancer patientes. When FGF3 and FGFR2 amplifications were also assessed, a combined FGF-pathway amplified patient group had a higher mean reduction in target lesion size than patients with FGF-non-amplified tumors. 23658459 PubMed André et al., 2013, Clin. Cancer Res. 2 accepted 1604 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). N/A 2016-09-11 13:26:17 UTC https://civicdb.org/links/evidence_items/1604 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false FGFR2 2263 Amplification Breast Cancer 1612 Dovitinib Predictive Supports B Sensitivity/Response Dovitinib was evaluated in-vitro, in xenograft and in a phase 2 study. Dovitinib inhibited proliferation in one FGFR1- and one FGFR2-amplified breast cancer cell lines at higher IC50 values than in 11 nonamplified cell lines. Dovitinib inhibited tumor growth and caused regression in both a FGFR1- and FGFR2-amplified xenograft model. 81 patients were enrolled in the trial and treated with dovitinib. 2 patients were reported to harbor FGFR2 amplifications and both had a reduction in tumor size of 18.5 and 28.2%, respectively. When FGFR1, FGF3 and FGFR2 amplifications were combined, a combined FGF-pathway amplified patient group had a higher mean reduction in target lesion size than patients with FGF-non-amplified tumors. 23658459 PubMed André et al., 2013, Clin. Cancer Res. 2 accepted 1605 629 22 10 123239371 123357917 ENST00000457416.2 75 GRCh37 N/A 2016-09-11 13:26:33 UTC https://civicdb.org/links/evidence_items/1605 https://civicdb.org/links/variants/629 https://civicdb.org/links/genes/22 false FGF3 2248 Amplification Breast Cancer 1612 Dovitinib Predictive Supports B Sensitivity/Response 81 patients were enrolled in a clinical trial with the FGFR inhibitor dovitinib. Four of these patients had FGF3 amplifications (qPCR) and showed tumor reductions of 100%, 30.8%, 23.0%, and 7.5%, respectively. 3 of these 4 patients also had FGFR1 amplifications (≥6 copies by qPCR) and the fourth presented with FGFR1-gene gain (3.4 copies of FGFR1 by qPCR and SISH negative). 23658459 PubMed André et al., 2013, Clin. Cancer Res. 2 accepted 1606 630 1873 11 69624992 69633792 ENST00000334134.2 75 GRCh37 N/A 2016-09-11 13:28:59 UTC https://civicdb.org/links/evidence_items/1606 https://civicdb.org/links/variants/630 https://civicdb.org/links/genes/1873 false PIK3CA 5290 Mutation Breast Cancer 1612 Palbociclib,Phosphatidylinositide 3-Kinase Inhibitor Combination Predictive Supports D Sensitivity/Response Three PIK3CA mutant breast cancer cell lines were rendered resistant to PI3K inhibitors (BYL719 or GDC-0941) by chronic exposure. Co-treatment of all three cell lines with PI3K inhibitor and CDK4/6 inhibitor palbociclib resulted in synergistic reductions in cell viability which were not seen with treatment of either compound alone, and resulted in similar suppression to viability as seen in the respective PI3K inhibitor sensitive parental cell lines. 25002028 PubMed Vora et al., 2014, Cancer Cell NCT01219699 3 accepted 1607 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-08-17 14:42:02 UTC https://civicdb.org/links/evidence_items/1607 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false VHL 7428 R200W (c.598C>T) Chuvash Polycythemia 0060474 Polycythemia Ruxolitinib Predictive Supports C Sensitivity/Response Homozygous VHL R200W mutations result in a rare congenital polycythemia known as Chuvash polycythemia. Treatment of 3 patients with this disease with the JAK1/2 inhibitor ruxolitinib led to symptomatic and hematologic improvements in all patients through 21-78 weeks of treatment. 27518686 PubMed Zhou et al., 2016, N. Engl. J. Med. 4 accepted 1608 631 58 3 10191605 10191605 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/1608 https://civicdb.org/links/variants/631 https://civicdb.org/links/genes/58 false RB1 5925 PHOSPHORYLATION Breast Cancer 1612 Alpelisib Predictive Supports B Resistance The p110alpha-specific PI3K inhibitor BYL719 (Alpelisib) was used on a panel of five PI3K inhibitor sensitive and five resistant breast cancer cell lines. Sensitive cells (IC50<400nM) showed reduced phospho-Rb (p-Rb) western blot levels in response to BYL719 treatment, while resistant cell lines (IC50>800nM) showed significantly less reduction in p-Rb after BYL719. Paired biopsies before and after treatment were taken from a set of eight patients classified as either responder or non-responder to BYL719. Responder samples showed significantly reduced p-Rb staining after treatment in comparison to non-responder biopsies. In biopsies taken from a group of three responders who progressed, p-Rb levels were increased after progression. 25002028 PubMed Vora et al., 2014, Cancer Cell NCT01219699 3 accepted 1609 632 4795 13 48877911 49056122 ENST00000267163.4 75 GRCh37 N/A 2019-08-29 21:51:36 UTC https://civicdb.org/links/evidence_items/1609 https://civicdb.org/links/variants/632 https://civicdb.org/links/genes/4795 false PIK3CA 5290 Mutation Breast Cancer 1612 MTOR Kinase Inhibitor PP242,Everolimus Substitutes Predictive Supports D Sensitivity/Response A panel of 31 breast cancer cell lines was tested for sensitivity to mTORC1 inhibitor everolimus and mTORC1/mTORC2 inhibitor PP242. Inhibitor concentrations for 50% survival fraction (SF50) were measured and SF50 less than one micro molar was considered sensitive. PIK3CA mutant cell lines were significantly more sensitive to both everolimus and PP242 than PIK3CA wild type cell lines. Apoptotic indicators and cell cycle analysis indicated that the mTOR inhibitors induced G1 arrest instead of apoptosis in the cell lines. 21358673 PubMed Weigelt et al., 2011, Oncogene 3 accepted 1610 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-11-11 17:32:35 UTC https://civicdb.org/links/evidence_items/1610 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PTEN 5728 Loss Breast Cancer 1612 Everolimus,MTOR Kinase Inhibitor PP242 Substitutes Predictive Does Not Support D Sensitivity/Response In a panel of 31 breast cancer cell lines, 11 had loss of PTEN function. Cells were tested for sensitivity to mTORC1 inhibitor everolimus and mTORC1/2 inhibitor PP242, and no significant correlation was found between PTEN status and sensitivity to mTORC inhibition. 21358673 PubMed Weigelt et al., 2011, Oncogene 3 accepted 1611 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-11-11 17:40:16 UTC https://civicdb.org/links/evidence_items/1611 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PIK3R1 5295 Mutation Breast Cancer 1612 MTOR Kinase Inhibitor PP242 Predictive Supports D Sensitivity/Response Sensitivity to mTORC1/2 inhibitor PP242 was assessed in a panel of breast cancer cell lines with various mutation backgrounds. PTEN and PIK3CA mutations were heavily represented in the panel. However, a PTEN and PIK3CA wild type cell line 'HS578T' was found to harbor a mutation in the PI3K regulatory protein PIK3R1. Like PIK3CA mutant cell lines, the PIK3R1 mutant HS578T line was also determined to be sensitive to PP242. Approximately 70% of PIK3CA wild type lines were not sensitive to PP242. This suggests that mutations in the PI3K holoenzyme may be targetable by mTORC1/2 inhibition. 21358673 PubMed Weigelt et al., 2011, Oncogene 2 accepted 1612 633 4289 5 67511548 67597649 ENST00000521381.1 75 GRCh37 Somatic 2016-11-08 02:38:34 UTC https://civicdb.org/links/evidence_items/1612 https://civicdb.org/links/variants/633 https://civicdb.org/links/genes/4289 false ERBB2 2064 Amplification Breast Cancer 1612 MTOR Kinase Inhibitor PP242 Predictive Supports D Sensitivity/Response In a panel of 31 breast cancer cell lines with varied mutation backgrounds, 10 cell lines harbored HER2 (ERBB2) amplification. Sensitivity to the mTORC1/2 inhibitor PP242 was assessed, and 8/10 HER2 positive cell lines were reported to be sensitive (IC50 < 1 micro molar PP242). 8/21 without HER2 amplification were reported as resistant (IC50 > 1 micro molar PP242). This pattern of HER2 positive cell sensitivity was not reported with the rapamycin analog mTORC1 inhibitor everolimus. 21358673 PubMed Weigelt et al., 2011, Oncogene 2 accepted 1613 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-11-12 03:13:54 UTC https://civicdb.org/links/evidence_items/1613 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false PTEN 5728 Loss Endometrial Cancer 1380 Temsirolimus Predictive Supports D Sensitivity/Response A panel of 24 endometroid endometrial cancer (EEC) cell lines was characterized for mutations and 18 cell lines were found to have mutations in PTEN or absence of expression. Cell lines were assessed for sensitivity to mTORC1 allosteric inhibitor temsirolimus, and it was reported that PTEN loss had significant association with temsirolimus sensitivity. . 23674493 PubMed Weigelt et al., 2013, Clin. Cancer Res. 3 accepted 1614 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-11-11 19:31:13 UTC https://civicdb.org/links/evidence_items/1614 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false CD274 29126 Expression Melanoma 1909 Nivolumab,Ipilimumab Combination Predictive Does Not Support B Sensitivity/Response A clinical trial of 86 patients evaluated concurrent (n=53) or sequential (n=33) treatment of ipilimumab (anti-CTLA4) and nivolumab (anti-PD1). In the concurrent regimen cohort, 65% of patients showed clinical activity with no correlation between PD-L1 expression and response (6 of 13 patients were PD-L1 positive versus 9 of 22 patients were PD-L1 negative). In the sequential regimen cohort, 20% of patients had an objective response with a potential correlation between PD-L1 expression and response (4 of 8 patients were PD-L1 positive versus 1 of 13 patients were PD-L1 negative). 23724867 PubMed Wolchok et al., 2013, N. Engl. J. Med. NCT01024231 3 accepted 1615 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2020-10-21 04:31:56 UTC https://civicdb.org/links/evidence_items/1615 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false PIK3CA 5290 Mutation Endometrial Cancer 1380 Pictilisib Predictive Supports D Sensitivity/Response A panel of 24 endometrioid endometrial cancer (EEC) cell lines was characterized for a set of mutations and sensitivity to pan PI3K class I inhibitor GDC-0941 (pictilisib) was assessed. EEC cell lines with PIK3CA mutations were significantly more sensitive to GDC-0941 (Fisher’s exact test, two-tailed, P=0.038). Some of the PIK3CA mutant cells contained PTEN and KRAS mutations, but in these cells, these mutations did not effect sensitivity. 23674493 PubMed Weigelt et al., 2013, Clin. Cancer Res. 3 accepted 1616 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-11-12 03:22:17 UTC https://civicdb.org/links/evidence_items/1616 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false STK11 6794 D194E Pancreatic Cancer 1793 Everolimus Predictive Supports C Sensitivity/Response Case study of a 46-year old male patient with Peutz-Jeghers Syndrome and pancreatic cancer. A germline STK11 D194E mutation was identified with LOH in the tumor sample. phospho-S6 ribosomal protein staining was observed in the tumor indicating mTOR pathway activation. Everolimus treatement led to partial response (but no change in phospho-S6 ribosomal protein staining) for 9 months. 21189378 PubMed Klümpen et al., 2011, J. Clin. Oncol. 2 accepted 1617 634 5534 19 1220489 1220489 C A ENST00000326873.7 75 GRCh37 Rare Germline 2016-11-06 00:48:13 UTC https://civicdb.org/links/evidence_items/1617 https://civicdb.org/links/variants/634 https://civicdb.org/links/genes/5534 false STK11 6794 Loss Peutz-Jeghers Syndrome 3852 Sirolimus Predictive Supports D Sensitivity/Response Preclinical study in a mouse model of Peutz-Jeghers syndrome. Heterozygous Lkb1 (STK11) knockout mice were generated and treated with rapamycin after the onset of polyposis at 9 months of age. Rapamycin treatment significantly suppressed polyposis (p=0.017) and pS6 staining (IHC, p=0.011). 18281551 PubMed Wei et al., 2008, Clin. Cancer Res. 1 accepted 1618 485 5534 19 1205740 1228428 ENST00000326873.7 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/1618 https://civicdb.org/links/variants/485 https://civicdb.org/links/genes/5534 false STK11 6794 Loss Peutz-Jeghers Syndrome 3852 Sirolimus Predictive Supports D Sensitivity/Response Treatment of mice with a heterozygous loss of Lkb1 (STK11) with rapamycin led to reduction in polyp size (p < 0.0001) and number of polyps (p=0.00022). pS6 staining was also reduced after rapamycin treatment. Rapamycin treatment abolished FDG-PET signal on imaging. 19541609 PubMed Shackelford et al., 2009, Proc. Natl. Acad. Sci. U.S.A. 1 accepted 1619 485 5534 19 1205740 1228428 ENST00000326873.7 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/1619 https://civicdb.org/links/variants/485 https://civicdb.org/links/genes/5534 false STK11 6794 Loss Lung Non-small Cell Carcinoma 3908 Everolimus,Sirolimus Substitutes Predictive Does Not Support D Sensitivity/Response Preclinical study in 5 NSCLC cell lines. Two LKB1 (STK11) mutant cell lines had higher basal levels of mTOR activity (pS6K and p4EBP1 levels) but were not more sensitive to mTOR inhibitors (everolimus or rapamycin) than two wild type cell lines. Knockdown of LKB1 in one additional cell line did not lead to an increase in sensitivity to mTOR inhibitors. 26027660 PubMed Xiao et al., 2015, Acta Pharmacol. Sin. 3 accepted 1620 485 5534 19 1205740 1228428 ENST00000326873.7 75 GRCh37 Somatic 2016-11-07 22:22:28 UTC https://civicdb.org/links/evidence_items/1620 https://civicdb.org/links/variants/485 https://civicdb.org/links/genes/5534 false AKT2 208 Amplification Lung Adenocarcinoma 3910 Vandetanib,Everolimus Combination Predictive Supports C Sensitivity/Response Case report of a 74-year old woman with EGFR- and ALK-negative lung adenocarcinoma. FISH identified a deletion of 5'RET (FISH, indicating RET-gene rearrangement) and genomic testing confirmed a fusion of KIF5B and RET, as well as an AKT2 gene amplification. The patient was enrolled in a clinical trial with vandetanib and everolimus (NCT01582191) with everolimus used to enhance brain accumulation of vandetanib. After two cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET/CT showed systemic response as well. 25982012 PubMed Subbiah et al., 2015, Lung Cancer NCT01582191 1 accepted 1621 635 254 19 40736224 40791302 ENST00000392038.2 75 GRCh37 N/A 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1621 https://civicdb.org/links/variants/635 https://civicdb.org/links/genes/254 false RET 5979 KIF5B::RET Lung Adenocarcinoma 3910 Everolimus,Vandetanib Combination Predictive Supports C Sensitivity/Response Case report of a 74-year old woman with EGFR- and ALK-negative lung adenocarcinoma. FISH identified a deletion of 5'RET (FISH, indicating RET-gene rearrangement) and genomic testing confirmed a fusion of KIF5B and RET. The patient was enrolled in a clinical trial with vandetanib and everolimus (NCT01582191) with everolimus used to enhance brain accumulation of vandetanib. After two cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET/CT showed systemic response as well. 25982012 PubMed Subbiah et al., 2015, Lung Cancer NCT01582191 2 accepted 1622 273 42 10 32306071 32345359 ENST00000302418.4 10 43609928 43625799 ENST00000355710.3 75 GRCh37 In a study by Takeuchi et. al. a fusion screen was performed in 1529 lung cancer samples. 14 adenocarcinomas with KIF5B-RET and CCDC6-RET fusions were identified. (Takeuchi K et. al., 2012) Somatic 2020-09-23 05:59:44 UTC https://civicdb.org/links/evidence_items/1622 https://civicdb.org/links/variants/273 https://civicdb.org/links/genes/42 false PIK3CA 5290 H1047R Her2-receptor Positive Breast Cancer 0060079 Fulvestrant,Everolimus Combination Predictive Supports C Sensitivity/Response Case report of a 44-year-old patient with recurrent HER2-positive breast cancer. The primary tumor was HR positive; however, the metastatic tumor was HR negative. The patient was resistant to classical chemotherapeutic agents and anti-HER2 treatment. Thus, the combination of everolimus and fulvestrant was administered. The patient experienced stable disease and PFS of 10 months. Genetic testing of pleural effusion after disease progression revealed a PIK3CA H1047R gene mutation but was positive for PTEN expression (IHC). 27445490 PubMed Sun et al., 2016, Onco Targets Ther 2 accepted 1623 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2016-11-05 23:21:05 UTC https://civicdb.org/links/evidence_items/1623 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false PTEN 5728 Expression Her2-receptor Positive Breast Cancer 0060079 Everolimus,Fulvestrant Combination Predictive Supports C Resistance Case report of a 44-year-old patient with recurrent HER2-positive breast cancer. The primary tumor was HR positive; however, the metastatic tumor was HR negative. The patient was resistant to classical chemotherapeutic agents and anti-HER2 treatment. Thus, the combination of everolimus and fulvestrant was administered. The patient experienced stable disease and PFS of 10 months. Genetic testing of pleural effusion after disease progression revealed a PIK3CA H1047R gene mutation but was positive for PTEN expression (IHC). 27445490 PubMed Sun et al., 2016, Onco Targets Ther 1 accepted 1624 313 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 N/A 2020-10-20 06:08:44 UTC https://civicdb.org/links/evidence_items/1624 https://civicdb.org/links/variants/313 https://civicdb.org/links/genes/41 false PIK3CA 5290 H1047R Thyroid Gland Cancer 1781 Temsirolimus,Perifosine Substitutes Predictive Supports D Sensitivity/Response Preclinical study in thyroid cancer cell lines. 6 cell lines with alterations of the PI3K/Akt pathway were more sensitive to Akt inhibitor perifosine or MTOR inhibitor temsirolimus than 5 cell lines without genetic alterations in the PI3K/Akt pathway. Among the alterations, One cell line harbored a PIK3CA H1047R mutation. Transfection of another cell line with this mutation led to lower IC50 values to perifosine and temsirolimus than in a cell line transfected with a control vector. Perifosine treatment also increased apoptosis of a thyroid tumor xenograft with PIK3CA H1047R mutation. 19706758 PubMed Liu et al., 2009, Cancer Res. 3 accepted 1625 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2016-11-05 23:23:54 UTC https://civicdb.org/links/evidence_items/1625 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false PIK3CA 5290 E542K Thyroid Gland Cancer 1781 Temsirolimus,Perifosine Substitutes Predictive Supports D Sensitivity/Response Preclinical study in thyroid cancer cell lines. 6 cell lines with alterations of the PI3K/Akt pathway were more sensitive to Akt inhibitor perifosine or MTOR inhibitor temsirolimus than 5 cell lines without genetic alterations in the PI3K/Akt pathway. Among the alterations, One cell line harbored a PIK3CA E542K mutation. Transfection of another cell line with this mutation led to lower IC50 values to perifosine and temsirolimus than in a cell line transfected with a control vector 19706758 PubMed Liu et al., 2009, Cancer Res. 3 accepted 1626 103 37 3 178936082 178936082 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K variants are the second most recurrent PIK3CA mutations in breast cancer and are highly recurrent mutations in many other cancer types. Colorectal cancer patients with the PIK3CA E545K variant, and possibly other variants in the E545 region, may indicate poor prognosis relative to patients with other PIK3CA variants or wild-type PIK3CA. The literature also suggests that E545/E542 variants may confer resistance to EGFR inhibitors (e.g., cetuximab). An FDA approved treatment regimen including a targeted PIK3CA inhibitor is available for specific subtypes of breast cancer. While PIK3CA variants are highly prevalent in many other cancer types, targeted therapies for PIK3CA variants are still in early clinical trial phases in other cancer types. Somatic 2016-11-05 23:25:45 UTC https://civicdb.org/links/evidence_items/1626 https://civicdb.org/links/variants/103 https://civicdb.org/links/genes/37 false PTEN 5728 R130* Thyroid Gland Cancer 1781 Temsirolimus,Perifosine Substitutes Predictive Supports D Sensitivity/Response Preclinical study in thyroid cancer cell lines. 6 cell lines with alterations of the PI3K/Akt pathway were more sensitive to Akt inhibitor perifosine or MTOR inhibitor temsirolimus than 5 cell lines without genetic alterations in the PI3K/Akt pathway. Among the alterations, one cell line harbored a PTEN allele deletion and R130* mutation. This cell line harbored the lowest IC50 values to both perifosine and temsirolimus and also showed increased apoptosis with perifosine in a xenograft model. 19706758 PubMed Liu et al., 2009, Cancer Res. 2 accepted 1627 636 41 10 89692904 89692904 C T ENST00000371953.3 75 GRCh37 N/A 2016-11-11 19:40:29 UTC https://civicdb.org/links/evidence_items/1627 https://civicdb.org/links/variants/636 https://civicdb.org/links/genes/41 false FBXW7 55294 Loss-of-function Renal Cell Carcinoma 4450 Everolimus Predictive Supports E Sensitivity/Response mTOR protein levels were found to underly a circadian 24-hour rhythm regulated by time-dependent Fbxw7-mediated ubiquitination. Survival rates of tumor-bearing mice with everolimus showed time-dependency consistent with mTOR protein levels. It could be hypothesized that FBXW7 loss leads to an increase in mTOR protein levels independent of circadian regulation and higher sensitivity to mTOR inhibitors. 24253377 PubMed Okazaki et al., 2014, Cancer Res. 2 accepted 1628 637 12903 4 153242410 153457253 ENST00000281708.4 75 GRCh37 N/A 2016-11-11 20:18:41 UTC https://civicdb.org/links/evidence_items/1628 https://civicdb.org/links/variants/637 https://civicdb.org/links/genes/12903 false CCNE1 898 Amplification Estrogen-receptor Positive Breast Cancer 0060075 Palbociclib Predictive Supports D Resistance Preclinical study in breast cancer cell lines treated with CDK4/6 inhibitor palbociclib. Cell lines with acquired resistance to palbociclib were developed. Two palbociclib-resistant cell lines were derived through chronic exposure to 1 μmol/L palbociclib during 3 to 4 months. Copy number profiling from exome sequencing of MCF-7 and MCF-7pR, confirmed relative amplification of CCNE1. Silencing of CCNE1 or CDK2 alone in MCF-7pR cells had no effect on cell-cycle arrest, but resulted in substantially increased cell-cycle arrest and reduction in cell growth in combination with palbociclib. 27020857 PubMed Herrera-Abreu et al., 2016, Cancer Res. 3 accepted 1629 187 11 19 30302805 30315215 ENST00000262643.3 75 GRCh37 N/A 2016-11-11 22:07:19 UTC https://civicdb.org/links/evidence_items/1629 https://civicdb.org/links/variants/187 https://civicdb.org/links/genes/11 false RB1 5925 M695FS*26 Estrogen-receptor Positive Breast Cancer 0060075 Palbociclib Predictive Supports D Resistance Preclinical study in breast cancer cell lines treated with CDK4/6 inhibitor palbociclib. Palbociclib-resistant xenografts from one cell line (PDX244) were developed in-vivo. In resistant xenografts, western blot analysis showed a decrease of pRb protein levels in 4 of 7 CDK4/6-acquired resistant tumors and a sustained expression of the E2F target cyclin E2, in contrast to CDK4/6 inhibitor-sensitive PDX244. Genomic characterization of PDX244LR1 showed the acquisition of an RB1 frameshift mutation (RB1 p.M695fs*26). 27020857 PubMed Herrera-Abreu et al., 2016, Cancer Res. 2 accepted 1630 638 4795 13 49033946 49033947 A ENST00000267163.4 75 GRCh37 Somatic 2016-11-07 20:23:16 UTC https://civicdb.org/links/evidence_items/1630 https://civicdb.org/links/variants/638 https://civicdb.org/links/genes/4795 false FBXW7 55294 Mutation Cancer 162 MTOR Inhibitor Predictive Supports B Sensitivity/Response 418 patients with advanced cancer were screened for FBXW7 mutations using a multiplex gene panel. 17 FBXW7 mutations were detected (isolated mutation in 2 patients). Ten patients were treated with an mTOR inhibitor with 7 patients having stable disease as best responses and a median time to treatment failure of 2.8 months, two patients had prolonged stable disease of >16 weeks. 24586741 PubMed Jardim et al., 2014, PLoS ONE 2 accepted 1631 281 12903 4 153245446 153332714 ENST00000281708.4 75 GRCh37 Somatic 2016-09-11 13:36:12 UTC https://civicdb.org/links/evidence_items/1631 https://civicdb.org/links/variants/281 https://civicdb.org/links/genes/12903 false FBXW7 55294 Loss-of-function Cancer 162 Sirolimus Predictive Supports D Sensitivity/Response FBXW7 was shown to target mTOR for ubiquitination and degradation. A reciprocal relationship between FBXW7 or PTEN loss was identified in breast cancer tumors and cell lines (mutual exclusivity of these two events). In total only 4 out of 450 tumor and cell line samples had concomitant loss of both genes (p=4.9x10^-7). Cell lines (n=5) with FBXW7 mutations or deletions were significantly sensitive to rapamycin and downregulation of FBXW7 (shRNA) increased the sensitivity to rapamycin. In summary, this evidence suggests that FBXW7 may be a biomarker for cancers sensitivity to inhibitors of the mTOR pathway. 18787170 PubMed Mao et al., 2008, Science 4 accepted 1632 637 12903 4 153242410 153457253 ENST00000281708.4 75 GRCh37 Somatic 2016-11-11 20:19:42 UTC https://civicdb.org/links/evidence_items/1632 https://civicdb.org/links/variants/637 https://civicdb.org/links/genes/12903 false JUN 3725 Overexpression Colorectal Adenocarcinoma 0050861 Irbesartan Predictive Supports C Sensitivity/Response A 67-year-old female presents with recurrent metastatic colonic adenocarcinoma. Immunohistochemical and genetic workup showed overexpression of c-JUN and FOS, which presumably signals through the RAAS pathway. The patient was treated with irbesartan and after 5 weeks of therapy, the CEA value decreased from 18 to 3.1 and there was radiological resolution of the disease. Her 10 month CEA was 1.4. 27022066 PubMed Jones et al., 2016, Ann. Oncol. 2 accepted 1633 639 3094 1 59246465 59249785 ENST00000371222.2 75 GRCh37 Somatic 2016-11-05 22:28:17 UTC https://civicdb.org/links/evidence_items/1633 https://civicdb.org/links/variants/639 https://civicdb.org/links/genes/3094 false FOS 2353 Overexpression Colon Adenocarcinoma 234 Irbesartan Predictive Supports C Sensitivity/Response A 67-year-old female presents with recurrent metastatic colonic adenocarcinoma. Immunohistochemical and genetic workup showed overexpression of c-JUN and FOS, which presumably signals through the RAAS pathway. The patient was treated with Irbesartan and after 5 weeks of therapy, the CEA value decreased from 18 to 3.1 and there was radiological resolution of the disease. Her 10 month CEA was 1.4. 27022066 PubMed Jones et al., 2016, Ann. Oncol. 2 accepted 1634 640 1955 14 75745477 75748933 ENST00000303562.4 75 GRCh37 Somatic 2016-11-05 23:31:09 UTC https://civicdb.org/links/evidence_items/1634 https://civicdb.org/links/variants/640 https://civicdb.org/links/genes/1955 false CDKN2A 1029 RS3814960 Esophagus Squamous Cell Carcinoma 3748 Prognostic Supports B Poor Outcome 124 esophageal squamous cell carcinoma patients with radical resection were genotyped using MassArray. The TC/CC genotype of p14ARF at rs3814960 had decreased overall survival (HR = 2.77, 95% CI: 1.33–5.75, P = 0.006, Pc = 0.030) and decreased disease-free survival (DFS) (HR = 2.45, 95% CI: 1.30–4.61, P = 0.005) compared to patients without this mutation. 27414035 PubMed Li et al., 2016, PLoS ONE 3 accepted 1635 641 14 9 21975017 21975017 C T ENST00000498124.1 75 GRCh37 Somatic 2016-09-11 13:07:38 UTC https://civicdb.org/links/evidence_items/1635 https://civicdb.org/links/variants/641 https://civicdb.org/links/genes/14 false MDM2 4193 RS34886328 Esophagus Squamous Cell Carcinoma 3748 Prognostic Supports B Better Outcome 124 esophageal squamous cell carcinoma patients with radical resection were genotyped using MassArray. Patients with the DEL/A +AA genotype of MDM2 rs34886328 had a notably increased overall survival (HR = 0.27, 95% CI: 0.13–0.56, P = 4.7×10−4, Pc = 0.003) and increased disease free survival (HR = 0.22, 95% CI: 0.11–0.43, P < .0001) when compared to patients without this mutation. 27414035 PubMed Li et al., 2016, PLoS ONE 2 accepted 1636 642 3465 12 69234988 69234988 A ENST00000462284.1 75 GRCh37 Somatic 2016-09-27 23:18:53 UTC https://civicdb.org/links/evidence_items/1636 https://civicdb.org/links/variants/642 https://civicdb.org/links/genes/3465 false CBLB 868 RS2305035 Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Better Outcome Samples from 393 patients with NSCLC were evaluated for 3 SNPs in CBLB (rs1042852, rs2305035, and rs7649466). Genotypes rs7649466 and rs1042852 were not associated with a change in clinical outcome compared to wildtype however, rs2305035 A genotype (A/A or A/G) had better local recurrence-free survival, metastasis-free survival and overall survival when compared to GG genotype (n=186). 26732495 PubMed Li et al., 2016, Clin Lung Cancer 2 accepted 1637 643 779 3 105439026 105439026 G A ENST00000264122.4 75 GRCh37 Common Germline 2016-09-13 22:53:08 UTC https://civicdb.org/links/evidence_items/1637 https://civicdb.org/links/variants/643 https://civicdb.org/links/genes/779 false PRDM1 639 MUTATION Diffuse Large B-cell Lymphoma 0050745 Prognostic Supports B Poor Outcome Biopsies from 520 DLBCL patients treated with R-CHOP were evaluated for PRDM1 mutations or protein (BLIMP-1) expression. Patients with a homozygous deletion of PRDM1 (7%, N=19) had a significantly shorter overall survival and poorer progression free survival compared to heterozygous or wildtype PRDM1. 27568520 PubMed Xia et al., 2016, Leukemia 2 accepted 1638 644 593 6 106534195 106557813 ENST00000369096.4 75 GRCh37 Somatic 2016-11-05 21:26:32 UTC https://civicdb.org/links/evidence_items/1638 https://civicdb.org/links/variants/644 https://civicdb.org/links/genes/593 false IDH1 3417 Mutation Brain Glioma 0060108 Prognostic Supports B Better Outcome Genomewide analysis of 250 low-grade adult gliomas revealed that patients with a wildtype IDH1/2 had significantly shorter overall survival than those with a mutated IDH gene (HR 7.4; 95%CI: 4.0-13.8). The median survival for patients with low grade gliomas was 1.7 years for patients with wild-type IDH (N=55); 6.3 years for patients with mutated IDH and no 1p/19q co-deletion (N=139); and 8.0 years for patients with IDH mutation and a 1p/19q co-deletion (N=84). 26061751 PubMed 2015, N. Engl. J. Med. 3 accepted 1639 645 26 2 209101803 209116275 ENST00000415913.1 75 GRCh37 Somatic 2016-09-07 06:58:06 UTC https://civicdb.org/links/evidence_items/1639 https://civicdb.org/links/variants/645 https://civicdb.org/links/genes/26 false IDH2 3418 Mutation Brain Glioma 0060108 Prognostic Supports B Better Outcome Genomewide analysis of 250 low-grade adult gliomas revealed that patients with a wildtype IDH1/2 had significantly shorter overall survival than those with a mutated IDH gene (HR 7.4; 95%CI: 4.0-13.8). The median survival for patients with low grade gliomas was 1.7 years for patients with wild-type IDH (N=55); 6.3 years for patients with mutated IDH and no 1p/19q co-deletion (N=139); and 8.0 years for patients with IDH mutation and a 1p/19q co-deletion (N=84). 26061751 PubMed 2015, N. Engl. J. Med. 3 accepted 1640 570 27 15 90626277 90645736 ENST00000330062.3 75 GRCh37 Somatic 2016-11-03 19:03:23 UTC https://civicdb.org/links/evidence_items/1640 https://civicdb.org/links/variants/570 https://civicdb.org/links/genes/27 false MYD88 4615 L265P Waldenstroem's Macroglobulinemia 0060901 IRAK-1/4 Inhibitor,IMG-2005-5 Substitutes Predictive Supports D Sensitivity/Response In a study of 30 patients with Waldenström’s macroglobulinemia, 87% had MYD88(L265P) mutations. Waldenstrom macroglobulinemia cells expressing MYD88(L265P) were treated with an MYD88 homodimerization inhibitor or an IRAK 1/4 kinase inhibitor. The cells showed a decrease in staining of NF-kappa-B p65 phosphorylation. 22931316 PubMed Treon et al., 2012, N. Engl. J. Med. 1 accepted 1641 424 3742 3 38182641 38182641 T C ENST00000396334.3 75 GRCh37 Somatic 2016-09-04 03:24:31 UTC https://civicdb.org/links/evidence_items/1641 https://civicdb.org/links/variants/424 https://civicdb.org/links/genes/3742 false KRAS 3845 Mutation Hepatocellular Carcinoma 684 Sorafenib,Refametinib Combination Predictive Supports B Sensitivity/Response Phase 2 study in Asian patients with unresectable hepatocellular carcinoma. 70 patients received refametinib (BAY 86-9766) plus sorafenib as study treatment. A retrospective biomarker analysis was performed in 69 patients for KRAS, NRAS and BRAF mutations (BEAM technology). 4 patients were identified to harbor RAS mutations. 3 of whom still received study treatment at the cutoff date used for the final data analysis. These 3 patients had achieved confirmed PR, with duration responses ranging from 128 to 382 days. The fourth patient with a RAS mutation discontinued study treatment after 41 days on therapy due to PD. An overall of 4 (6 by modified RECIST) patients achieved PR. 25294897 PubMed Lim et al., 2014, Clin. Cancer Res. NCT01204177 2 accepted 1642 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-09-11 13:37:32 UTC https://civicdb.org/links/evidence_items/1642 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false PRKACA 5566 DNAJB1::PRKACA Mixed Fibrolamellar Hepatocellular Carcinoma 0080182 Diagnostic Supports C Positive A DNAJB1:PRKACA fusion transcript was detected at very high expression levels by RNA-Seq in a case of mixed fibrolamellar hepatocellular carcinoma. Subsequent analysis revealed the presence of this fusion in all primary and metastatic samples, including those with mixed or conventional HCC pathology. A second case of mFL-HCC confirmed that the fusion was detectable in conventional components. An expanded screen of 112 additional HCC samples and 44 adjacent non-tumor liver samples was positive for a third case of HCC with both conventional and fibrolamellar features but negative for all conventional HCC and adjacent non-tumor liver samples. 27029710 PubMed Griffith et al., 2016, Ann. Oncol. 4 accepted 1643 31 17 19 14628951 14629232 ENST00000254322.2 19 14202500 14218221 ENST00000308677.4 75 GRCh37 This fusion has been found to be very recurrent in the rare form of adolescent liver cancer, fibrolamellar hepatocellular carcinoma. In one study, this fusion was observed in 15/15 FL-HCC cases examined and functional studies found that the fusion retained kinase activity. The presence of this fusion may be used as a diagnostic marker for this rare tumor type. Somatic 2020-10-08 20:12:43 UTC https://civicdb.org/links/evidence_items/1643 https://civicdb.org/links/variants/31 https://civicdb.org/links/genes/17 false SMAD4 4089 Deletion Colorectal Cancer 9256 Fluorouracil Predictive Supports B Resistance A retrospective study with 202 colorectal cancer patients found that SMAD4 deletion was associated with worse outcomes during 5-fluorouracil treatment. The hazard ratio for disease-free survival was 2.89 times greater for patients with SMAD4 deletion as compared to those with normal SMAD4 diploidy (P = .045). For overall survival, the hazard ratio was 3.23 times greater for SMAD4 deletion (P = .056). 12237773 PubMed Boulay et al., 2002, Br. J. Cancer 3 accepted 1644 646 77 18 48556583 48611409 ENST00000342988.3 75 GRCh37 N/A 2016-09-10 18:30:18 UTC https://civicdb.org/links/evidence_items/1644 https://civicdb.org/links/variants/646 https://civicdb.org/links/genes/77 false LRP1B 53353 DELETION Glioblastoma 3068 Prognostic Supports B Poor Outcome A retrospective study of 178 glioblastoma patients found that LRP1B deletion (complete transcript, N=4 or focal transcript deletion of >150kb, N=13) was associated with a lower progress free survival (6.4 months vs. 10.1 months; P = 0.004) and overall free survival (13.4 months vs. 17.8 months; P = 0.001). Multivariate analysis adjusting for age and type of surgery also supported LRP1B deletion being associated with a higher hazard ratio. 26428308 PubMed Tabouret et al., 2015, J. Neurol. Sci. 4 accepted 1645 647 12146 2 140988992 142889270 ENST00000389484.3 75 GRCh37 N/A 2016-10-25 04:20:38 UTC https://civicdb.org/links/evidence_items/1645 https://civicdb.org/links/variants/647 https://civicdb.org/links/genes/12146 false TERT 7015 C228T Thyroid Gland Cancer 1781 Diagnostic Supports B Positive In 308 thyroid fine-needle aspiration biopsies, 0 of the 179 benign tumors displayed either the C228T or the C250T TERT promoter mutation; however, 9 of the 129 differentiated thyroid cancers had either of these mutations. The biomarker displayed 100% diagnostic specificity and 7% sensitivity. 25121551 PubMed Liu et al., 2014, Endocr. Relat. Cancer 3 accepted 1646 248 79 5 1295228 1295228 G A ENST00000310581.5 75 GRCh37 Somatic 2016-09-11 13:06:38 UTC https://civicdb.org/links/evidence_items/1646 https://civicdb.org/links/variants/248 https://civicdb.org/links/genes/79 false ATRX 546 Underexpression Malignant Astrocytoma 3069 PCV Regimen,Temozolomide Substitutes Predictive Supports B Sensitivity/Response A retrospective tumor sample study found that the loss of ATRX expression (less than 10% of nuclei) in IDH-mutant astrocytomas treated with temozolomide or a combination of procarbazine, lomustine and vincristine (PCV) was associated with better outcomes. Patients with IDH-mutant tumors and ATRX expression loss (n=40) experienced greater time to treatment failure (55.6 months vs. 31.8 months; P = 0.0168) and a greater progression-free survival (37.1 months vs. 18.1 months; P = 0.038) compared to patients with IDH-mutant tumors with ATRX expression (n=9). 23904111 PubMed Wiestler et al., 2013, Acta Neuropathol. 3 accepted 1647 648 525 X 76760356 77041702 ENST00000373344.5 75 GRCh37 N/A 2020-12-10 02:11:31 UTC https://civicdb.org/links/evidence_items/1647 https://civicdb.org/links/variants/648 https://civicdb.org/links/genes/525 false ATRX 546 Underexpression Glioblastoma 3068 Prognostic Supports D Poor Outcome In a glioblastoma mouse model induced by NRAS and p53 knockdown, ATRX loss was associated with a decreased median survival (69 days vs. 84 days; P = .0032). Also, the tumors grew to a larger size at earlier time points. ATRX loss was also associated with greater microsatellite instability. 26936505 PubMed Koschmann et al., 2016, Sci Transl Med 4 accepted 1648 648 525 X 76760356 77041702 ENST00000373344.5 75 GRCh37 N/A 2016-11-08 23:48:47 UTC https://civicdb.org/links/evidence_items/1648 https://civicdb.org/links/variants/648 https://civicdb.org/links/genes/525 false CALR 811 EXON 9 FRAMESHIFT Myelofibrosis 4971 Prognostic Supports B Better Outcome In patients with primary myelofibrosis CALR mutations were associated with improved median survival. For 277 patients, CALR mutated, ASXL1 wildtype patients (median survival, 10.4 years, N=46); CALR wildtype, ASXL1 mutant patients (2.3 years; HR, 5.9; 95% CI, 3.5–10.0, N=62); and either CALR/ASXL1wildtype or CALR/ASXL1 mutant patients (5.8 years; HR, 2.5; 95% CI, 1.5–4.0, N=169). These results were independent of DIPSS-plus risk but added prognostic information to this risk categorization. These results were also validated in an independent cohort of 293 patients. 24496303 PubMed Tefferi et al., 2014, Leukemia 4 accepted 1649 559 732 19 13054527 13054727 ENST00000316448.5 75 GRCh37 Exon 9 insertions and deletions have become part of the WHO diagnostic criteria for essential thrombocythemia (ET) and primary myelofibrosis (PMF) (Arber et al, 2016). These mutations are typically heterozygous and in the absence of JAK2 and MPL mutations. Approximately 80% of observed mutations are type 1 (p.L367fs*46), the result of a 52 bp deletion, or type 2 (p.K385fs*47), the result of a 5-bp TTGTC insertion, and studies have suggested phenotypic and prognostic differences between them. In PMF patients, CALR exon 9 mutations have been associated with improved median survival. Somatic 2016-09-23 19:33:25 UTC https://civicdb.org/links/evidence_items/1649 https://civicdb.org/links/variants/559 https://civicdb.org/links/genes/732 false AURKA 6790 Overexpression Ovarian Serous Carcinoma 0050933 Platinum Compound Predictive Supports B Resistance A study of 41 patients with high-grade ovarian serous carcinoma found that high expression levels of AURKA correlated with poorer overall survival (P = 0.001; HR 0.14) and platinum therapy resistance (P < 0.001). Expression of AURKA was measured using immunohistochemical techniques on tumor samples. 27209210 PubMed Mignogna et al., 2016, J Ovarian Res 3 accepted 1650 181 61 20 54944446 54967393 ENST00000395913.3 75 GRCh37 N/A 2016-09-13 22:51:44 UTC https://civicdb.org/links/evidence_items/1650 https://civicdb.org/links/variants/181 https://civicdb.org/links/genes/61 false MET 4233 EXON 14 SKIPPING MUTATION Lung Adenocarcinoma 3910 Crizotinib Predictive Supports C Sensitivity/Response Case report of a patient with lung adenocarcinoma harboring a MET exon 14 skipping mutation and major response to crizotinib. 26845194 PubMed Shea et al., 2016, J Thorac Oncol 2 accepted 1651 324 52 7 116411903 116412043 ENST00000318493.6 75 GRCh37 Exon 14 mutations have been observed in ~3% of patients with NSCLC (28/933 reported by Awad et al J Clin Onc 2016), confirmed to cause exon skipping when available, and associated with concurrent MET amplification. Responses to the c-MET inhibitor crizotinib have been reported in preclinical models and in individual case reports as well as a small-scale clinical trial (17 patients treated, Drilon et al., 2016 (suppl; abstr 108; ASCO ID 167889-176)). Larger studies are needed but enrollment of patients with MET exon 14 skipping mutation in trials with MET inhibitors or off-label treatment is encouraged (Paik et al., 2015 (suppl; abstr 8021)). Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1651 https://civicdb.org/links/variants/324 https://civicdb.org/links/genes/52 false MET 4233 D1228N Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Resistance Case report of a patient with NSCLC harboring a MET exon 14 skipping mutation and initial response to crizotinib. A second biopsy at the time of progression revealed an acquired MET D1228N mutation. 27343442 PubMed Heist et al., 2016, J Thorac Oncol 2 accepted 1652 649 52 7 116423407 116423407 G A ENST00000397752.3 75 GRCh37 Somatic 2016-11-05 23:27:02 UTC https://civicdb.org/links/evidence_items/1652 https://civicdb.org/links/variants/649 https://civicdb.org/links/genes/52 false AURKA 6790 EXPRESSION Esophagus Squamous Cell Carcinoma 3748 Fluorouracil,Cisplatin,Radiation Therapy Combination Predictive Supports B Sensitivity/Response A retrospective study examining the expression of AURKA in tumor samples of 78 esophageal squamous cell carcinoma patients found that positive expression of AURKA (>10% of cells by IHC) was correlated with increased clinical response to chemoradiation therapy consisting of cisplatin, 5-fluorouracil, and 40 gy radiation (P = 0.0003). 25924824 PubMed Tamotsu et al., 2015, BMC Cancer 3 accepted 1653 158 61 20 54944446 54967393 ENST00000395913.3 75 GRCh37 N/A 2016-09-23 20:20:58 UTC https://civicdb.org/links/evidence_items/1653 https://civicdb.org/links/variants/158 https://civicdb.org/links/genes/61 false CASP8 841 D302H Neuroblastoma 769 Prognostic Supports B Poor Outcome 21 SNPs were analyzed using qRT-PCR genotyping assays in 500 Neuroblastoma tumor samples, and the CASP8 D302H missense variant was found to be associated with worse overall survival (P = 0.0006; Q = 0.049) and worse event-free survival (P = 0.0002; Q = 0.042) in those samples that had MYCN amplification (N = 94). 25502557 PubMed Rihani et al., 2014, PLoS ONE 3 accepted 1654 650 761 2 202149589 202149589 G C ENST00000264275.5 75 GRCh37 Common Germline 2016-10-04 08:13:12 UTC https://civicdb.org/links/evidence_items/1654 https://civicdb.org/links/variants/650 https://civicdb.org/links/genes/761 false AXL 558 EXPRESSION Esophagus Squamous Cell Carcinoma 3748 Prognostic Supports B Poor Outcome Immunohistochemical analysis of tumors from 116 esophageal squamous cell carcinoma found that expression of AXL was associated with increased progression of the tumor (P < 0.0001), increased risk of death (HR = 2.09 ; P = 0.028), and increased risk of distant metastasis (OR = 3.96 ; P = 0.029). 27172793 PubMed Hsieh et al., 2016, Oncotarget 4 accepted 1655 651 533 19 41725108 41767671 ENST00000301178.4 75 GRCh37 N/A 2016-10-12 03:37:20 UTC https://civicdb.org/links/evidence_items/1655 https://civicdb.org/links/variants/651 https://civicdb.org/links/genes/533 false GAS6 2621 EXPRESSION Prostate Cancer 10283 Docetaxel Predictive Supports D Resistance Prostate Cancer (PCa) cell lines were either cultured alone, co-cultured with osteoblasts expressing GAS6, or cultured in the presence of media with GAS6 to examine their response to therapy with docetaxel. Docetaxel efficiently induced apoptosis in the cells cultured without any GAS6, but it was not able to do so in the cells that were in media with GAS6 present or that were co-cultured with osteoblasts expressing GAS6. PCa cells in the presence of GAS6 were found to be in G1 phase for a greater duration which may help explain the increased resistance to docetaxel. 27153245 PubMed Lee et al., 2016, J. Cell. Biochem. 3 accepted 1656 652 2186 13 114523524 114567046 ENST00000357389.3 75 GRCh37 N/A 2016-09-16 19:30:05 UTC https://civicdb.org/links/evidence_items/1656 https://civicdb.org/links/variants/652 https://civicdb.org/links/genes/2186 false GAS6 2621 EXPRESSION Oral Squamous Cell Carcinoma 0050866 Prognostic Supports B Poor Outcome 128 patients with oral squamous cell carcinoma (OSCC) and 145 normal control subjects were evaluated for the concentration of GAS6 in their plasma serum. OSCC patients were found to be associated with a significantly higher level of GAS6 in serum ( P = .05 ). Furthermore, within the OSCC patients, increased GAS6 serum concentration was associated with higher stage tumors ( P < .01) , poorly differentiated tumors ( P < .01 ), and increased lymph node metastasis ( OR = 2.79 ; CI = 1.72-4.48 ). 26207647 PubMed Jiang et al., 2015, PLoS ONE 4 accepted 1657 652 2186 13 114523524 114567046 ENST00000357389.3 75 GRCh37 N/A 2016-09-16 19:29:43 UTC https://civicdb.org/links/evidence_items/1657 https://civicdb.org/links/variants/652 https://civicdb.org/links/genes/2186 false ETV4 2118 Overexpression Prostate Cancer 10283 Prognostic Supports B Poor Outcome Immunohistochemical methods were used to evaluate the expression levels of ETV4 in prostate cancer (PCa) tumor samples. Increased expression of ETV4 was associated with greater Gleason score (P = 0.045) , pathological tumor stage (P = 0.041), and an unfavorable prognosis (P = 0.040). 25544710 PubMed Qi et al., 2015, Tumour Biol. 3 accepted 1658 653 1767 17 41605212 41623800 ENST00000319349.5 75 GRCh37 N/A 2016-09-23 20:21:42 UTC https://civicdb.org/links/evidence_items/1658 https://civicdb.org/links/variants/653 https://civicdb.org/links/genes/1767 false STAG2 10735 Underexpression Melanoma 1909 Vemurafenib Predictive Supports D Resistance A375 melanoma cells containing an inducible shRNA for STAG2 were grown as xenograft tumors in nude mice. The mice in which STAG2 was silenced had tumors that were more sensitive to vemurafenib-induced tumor shrinkage than the tumors of the control mice (P < .01). 27500726 PubMed Shen et al., 2016, Nat. Med. 4 accepted 1659 422 8553 X 123095568 123236506 ENST00000371157.3 75 GRCh37 N/A 2016-11-07 18:53:06 UTC https://civicdb.org/links/evidence_items/1659 https://civicdb.org/links/variants/422 https://civicdb.org/links/genes/8553 false STAG3 10734 Underexpression Melanoma 1909 Vemurafenib Predictive Supports D Resistance A375 melanoma cells containing an inducible shRNA for STAG3 were grown as xenograft tumors in nude mice. The mice in which STAG3 was silenced had tumors that were more sensitive to vemurafenib-induced tumor shrinkage than the tumors of the control mice (P < .01). 27500726 PubMed Shen et al., 2016, Nat. Med. 4 accepted 1660 654 8552 7 99775186 99812003 ENST00000426455.1 75 GRCh37 N/A 2016-11-07 20:22:43 UTC https://civicdb.org/links/evidence_items/1660 https://civicdb.org/links/variants/654 https://civicdb.org/links/genes/8552 false MAP2K1 5604 Q56_V60del Ovarian Serous Carcinoma 0050933 Selumetinib Predictive Supports C Sensitivity/Response Case report of a 51-year old patient with recurrent low-grade serous ovarian cancer. Selumetinib treatment in a phase-II trial led to a complete and durable response > 5 years. Sequencing (MSK-IMPACT Panel) was performed on the patients tumor and germline and identified a 15-bp in-frame deletion of MAP2K1 (8.3% of tumor reads but 0% in germline). In-silico modelling suggested loss of negative feedback on kinase activity from this deletion.In-vitro expression of the MEK1 Q56_V60 deletion as well as the previously characterized MEK1 F53L mutation in 293H cells resulted in elevated levels of phosphorylated ERK and phosphorylated ribosomal protein S6 kinase as compared with wild-type MEK1 as well as increased colony formation and tumor growth in-vivo. Selumetinib treatment of MEK1-transfected cells confirmed retained sensitivity to MEK inhibition and inhibition of colony formation. 26324360 PubMed Grisham et al., 2015, J. Clin. Oncol. 4 accepted 1661 655 31 15 66727449 66727463 CCAGAAGCAGAAGGT ENST00000307102.5 75 GRCh37 Somatic 2016-11-05 21:38:05 UTC https://civicdb.org/links/evidence_items/1661 https://civicdb.org/links/variants/655 https://civicdb.org/links/genes/31 false BRAF 673 BRAF::CUL1 Ovarian Serous Carcinoma 0050933 Mitogen-Activated Protein Kinase Kinase Inhibitor Predictive Supports C Sensitivity/Response One patient with low-grade serous ovarian cancer had an in-frame fusion between the BRAF kinase domain and CUL1 identified by panel sequencing (MSK-IMPACT), with expression confirmed by whole-transcriptome sequencing. This patient with metastatic disease after treatment with carboplatin and paclitaxel, was enrolled onto a study of paclitaxel in combination with an oral MEK inhibitor and achieved a CR. She continued to receive therapy for 7 months, until discontinuation because of the development of pneumonitis. At publication, sustained CR had lasted > 18 months. 26324360 PubMed Grisham et al., 2015, J. Clin. Oncol. 2 accepted 1662 656 5 7 140434279 140487384 ENST00000288602.6 7 148395737 148457588 ENST00000602748.1 75 GRCh37 Somatic 2016-10-22 14:43:20 UTC https://civicdb.org/links/evidence_items/1662 https://civicdb.org/links/variants/656 https://civicdb.org/links/genes/5 false BRAF 673 ZKSCAN1::BRAF Melanoma 1909 Trametinib Predictive Supports C Sensitivity/Response Analysis of BRAF fusions in 20,573 tumors, across 12 distinct tumor types. BRAF fusions were identified in 55 (0.3%) patients and enriched in spitzoid melanoma, pilocytic astrocytomas, pancreatic acinar and papillary thyroid cancers. Clinical data were available for two patients. Among them one 46-year old woman with spitzoid melanoma that harbored a ZKSCAN1-BRAF fusion responded to treatment with the MEK inhibitor trametinib. Subcutaneous tumor nodules exhibited clinical responses within 14 days of therapy, and her dominant bulky right lung metastases showed significant response by Day 45. Subsequent robotic-assisted lobectomy was able to remove the previously unresectable tumor with clean surgical margins. 26314551 PubMed Ross et al., 2016, Int. J. Cancer 3 accepted 1663 657 5 7 99613222 99627575 ENST00000426572.1 7 140434279 140482957 ENST00000288602.6 75 GRCh37 Somatic 2016-11-05 22:15:14 UTC https://civicdb.org/links/evidence_items/1663 https://civicdb.org/links/variants/657 https://civicdb.org/links/genes/5 false BRAF 673 KIAA1549::BRAF Spindle Cell Sarcoma 4235 Bevacizumab,Temsirolimus,Sorafenib Combination Predictive Supports C Sensitivity/Response A patient with a malignant spindle cell tumor of the chest wall treated as a soft tissue sarcoma was identified to harbor a KIAA1549-BRAF fusion. This patient responded to treatment with the pan-kinase inhibitor sorafenib in combination with bevacizumab and temsirolimus, achieving stable disease after 2 cycles extending into 11 cycles at which time she expired due to co-morbidities (acute myocardial infarction, hypotension). Of note, sequencing of 236 cancer-related genes identified CDKN2A A68fs*51, SUFU E283fs*3, MAP3K1 N325fs*3 and homozygous deletion of PTEN as well. 24422672 PubMed Subbiah et al., 2014, J Hematol Oncol NCT01187199 2 accepted 1664 618 5 7 138545885 138666064 ENST00000440172.1 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2022-01-07 22:26:46 UTC https://civicdb.org/links/evidence_items/1664 https://civicdb.org/links/variants/618 https://civicdb.org/links/genes/5 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports B Sensitivity/Response 90 NSCLC patients with stage IIIB/IV chemotherapy-resistant tumors were treated with gefitinib, and the L858R EGFR mutation was associated with longer time to treatment failure than those with wild-type EGFR (median 9.1 versus 2.1). In multivariate analysis, L858R mutations plus adenocarcinoma was a significant predictive factor for time to treatment failure (HR = 0.1030; P = .0004). 18509184 PubMed Yang et al., 2008, J. Clin. Oncol. 3 accepted 1665 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2021-04-02 17:35:35 UTC https://civicdb.org/links/evidence_items/1665 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 Exon 19 Deletion Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports B Sensitivity/Response 90 NSCLC patients with stage IIIB/IV chemotherapy-resistant tumors were treated with gefitinib, and exon 19 deletion of EGFR was associated with longer time to treatment failure than those with wild-type EGFR (median 8.9 versus 2.1). In multivariate analysis, exon 19 deletion was a significant predictive factor for TTF (HR = 0.0320; P < .0001). 18509184 PubMed Yang et al., 2008, J. Clin. Oncol. 3 accepted 1666 133 19 7 55242415 55242513 ENST00000275493.2 75 GRCh37 Deletions within exon 19 of EGFR are most common in lung cancer. These deletions, in non-small cell lung cancer, have been shown to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib, afatinib, and erlotinib. There is also data to suggest that this event is a good prognostic marker in lung adenocarcinoma. Examples of exon 19 deletions include: p.746_A750delELREA, p.747_753delinsS, p.747_752delLREATS, and p.747_751delLREAT. Somatic 2016-09-15 16:44:53 UTC https://civicdb.org/links/evidence_items/1666 https://civicdb.org/links/variants/133 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Gefitinib,Erlotinib Substitutes Predictive Supports B Resistance 48 tumor samples from 41 patients with EGFR mutant lung adenocarcinoma that were resistant to tyrosine kinase inhibition by gefitinib (n=1) or erlotinib (n=40) underwent next generation sequencing (NGS failed in 5 samples leading to a remaining 43 specimens from 39 patients). The prevalence of various mutations post-treatment was analyzed. 79%, or 31 out of the 39 patients, had the T790M EGFR mutation present, indicating its importance in the development of resistance. 27304188 PubMed Belchis et al., 2016, Oncotarget 3 accepted 1667 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2022-01-11 18:10:23 UTC https://civicdb.org/links/evidence_items/1667 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false BRAF 673 L505H Melanoma 1909 Vemurafenib Predictive Supports D Resistance Using a mutation screen in the BRAFV600E melanoma cell line A375, the L505H variant was identified as conferring resistance to vemurafenib. Analysis of the mutation in T293 cell lines found that the L505H mutant alone or with V600e had greater kinase activity and increased the levels of phospho-MEK. Finally, transduction of Ba/F3 cells with BRAF V600E/L505H IL3 independent proliferation. 24112705 PubMed Wagenaar et al., 2014, Pigment Cell Melanoma Res 4 accepted 1668 658 5 7 140477794 140477794 A T ENST00000288602.6 75 GRCh37 Somatic 2016-11-03 18:57:57 UTC https://civicdb.org/links/evidence_items/1668 https://civicdb.org/links/variants/658 https://civicdb.org/links/genes/5 false BRAF 673 L505H Melanoma 1909 Vemurafenib Predictive Supports B Resistance In this study, the investigators followed 10 patients treated with vemurafenib, and then they collected biopsies of lesions that progressed. In one of these patients, they identified the L505H mutation. 25515853 PubMed Hoogstraat et al., 2015, Pigment Cell Melanoma Res 3 accepted 1669 658 5 7 140477794 140477794 A T ENST00000288602.6 75 GRCh37 Somatic 2016-09-23 20:24:28 UTC https://civicdb.org/links/evidence_items/1669 https://civicdb.org/links/variants/658 https://civicdb.org/links/genes/5 false PIK3CA 5290 E545K Lung Adenocarcinoma 3910 Erlotinib,Gefitinib Substitutes Predictive Supports C Resistance 48 tumor samples from 41 patients with EGFR mutant lung adenocarcinoma that were resistant to tyrosine kinase inhibition underwent next generation sequencing (AmpliSeq Cancer Hotspot Panel (v2) failed in 5 samples leading to a remaining 43 specimens from 39 patients). The prevalence of various mutations post-treatment was analyzed. 2 out of the 39 patients had the E545K PIK3CA mutation in the absence of EGFR T790M, indicating that E545K may be an alternative mutation contributing to resistance. 27304188 PubMed Belchis et al., 2016, Oncotarget 2 accepted 1670 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2022-01-11 17:41:41 UTC https://civicdb.org/links/evidence_items/1670 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false VHL 7428 Mutation Renal Cell Carcinoma 4450 Pazopanib Predictive Does Not Support B Sensitivity/Response VHL mutations were evaluated in 78 tumors samples of patients with metastatic RCC treated with pazopanib as part of a clinical trial. Overall, 87% had one VHL mutation, 12% showed promoter hypermethylation, and 6 patients had both. 8 patients exhibited neither mutation nor methylation of VHL. There was no correlation between VHL status and overall response rate or progression free survival under pazopanib therapy. 23881929 PubMed Choueiri et al., 2013, Clin. Cancer Res. 2 accepted 1672 160 58 3 10182692 10193904 ENST00000256474.2 75 GRCh37 Somatic 2016-10-15 16:29:16 UTC https://civicdb.org/links/evidence_items/1672 https://civicdb.org/links/variants/160 https://civicdb.org/links/genes/58 false EPAS1 2034 Overexpression Renal Cell Carcinoma 4450 Pazopanib Predictive Does Not Support B Sensitivity/Response HIF2A (EPAS1) staining was conducted on tumors from 66 patients, of which 27 were classified as low expression and 39 were classified as high expression. The response rates of patients with low and high HIF2A expression to pazopanib were 44% and 33% (p=0.36) respectively and no significant difference in PFS between the two groups (p=0.76) was observed. The authors concluded that HIF2A expression levels are not associated with clinical response to pazopanib. 23881929 PubMed Choueiri et al., 2013, Clin. Cancer Res. 2 accepted 1673 435 1705 2 46524541 46613836 ENST00000263734.3 75 GRCh37 N/A 2020-12-19 06:28:38 UTC https://civicdb.org/links/evidence_items/1673 https://civicdb.org/links/variants/435 https://civicdb.org/links/genes/1705 false HIF1A 3091 EXPRESSION Renal Cell Carcinoma 4450 Pazopanib Predictive Does Not Support B Sensitivity/Response Immunohistochemical staining for HIF1A was performed on tumor samples from 65 patients that received pazopanib as part of VEG102616, of which 17 were classified as low expression and 48 were classified as high expression. The response rates of patients with low and high HIF1a expression to pazopanib were 52.9% and 29.1% (p=0.13), and there was no significant difference in PFS between the two groups (p=0.25). The authors concluded that HIF1a expression levels are not associated with clinical response to pazopanib. 23881929 PubMed Choueiri et al., 2013, Clin. Cancer Res. 2 accepted 1674 660 2596 14 62164340 62214489 ENST00000539097.1 75 GRCh37 N/A 2020-12-19 06:28:21 UTC https://civicdb.org/links/evidence_items/1674 https://civicdb.org/links/variants/660 https://civicdb.org/links/genes/2596 false BRCA1 672 Mutation Ovarian Cancer 2394 Prognostic Supports B Better Outcome 664 patients with non-bulky FIGO Stage II-IV ovarian cancer were evaluated for PFS when treated with Pazopanib versus placebo. Of the 664 patients, 10% (n=68) were BRCA1+, 4% were BRCA 2+ (n=29) and 85% (n=567) were BCRA1/2 negative. Longer progression free survival was observed in BRCA1/2 positive carriers versus BRCA1/2 negative carriers in both the Pazopanib arm and the placebo arm, however, due to small sample size, the PFS increase in the Pazopanib arm was not statistically significant. 26740259 PubMed Harter et al., 2016, Gynecol. Oncol. 3 accepted 1675 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Rare Germline 2016-09-23 19:25:48 UTC https://civicdb.org/links/evidence_items/1675 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false BRCA2 675 Mutation Ovarian Cancer 2394 Prognostic Supports B Better Outcome 664 patients with non-bulky FIGO Stage II-IV ovarian cancer were evaluated for PFS when treated with Pazopanib versus placebo. Of the 664 patients, 10% (n=68) were BRCA1+, 4% were BRCA 2+ (n=29) and 85% (n=567) were BCRA1/2 negative. Longer progression free survival was observed in BRCA1/2 positive carriers versus BRCA1/2 negative carriers in both the Pazopanib arm and the placebo arm, however, due to small sample size, the PFS increase in the Pazopanib arm was not statistically significant. 26740259 PubMed Harter et al., 2016, Gynecol. Oncol. 3 accepted 1676 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Rare Germline 2016-09-23 20:15:04 UTC https://civicdb.org/links/evidence_items/1676 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false BRCA1 672 Mutation Ovarian Cancer 2394 Olaparib,Cediranib Combination Predictive Supports B Sensitivity/Response 46 women with platinum-sensitive, high-grade, BRCA1/2+ ovarian cancer received either olaparib monotherapy or olaparib/cediranib combination therapy. Median PFS was increased in combination therapy (17.7 months versus 9.0 months; HR=0.42; 95%CI 0.23-0.76; p=0.005); overall response rate was increased in the combination therapy (79.6% versus 47.8%; p=0.002); and total deaths were reduced in combination therapy (6 patients versus 10 patients). 25218906 PubMed Liu et al., 2014, Lancet Oncol. NCT01116648 3 accepted 1677 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Rare Germline 2016-09-23 19:25:38 UTC https://civicdb.org/links/evidence_items/1677 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false BRCA2 675 Mutation Ovarian Cancer 2394 Cediranib,Olaparib Combination Predictive Supports B Sensitivity/Response 46 women with platinum-sensitive, high-grade, BRCA1/2+ ovarian cancer received either olaparib monotherapy or olaparib/cediranib combination therapy. Median PFS was increased in combination therapy (17.7 months versus 9.0 months; HR=0.42; 95%CI 0.23-0.76; p=0.005); overall response rate was increased in the combination therapy (79.6% versus 47.8%; p=0.002); and total deaths were reduced in combination therapy (6 patients versus 10 patients). 25218906 PubMed Liu et al., 2014, Lancet Oncol. NCT01116648 3 accepted 1678 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Rare Germline 2016-09-23 20:15:38 UTC https://civicdb.org/links/evidence_items/1678 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false BRCA2 675 D3095E Breast Cancer 1612 Predisposing N/A C N/A 49-year old woman diagnosed with breast cancer was assessed for BRCA2 mutations. Algorithms including Align-GVGD predicted pathogenicity, however PolyPhen predicted that this variant was benign. The author’s assessment of the factors predicts a pathogenicity probability of 0.73 and an Odds Ratio of 2.7. 18951446 PubMed Plon et al., 2008, Hum. Mutat. 3 accepted 1679 661 7 13 32968854 32968854 C A ENST00000544455.1 75 GRCh37 Rare Germline 2020-12-12 22:27:09 UTC https://civicdb.org/links/evidence_items/1679 https://civicdb.org/links/variants/661 https://civicdb.org/links/genes/7 false MLH1 4292 EXPRESSION Stomach Carcinoma 5517 Prognostic Supports B Poor Outcome 46 patients with poorly cohesive, signet-cell ring, gastric carcinoma were evaluated for genetic mutations and MLH1 expression (immunohistochemistry). Overall survival rate of MLH1 negative cases were significantly better than MLH1 positive cases (p=0.020). 27313181 PubMed Rokutan et al., 2016, J. Pathol. 3 accepted 1680 662 3532 3 37034823 37092409 ENST00000231790.2 75 GRCh37 Somatic 2016-11-03 19:01:46 UTC https://civicdb.org/links/evidence_items/1680 https://civicdb.org/links/variants/662 https://civicdb.org/links/genes/3532 false BCOR 54880 Mutation Stomach Cancer 10534 Prognostic Supports B Better Outcome 46 patients with poorly cohesive, signet-cell ring, gastric carcinoma were evaluated for genetic mutations. Overall survival rate of BCOR positive cases were significantly better than BCOR negative cases cases (p=0.038). 27313181 PubMed Rokutan et al., 2016, J. Pathol. 3 accepted 1681 663 12555 X 39910501 40036582 ENST00000342274.4 75 GRCh37 Somatic 2016-09-23 20:17:55 UTC https://civicdb.org/links/evidence_items/1681 https://civicdb.org/links/variants/663 https://civicdb.org/links/genes/12555 false CDH1 999 MUTATION Stomach Carcinoma 5517 Prognostic Supports E Poor Outcome 285 intestinal-type tumors and 183 diffuse-type tumors were evaluated for mutational profiles. CDH1 mutations are associated with diffuse type mucinous gastric carcinoma, which indicate worse prognosis when compared to intestinal type (p<0.001). 27313181 PubMed Rokutan et al., 2016, J. Pathol. 2 accepted 1682 664 888 16 68771128 68869451 ENST00000261769.5 75 GRCh37 Somatic 2016-10-12 03:25:22 UTC https://civicdb.org/links/evidence_items/1682 https://civicdb.org/links/variants/664 https://civicdb.org/links/genes/888 false RHOA 387 MUTATION Stomach Carcinoma 5517 Prognostic Supports E Poor Outcome 285 intestinal-type tumors and 183 diffuse-type tumors were evaluated for mutational profiles. RHOA mutations are associated with diffuse type mucinous gastric carcinoma, which indicate worse prognosis when compared to intestinal type (p<0.001). 27313181 PubMed Rokutan et al., 2016, J. Pathol. 2 accepted 1683 665 399 3 49396578 49449635 ENST00000418115.1 75 GRCh37 Somatic 2016-10-10 22:14:32 UTC https://civicdb.org/links/evidence_items/1683 https://civicdb.org/links/variants/665 https://civicdb.org/links/genes/399 false BRCA1 672 Mutation Triple-receptor Negative Breast Cancer 0060081 Carboplatin,Cisplatin Substitutes Predictive Supports B Sensitivity/Response In an evaluation of 77 patients, those who had BRCA1/2 germline mutations (n=11) had an increase response rate to cisplatin when compared to those without germline mutations (54.5% versus 19.7%; P=0.022) although progression free survival and overall survival was not significantly different. 25847936 PubMed Isakoff et al., 2015, J. Clin. Oncol. NCT00483223 3 accepted 1684 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Rare Germline 2016-09-23 19:25:13 UTC https://civicdb.org/links/evidence_items/1684 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false BRCA2 675 Mutation Triple-receptor Negative Breast Cancer 0060081 Carboplatin,Cisplatin Substitutes Predictive Supports B Sensitivity/Response In an evaluation of 77 patients, those who had BRCA1/2 germline mutations (n=11) had an increase response rate to cisplatin when compared to those without germline mutations (54.5% versus 19.7%; P=0.022) although progression free survival and overall survival was not significantly different. 25847936 PubMed Isakoff et al., 2015, J. Clin. Oncol. NCT00483223 3 accepted 1685 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Rare Germline 2016-09-23 20:15:29 UTC https://civicdb.org/links/evidence_items/1685 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false ERBB2 2064 Amplification Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance A cohort of patient-derived xenografts (PDX) from 85 patients with metastatic colorectal cancer was created. PDX were treated with cetuximab and mechanisms of resistance investigated. None of the xenografts harboring KRAS (N=18), NRAS (N=7) or BRAF (N=3) mutations showed a response to cetuximab whereas 1 out of 4 xenografts with a PIK3CA mutation responded to cetuximab. Among 11 quadruple-negative samples with resistance to cetuximab, HER2 overexpression and amplification (N=3) and amplification (N=1) were identified. In an independent second retrospective patient cohort, 3 out of 17 patients with KRAS wt, cetuximab resitant CRC were found to harbor HER2 overexpression and amplification. In this cohort no HER2 overexpression or amplification was identified in 14 KRAS wt patients with response to cetuximab. 22586653 PubMed Bertotti et al., 2011, Cancer Discov 4 accepted 1686 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. N/A 2016-09-23 15:55:59 UTC https://civicdb.org/links/evidence_items/1686 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance A cohort of patient-derived xenografts (PDX) from 85 patients with metastatic colorectal cancer was created. PDX were treated with cetuximab and mechanisms of resistance investigated. None of the xenografts harboring KRAS (N=18), NRAS (N=7) or BRAF (N=3) mutations showed resistance whereas 1 out of 4 xenografts with a PIK3CA mutation responded to cetuximab. Among 11 quadruple-negative samples with resistance to cetuximab, HER2 overexpression and amplification (N=3) and amplification (N=1) were identified. In an independent second retrospective cohort, 3 out of 17 patients with KRAS wt, cetuximab resitant CRC were found to harbor HER2 overexpression and amplification. In this cohort no HER2 overexpression or amplification was identified in 14 KRAS wt patients with response to cetuximab. 22586653 PubMed Bertotti et al., 2011, Cancer Discov 4 accepted 1687 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. N/A 2016-10-06 18:38:51 UTC https://civicdb.org/links/evidence_items/1687 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Supports B Resistance HER2 amplification (FISH) was assessed in 170 KRAS wt mCRC patients treated with cetuximab or panitumumab. HER2 copy number status was significantly correlated with response rate, PFS and OS. Patients with amplification in all neoplastic cells (4%) had worse outcome compared to patients without amplification (35%, intermediate outcome) or amplification in minor clones (61%, highest survival probability). 23348520 PubMed Martin et al., 2013, Br. J. Cancer 2 accepted 1688 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. N/A 2020-08-13 00:39:18 UTC https://civicdb.org/links/evidence_items/1688 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Colorectal Cancer 9256 Trastuzumab,Lapatinib Combination Predictive Supports B Sensitivity/Response Phase 2 study in 27 patients with HER2 positive (IHC, FISH), KRAS wt metastatic colorectal cancer refractory to standard of care received trastuzumab and lapatinib. After a median follow-up of 94 weeks, eight (30%, 95% CI 14-50) of 27 patients had achieved an objective response, with one patient (4%, 95% CI -3 to 11) achieving a complete response, and seven (26%, 95% CI 9-43) achieving partial responses; 12 (44%, 95% CI 25-63) patients had stable disease. A total of 914 patients with KRAS wt were screened for this study, 48 patients (5%) were identified to have HER2-positive tumors. 27108243 PubMed Sartore-Bianchi et al., 2016, Lancet Oncol. 4 accepted 1689 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. N/A 2016-09-23 15:57:31 UTC https://civicdb.org/links/evidence_items/1689 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ROS1 6098 Rearrangement Lung Adenocarcinoma 3910 Crizotinib Predictive Supports C Sensitivity/Response In an evaluation of a patient and never smoker with crizotinib-sensitive lung adenocarcinoma, an SDC4-ROS1 rearrangement was identified using comprehensive genomic profiling. The patient attained a decrease in RESIST target lesions by 26.8% (stable disease); however, the patient relapsed 4 months later. This patient also harbored a TP53 mutation, MCL1 amplification and CDKN2A deletion. 25922291 PubMed Le et al., 2015, Clin Lung Cancer 3 accepted 1690 269 4941 6 117609463 117747018 ENST00000368508.3 75 GRCh37 ROS1 is a receptor tyrosine kinase that frequently forms gene fusions in several cancer types. Approximately 2% of NSCLC patients harbor a ROS1 gene fusion. Several fusion partners have been described with a constant ROS1-breakpoint, maintaining the kinase domain (Solomon B, 2015). Following case-studies and retrospective analyses, an expansion cohort of a phase-1 study showed clinical benefit of crizotinib in ROS1 rearranged NSCLC. The benefit was independent of the type of ROS1-rearrangement (Shaw et. al.,2014). Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1690 https://civicdb.org/links/variants/269 https://civicdb.org/links/genes/4941 false ALK 238 Fusion Lung Adenocarcinoma 3910 Crizotinib Predictive Supports C Sensitivity/Response In an evaluation of a patient with crizotinib-sensitive lung adenocarcinoma, an EML4-ALK-E13;A20 rearrangement was identified using CGP. The patient attained a reduction in the target lesions by 14.2%, however, the patient relapsed 17 months later. 25922291 PubMed Le et al., 2015, Clin Lung Cancer 3 accepted 1691 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1691 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false MET 4233 Amplification Lung Adenocarcinoma 3910 Crizotinib Predictive Supports C Sensitivity/Response In an evaluation of a patient with crizotinib-sensitive lung adenocarcinoma, an MET-Amplification was identified using CGP. The patient attained a reduction in the target lesions by 38.7%, and the patient maintained response for at least 5 months post-treatment. 25922291 PubMed Le et al., 2015, Clin Lung Cancer 3 accepted 1692 270 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1692 https://civicdb.org/links/variants/270 https://civicdb.org/links/genes/52 false ERBB2 2064 Amplification Scrotum Paget's Disease 3444 Trastuzumab Predictive Supports C Sensitivity/Response A 71-year old male with metastatic extramammary Paget’s disease of the scrotum overexpressing Her2/neu was treated with trastuzumab, achieving a complete response. At 12 months, he maintains stable disease. 25692060 PubMed Barth et al., 2015, Case Rep Oncol Med 2 accepted 1693 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-09-23 19:20:06 UTC https://civicdb.org/links/evidence_items/1693 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Mutation Bladder Carcinoma 4007 Platinum Compound Predictive Supports C Sensitivity/Response In patients with muscle-invasive bladder chancer, a cohort of complete responders to platinum chemotherapy (n=38) and non-responders to platinum chemotherapy (n=33) were evaluated for 178 cancer-associated genes. Of the complete responders, 24% had an ERBB2 missense mutations and no non-responders had ERBB2 mutations (p=0.003). 25636205 PubMed Groenendijk et al., 2016, Eur. Urol. 3 accepted 1694 666 20 17 37868196 37881332 ENST00000269571.5 75 GRCh37 Somatic 2016-11-05 22:16:28 UTC https://civicdb.org/links/evidence_items/1694 https://civicdb.org/links/variants/666 https://civicdb.org/links/genes/20 false MEN1 4221 FRAMESHIFT TRUNCATION Thyroid Gland Hurthle Cell Carcinoma 8161 Diagnostic Supports C Positive Two patients diagnosed with oncocytic thyroid carcinoma (hurthle cell thyroid carcinoma) were evaluated for MEN1 mutations. One tumor showed 592-end deletion of MEN1 and the other showed a 521 frameshift mutation. These mutations are similar to the ones seen in MEN1 syndrome inducing endocrine gland tumors. 25625803 PubMed Kasaian et al., 2015, J. Clin. Endocrinol. Metab. 2 accepted 1695 667 3485 11 64572092 64572092 C ENST00000337652.1 75 GRCh37 Somatic 2016-11-06 00:51:14 UTC https://civicdb.org/links/evidence_items/1695 https://civicdb.org/links/variants/667 https://civicdb.org/links/genes/3485 false KMT2C 58508 MUTATION Skin Squamous Cell Carcinoma 3151 Prognostic Supports B Poor Outcome Evaluation of 39 aggressive cutaneous squamous cell carcinomas revealed that tumors with a KMT2C mutation were 5x more likely to invade the bone (53% versus 10%; p=0.008). Patients with KMT2C mutations also had significantly shorter recurrent free survival (21.6 versus 167.5; p=0.003) and an increased hazards ratio for death (HR=5.16; 95%CI:1.55 to 17.18). This worse prognosis did not appear to be correlated with bone invasion (p=0.98). 25303977 PubMed Pickering et al., 2014, Clin. Cancer Res. 3 accepted 1696 668 14089 7 151832010 152133090 ENST00000262189.6 75 GRCh37 Somatic 2017-01-18 17:23:24 UTC https://civicdb.org/links/evidence_items/1696 https://civicdb.org/links/variants/668 https://civicdb.org/links/genes/14089 false STAG2 10735 MUTATION Ewing Sarcoma Of Bone 3368 Prognostic Supports B Poor Outcome In a study of 96 Ewing sarcoma tumors, 15% showed heterogenous loss of STAG2 expression in IHC analysis. Of those with STAG2 expression loss, 88% presented with metastatic disease compared to only 27% of patients who expressed STAG2 on IHC (P=0.002). 25186949 PubMed Crompton et al., 2014, Cancer Discov 4 accepted 1697 669 8553 X 123176418 123217308 ENST00000218089.9 75 GRCh37 N/A 2016-11-07 18:19:40 UTC https://civicdb.org/links/evidence_items/1697 https://civicdb.org/links/variants/669 https://civicdb.org/links/genes/8553 false BRAF 673 V600E Multiple Myeloma 9538 Vemurafenib Predictive Supports C Sensitivity/Response A 65-year-old man presented with stage II myeloma. He was initially treated with chemotherapy and he received an autologous stem cell transplant. Sequencing of the recurrent tumor harbored BRAF V600E mutation and he was treated with vemurafenib. After 7 weeks of treatment, the patient relapsed and died. 24997557 PubMed Sharman et al., 2014, Clin Lymphoma Myeloma Leuk 3 accepted 1698 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-11-05 22:24:29 UTC https://civicdb.org/links/evidence_items/1698 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Multiple Myeloma 9538 Vemurafenib Predictive Supports C Sensitivity/Response A 54-year-old man presented with stage II myeloma. He was initially treated with chemotherapy and received an autologous stem cell transplant. Genomic profiling of the bone biopsy revealed BRAF V600E activating mutation and the patient was treated with vemurafenib. At 4-months post treatment (time of case study report) the patient maintains near-resolution of hypermetabolic lesions. 24997557 PubMed Sharman et al., 2014, Clin Lymphoma Myeloma Leuk 2 accepted 1699 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2016-11-05 22:24:12 UTC https://civicdb.org/links/evidence_items/1699 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false KRAS 3845 Mutation Lung Adenocarcinoma 3910 Prognostic Supports B Poor Outcome In a study of 1036 patients with lung adenocarcinoma, patients with KRAS mutations (n=241) showed worse prognosis (OS: 19 months versus 23 months; HR=1.21; P=0.048). 22810899 PubMed Johnson et al., 2013, Cancer 4 accepted 1700 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1700 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false EGFR 1956 Mutation Lung Adenocarcinoma 3910 Prognostic Supports B Better Outcome In a study of 1036 patients with lung adenocarcinomas, patients with EGFR mutations (n=275) showed better prognosis (OS: 34 months versus 23 months; HR=0.6; P<0.001). 22810899 PubMed Johnson et al., 2013, Cancer 4 accepted 1701 442 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1701 https://civicdb.org/links/variants/442 https://civicdb.org/links/genes/19 false KRAS 3845 Mutation Colorectal Cancer 9256 Cetuximab Predictive Supports D Resistance A cohort of patient-derived xenografts (PDX) from 85 patients with metastatic colorectal cancer was created. PDX were treated with cetuximab and mechanisms of resistance investigated. None of the xenografts harboring KRAS (N=18), NRAS (N=7) or BRAF (N=3) mutations showed a response to cetuximab whereas 1 out of 4 xenografts with a PIK3CA mutation responded to cetuximab. 22586653 PubMed Bertotti et al., 2011, Cancer Discov 3 accepted 1702 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2016-11-11 22:15:33 UTC https://civicdb.org/links/evidence_items/1702 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false NRAS 4893 Mutation Colorectal Cancer 9256 Cetuximab Predictive Supports D Resistance A cohort of patient-derived xenografts (PDX) from 85 patients with metastatic colorectal cancer was created. PDX were treated with cetuximab and mechanisms of resistance investigated. None of the xenografts harboring KRAS (N=18), NRAS (N=7) or BRAF (N=3) mutations showed a response to cetuximab whereas 1 out of 4 xenografts with a PIK3CA mutation responded to cetuximab. 22586653 PubMed Bertotti et al., 2011, Cancer Discov 2 accepted 1703 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2016-11-11 22:21:57 UTC https://civicdb.org/links/evidence_items/1703 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false BRAF 673 Mutation Colorectal Cancer 9256 Cetuximab Predictive Supports D Resistance A cohort of patient-derived xenografts (PDX) from 85 patients with metastatic colorectal cancer was created. PDX were treated with cetuximab and mechanisms of resistance investigated. None of the xenografts harboring KRAS (N=18), NRAS (N=7) or BRAF (N=3) mutations showed a response to cetuximab whereas 1 out of 4 xenografts with a PIK3CA mutation responded to cetuximab. 22586653 PubMed Bertotti et al., 2011, Cancer Discov 2 accepted 1704 399 5 7 140453136 140481403 ENST00000288602.6 75 GRCh37 Somatic 2016-11-11 22:24:22 UTC https://civicdb.org/links/evidence_items/1704 https://civicdb.org/links/variants/399 https://civicdb.org/links/genes/5 false PIK3CA 5290 Mutation Colorectal Cancer 9256 Cetuximab Predictive Supports D Resistance A cohort of patient-derived xenografts (PDX) from 85 patients with metastatic colorectal cancer was created. PDX were treated with cetuximab and mechanisms of resistance investigated. None of the xenografts harboring KRAS (N=18), NRAS (N=7) or BRAF (N=3) mutations showed a response to cetuximab and only 1 out of 4 xenografts with a PIK3CA mutation responded to cetuximab. 22586653 PubMed Bertotti et al., 2011, Cancer Discov 1 accepted 1705 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2016-11-12 03:24:27 UTC https://civicdb.org/links/evidence_items/1705 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false MYCL 4610 EXPRESSION Multiple Myeloma 9538 JQ1,I-BET151 Substitutes Predictive Supports D Sensitivity/Response Four myeloma cell lines were treated with two different BET inhibitors (I-BET151 or JQ1). Proliferation of three cell lines (KMS11, RPMI8226 and MM1S) but not U266 (only partial inhibition) was strongly inhibited by the BET inhibitors. Microarray analysis showed a downregulation of MYC-dependent genes after treatment. qRT-PCR showed that MYCL1 but not c-MYC and MYCN was expressed in U266 cells and I-BET151 induced downregulation of MYCL1. In contrast, c-MYC but not MYCL was expressed in the other cell lines and I-BET151 induced downregulation of c-MYC. 27276402 PubMed Suzuki et al., 2016, Anticancer Drugs 1 accepted 1706 670 3738 1 40361098 40367685 ENST00000397332.2 75 GRCh37 N/A 2016-11-09 22:18:23 UTC https://civicdb.org/links/evidence_items/1706 https://civicdb.org/links/variants/670 https://civicdb.org/links/genes/3738 false HGF 3082 EXPRESSION Glioblastoma 3068 MET Tyrosine Kinase Inhibitor SGX523 Predictive Supports D Sensitivity/Response Three metastatic glioblastoma cell lines were compared with their parental cell lines with regard to differential gene expression. HGF signalling was among the top pathways identified. Exogenous HFG led to an increase in MET activity (except in one cell line with high endogenous HGF levels) which was abrogated by MET inhibitor SGX523. Three HGF autocrine cell lines were grown in mice and showed significantly increased sensitivity to SGX523 than three non-HGF autocrine cell lines (P<0.05). 22203985 PubMed Xie et al., 2012, Proc. Natl. Acad. Sci. U.S.A. 2 accepted 1707 671 2591 7 81328322 81399514 ENST00000222390.5 75 GRCh37 N/A 2016-11-12 03:42:28 UTC https://civicdb.org/links/evidence_items/1707 https://civicdb.org/links/variants/671 https://civicdb.org/links/genes/2591 false EGFR 1956 Expression Colorectal Cancer 9256 Panitumumab Predictive Supports B Sensitivity/Response 463 patients with 1% or more EGFR tumor cell membrane staining, with metastatic CRC progressive after standard chemotherapy were randomized to panitumumab plus best supportive care (BSC, n = 231) or BSC alone (n = 232). Panitumumab significantly prolonged PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66, [P < .0001]). Objective response rates favored panitumumab over BSC; after a 12-month minimum follow-up, response rates were 10% for panitumumab and 0% for BSC (P < .0001). No difference was observed in OS (HR, 1.00; 95% CI, 0.82 to 1.22), but 76% of BSC patients entered the cross-over study. 17470858 PubMed Van Cutsem et al., 2007, J. Clin. Oncol. 2 accepted 1708 354 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 N/A 2016-09-27 23:14:31 UTC https://civicdb.org/links/evidence_items/1708 https://civicdb.org/links/variants/354 https://civicdb.org/links/genes/19 false EGFR 1956 Expression Colorectal Cancer 9256 Cetuximab Predictive Supports B Sensitivity/Response 57 patients with chemorefractory colorectal cancer expressing EGFR (IHC staining) were treated with single-agent cetuximab in this phase 2 study. Five patients (9%; 95% CI, 3% to 19%) achieved a partial response. Twenty-one additional patients had stable disease or minor responses. The median survival in these previously treated patients with chemotherapy-refractory colorectal cancer was 6.4 months. 14993230 PubMed Saltz et al., 2004, J. Clin. Oncol. 1 accepted 1709 354 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 N/A 2016-09-27 23:14:59 UTC https://civicdb.org/links/evidence_items/1709 https://civicdb.org/links/variants/354 https://civicdb.org/links/genes/19 false SOX10 6663 Loss Melanoma 1909 Vemurafenib Predictive Supports D Resistance FACS-assisted shRNA genetic screen identified SOX10 as a determinant of vemurafenib resistance. Suppression of SOX10 in melanoma cells confers resistance to BRAF and MEK inhibitors through activation of TGF-β signalling and upregulation of EGFR and PDGFRB. EGFR expression or exposure to TGF-β becomes beneficial for proliferation of melanoma cells in the presence of BRAF or MEK inhibitors. Melanoma cells with low SOX10 and consequently high EGFR expression are enriched in the presence of vemurafenib. This study finds evidence for SOX10 loss (N=2) and/or activation of TGF-β signalling (N=2) in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. 24670642 PubMed Sun et al., 2014, Nature 4 accepted 1710 672 5418 22 38368307 38380544 ENST00000396884.2 75 GRCh37 N/A 2016-09-28 15:53:43 UTC https://civicdb.org/links/evidence_items/1710 https://civicdb.org/links/variants/672 https://civicdb.org/links/genes/5418 false FGF2 2247 EXPRESSION Acute Myeloid Leukemia 9119 Quizartinib Predictive Supports D Resistance AML MOLM14 cells were cocultured with FLT3 inhibitor AC220 (10 nM) and selected proteins expressed in the bone marrow microenvironment. FL and FGF2 were the only proteins that increased viability >2 standard deviations. FGFR inhibitor PD173074 (and FGFR1 siRNA) was able to attenuate the protective effect of FGF2. Removing FL or FGF2 from ligand-dependent resistant cultures transiently restored sensitivity to AC220, but accelerated acquisition of secondary resistance mutations. 10 FLT3-ITD AML patients treated with AC220 developed increased FGF2 expression (IHC) in marrow stromal cells, which peaked prior to overt clinical relapse and detection of resistance mutations 27671675 PubMed Traer et al., 2016, Cancer Res. 4 accepted 1711 673 1872 4 123747863 123819391 ENST00000264498.3 75 GRCh37 N/A 2016-11-09 21:00:49 UTC https://civicdb.org/links/evidence_items/1711 https://civicdb.org/links/variants/673 https://civicdb.org/links/genes/1872 false EIF1AX 1964 MUTATION Uveal Melanoma 6039 Prognostic Supports C Better Outcome EIF1AX was identified as a uveal melanoma (UM) driver gene by whole-exome sequencing. Approximately 14%–20% of UM carry a mutation in EIF1AX, with most mutations found in exons 1 and 2. EIF1AX mutations are associated with a good prognosis, and are inversely associated with metastasis. This assertion is based on observed survival for 19 EIF1AX mutant UM cases compared to 69 EIF1AX wildtype cases. 23793026 PubMed Martin et al., 2013, Nat. Genet. 4 accepted 1712 674 1646 X 20156713 20159754 ENST00000379607.5 75 GRCh37 Somatic 2016-10-11 17:06:04 UTC https://civicdb.org/links/evidence_items/1712 https://civicdb.org/links/variants/674 https://civicdb.org/links/genes/1646 false MET 4233 Amplification Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Sensitivity/Response Case report of two patients with MET amplification (MET:CEP7 ratio ≥5) and no concomitant MET exon 14 deletion. A response to crizotinib was observed in both cases suggesting that MET amplification may predict response to this drug even in the absence of MET exon 14 mutations. 27664533 PubMed Caparica et al., 2017, J Thorac Oncol 2 accepted 1713 270 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 N/A 2016-11-09 17:44:49 UTC https://civicdb.org/links/evidence_items/1713 https://civicdb.org/links/variants/270 https://civicdb.org/links/genes/52 false MET 4233 Amplification Cancer 162 Crizotinib Predictive Supports C Sensitivity/Response Case report of a 59-year-old white female patient (60 pack-years) with a CUP-syndrome. Molecular profiling identified both MET amplification (16 copies) and a KRAS G12V mutation. The patient was treated with crizotinib and experienced a complete normalization of tumor metabolic activity for more than 19 months. Other identified aberrations include CCND1 amplification (8 copies), MYC amplification (9 copies) as well as KRAS G12V, TP53 R273L and CARD11 N184S. 25232318 PubMed Palma et al., 2014, Case Rep Oncol 3 accepted 1714 270 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 N/A 2016-11-07 20:33:27 UTC https://civicdb.org/links/evidence_items/1714 https://civicdb.org/links/variants/270 https://civicdb.org/links/genes/52 false KRAS 3845 G12V Cancer 162 Crizotinib Predictive Does Not Support C Resistance Case report of a 59-year-old white female patient (60 pack-years) with a CUP-syndrome. Molecular profiling identified both MET amplification (16 copies) and a KRAS G12V mutation. The patient was treated with crizotinib and experienced a complete normalization of tumor metabolic activity for more than 19 months. Other identified aberrations include CCND1 amplification (8 copies), MYC amplification (9 copies) as well as KRAS G12V, TP53 R273L and CARD11 N184S. 25232318 PubMed Palma et al., 2014, Case Rep Oncol 2 accepted 1715 425 30 12 25398284 25398284 C A ENST00000256078.4 75 GRCh37 KRAS mutations are the most common mutations in pancreatic cancer occurring in > 90% of cases. Of these the G12D activating mutation is the most prevalent and results in a loss of GTPase activity which in turn leads to a constitutively active form of KRAS. This is enough to cause pre-cancerous pancreatic intraepithelial lesions Somatic 2016-11-07 20:32:51 UTC https://civicdb.org/links/evidence_items/1715 https://civicdb.org/links/variants/425 https://civicdb.org/links/genes/30 false PAX8 7849 Expression Female Reproductive Organ Cancer 120 Diagnostic Supports A Positive The authors explored the viability of PAX8 expression as a biomarker for differentiating mullerian from non-mullerian tumors. 74 tumors (37 Mullerian/37 non-Mullerian) were examined for PAX8 expression via IHC. Of these 29/37 Mullerian and 1/37 non-Mullerian tumors exhibited PAX8 expression. The sensitivity and specificity of using this as a biomarker to differentiate between the two tumor types was 78.4% and 97.3% respectively. 24800185 PubMed Heidarpour et al., 2014, Adv Biomed Res 4 accepted 1716 683 75 2 113973574 114036527 ENST00000429538.3 75 GRCh37 N/A 2020-10-21 04:32:49 UTC https://civicdb.org/links/evidence_items/1716 https://civicdb.org/links/variants/683 https://civicdb.org/links/genes/75 false PRDM1 639 MUTATION Diffuse Large B-cell Lymphoma 0050745 Prognostic Supports B Poor Outcome In 177 patients with activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), PRDM1 mutations (N=46) were associated with worse overall (P=0.016) and progression-free (P=0.023) survival compared to wildtype patients. This may have been driven by patients with exon1-2 mutations (N=15; P=0.021 for OS; P=0.024 for PFS) versus those with exon 3-7 mutations (N=31; P=0.16 for OS; P=0.24 for PFS) when compared to wildtype patients. Multivariate analysis did not identify PRDM1 mutations as an independent prognostic factor. 27568520 PubMed Xia et al., 2016, Leukemia 2 accepted 1717 644 593 6 106534195 106557813 ENST00000369096.4 75 GRCh37 Somatic 2020-09-29 03:10:03 UTC https://civicdb.org/links/evidence_items/1717 https://civicdb.org/links/variants/644 https://civicdb.org/links/genes/593 false ERRFI1 54206 E384* Cholangiocarcinoma 4947 Erlotinib Predictive Supports C Sensitivity/Response An ERRFI1 (E384X) was detected in a patient with metastatic, recurrent/refractory cholangiocarcinoma (allelic fraction 11%) without any mutations or amplifications in other EGFR signaling members such as EGFR and BRAF. The patient was treated with erlotinib 150 mg orally/daily. After 3 months, RECIST v1.1 partial response evidenced by a decrease of 58% in the sum of largest diameters was observed. 24550739 PubMed Borad et al., 2014, PLoS Genet. 2 accepted 1724 691 12271 1 8073509 8073509 C A ENST00000377482.5 75 GRCh37 Somatic 2016-11-05 23:29:20 UTC https://civicdb.org/links/evidence_items/1724 https://civicdb.org/links/variants/691 https://civicdb.org/links/genes/12271 false KIT 3815 D816V Systemic Mastocytosis 349 Midostaurin Predictive Supports B Sensitivity/Response In a phase II clinical trial, 60% of patients (N=89) with advanced systemic mastocytosis responded to treatment with midostaurin. 27355533 PubMed Gotlib et al., 2016, N. Engl. J. Med. NCT00782067 4 accepted 1725 65 29 4 55599321 55599321 A T ENST00000288135.5 75 GRCh37 KIT D816V is a mutation observed in acute myeloid leukemia (AML). This variant has been linked to poorer prognosis and worse outcome in AML patients. Somatic 2016-11-04 23:12:13 UTC https://civicdb.org/links/evidence_items/1725 https://civicdb.org/links/variants/65 https://civicdb.org/links/genes/29 false KIT 3815 D816V Systemic Mastocytosis 349 Prognostic Supports B Poor Outcome The D816V+ advanced systemic mastocytosis patients with additional mutations in SRSF2 (N=30), ASLX1 (N=20), or RUNX1 (N=16) exhibited lower overall survival over 14 years as compared to D816V+ patients with wildtype SRSF2 (N=40), ASXL1(N=50), or RUNX1 (N=54). 26464169 PubMed Jawhar et al., 2016, Leukemia 4 accepted 1726 65 29 4 55599321 55599321 A T ENST00000288135.5 75 GRCh37 KIT D816V is a mutation observed in acute myeloid leukemia (AML). This variant has been linked to poorer prognosis and worse outcome in AML patients. Somatic 2016-11-04 23:08:09 UTC https://civicdb.org/links/evidence_items/1726 https://civicdb.org/links/variants/65 https://civicdb.org/links/genes/29 false ESR1 2099 S463P Estrogen-receptor Positive Breast Cancer 0060075 Aromatase Inhibitor Predictive Supports D Resistance ESR1 S463P variants were observed after extensive treatment with hormonal therapy (aromatase inhibition). Expression of the S463P mutant was found to induce modest activity in the absence of hormone. This mutation displayed elevated levels of Ser118 phosphorylation compared to wild-type ERα and appeared to possess estrogen-independent activity. 24185512 PubMed Toy et al., 2013, Nat. Genet. 2 accepted 1727 692 21 6 152415537 152415537 T C ENST00000440973.1 75 GRCh37 Somatic 2016-11-12 14:53:20 UTC https://civicdb.org/links/evidence_items/1727 https://civicdb.org/links/variants/692 https://civicdb.org/links/genes/21 false EGFR 1956 Mutation Lung Non-small Cell Carcinoma 3908 Afatinib Predictive Supports B Sensitivity/Response In the LUX-LUNG 7 trial, (NCT01466660) stage IIIB or IV NSCLC patients with EGFR exon 19 deletion, (n=186) Leu858Arg mutation, (n=132) or both (n=1) were divided into equal groups and treated with first line reversible EGFR inhibitor gefitinib or irreversible pan-ErbB family inhibitor afatinib in order to obtain a direct comparison of these two approved first line treatments. Significant difference was seen in objective response with 70% of cases with afatinib vs. 56% of cases with gefitinib. Median progression free survival was 11.0 months (10.6-12.9) with afatinib and 10.9 months (9.1-11.5) with gefitinib, HR 0.73 [0.57-0.95] p=0.017. 27083334 PubMed Park et al., 2016, Lancet Oncol. NCT01466660 4 accepted 1728 442 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2016-11-04 23:03:54 UTC https://civicdb.org/links/evidence_items/1728 https://civicdb.org/links/variants/442 https://civicdb.org/links/genes/19 false SGK1 6446 Overexpression Breast Cancer 1612 Alpelisib Predictive Supports D Resistance SGK1 mRNA expression was elevated in five breast cancer cell lines which were resistant to PI3Kalpha inhibitor alpelisib (NVP-BYL719) in comparison to five sensitive cell lines. Western blots showed clear elevation of protein levels in 3/5 resistant cell lines. Ectopic SGK1 expression in sensitive MDA-MB-361 cells resulted in alpelisib resistance and preservation of phopho-S6K and phospho-4EBP with alpelisib treatment. Knockdown of SGK1 in resistant HCC1954 cells increased alpelisib sensitivity and reduced p-S6K and p-4EBP levels with alpelisib treatment. Promoter methylation at SGK1 was increased in sensitive cells compared to alpelisib resistant cell lines. 27451907 PubMed Castel et al., 2016, Cancer Cell 5 accepted 1729 693 5225 6 134490384 134639196 ENST00000367858.5 75 GRCh37 Somatic 2019-08-29 21:51:54 UTC https://civicdb.org/links/evidence_items/1729 https://civicdb.org/links/variants/693 https://civicdb.org/links/genes/5225 false SGK1 6446 Overexpression Breast Cancer 1612 Alpelisib Predictive Supports B Resistance A group of 18 breast cancer patients were treated with PI3Kalpha inhibitor alpelisib (NVP-BYL719) plus an aromatase inhbitor (NCT01870505). 3 out of 3 patients expressing high tumor SGK1 mRNA had disease progression as best response with median progression free survival (PFS) of 56 days, while 15 patients classified with low to medium SGK1 mRNA had median PFS 111 days with 4/15 having disease progression as best response. 27451907 PubMed Castel et al., 2016, Cancer Cell 3 accepted 1730 693 5225 6 134490384 134639196 ENST00000367858.5 75 GRCh37 N/A 2021-03-10 23:48:34 UTC https://civicdb.org/links/evidence_items/1730 https://civicdb.org/links/variants/693 https://civicdb.org/links/genes/5225 false SGK1 6446 Overexpression Breast Cancer 1612 Alpelisib,SGK1-Inh Combination Predictive Supports D Sensitivity/Response The alpelisib (PI3Kalpha inhibitor) resistant breast cancer cell line HCC1954 was treated with alpelsisb alone or in combination with the SGK1 kinase inhibitor SGK1-Inh. Addition of SGK1 reduced viability over alpelisib alone, and phospho-S6K as well as phospho-4EBP1 levels decreased with combination treatment. HCC1954 xenografts showed increased tumor volume with treatment of alpelisib or SGK1-Inh alone, but only combination treatment resulted in lack of volume increase and decreased phospho-S6K levels in tumors by IHC. 27451907 PubMed Castel et al., 2016, Cancer Cell 4 accepted 1731 693 5225 6 134490384 134639196 ENST00000367858.5 75 GRCh37 Somatic 2017-05-31 15:27:19 UTC https://civicdb.org/links/evidence_items/1731 https://civicdb.org/links/variants/693 https://civicdb.org/links/genes/5225 false KRAS 3845 G12D Pancreatic Ductal Carcinoma 3587 Prognostic Supports B Poor Outcome Exon-2 KRAS mutation status was analyzed in 219 patients with pancreatic ductal carcinoma, excluding those who had previously undergone chemotherapy, first-line pancreatic resection, or neoadjuvant treatment with chemotherapy or radiotherapy. 72 patients had wild-type KRAS, 147 had a codon-12 KRAS mutation (G12D, G12V, or G12R) and 73 had a G12D KRAS mutation, specifically. There was no significant difference in overall survival between wild-type patients and patients with any type of exon-12 mutation. However, patients with the G12D mutation exhibited significantly lower overall survival compared to wild-type patients in univariate and multivariate analyses. This difference in overall survival between wild-type and G12D patients persisted in the subset of patients who underwent chemotherapy at any point after enrollment. 27010960 PubMed Bournet et al., 2016, Clin Transl Gastroenterol 3 accepted 1732 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2016-11-03 05:47:44 UTC https://civicdb.org/links/evidence_items/1732 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false CD274 29126 Expression Lung Non-small Cell Carcinoma 3908 Pembrolizumab Predictive Supports B Sensitivity/Response This open-label, randomized, phase-3 clinical trial compared pembrolizumab to chemotherapy in treating NSCLC patients with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of EGFR or translocation of ALK. Patients in the pembrolizumab group exhibited significantly better progression-free survival and overall survival compared to patients in the chemotherapy group. 27718847 PubMed Reck et al., 2016, N. Engl. J. Med. NCT02142738 3 accepted 1733 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2016-11-07 18:20:37 UTC https://civicdb.org/links/evidence_items/1733 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false CCNE1 898 Overexpression Ovarian Cancer 2394 CDK Inhibitor SNS-032 Predictive Supports D Sensitivity/Response Four ovarian cancer cell lines with elevated CCNE1 expression were 40x more sensitive to Cdk2 inhibitor SNS-032 than four cell lines without CCNE1 overexpression. SNS-032 greatly prolonged the survival of mice with CCNE1 overexpressing xenografts. 26204491 PubMed Yang et al., 2015, Oncotarget 2 accepted 1734 24 11 19 30302805 30315215 ENST00000262643.3 75 GRCh37 Cyclin E, while currenly not as widely implicated as its counterpart, cyclin D, has been implicated in various carcinomas, including breast, gastric, stomach and colorectal. High levels of cyclin E, either by gene amplification or overexpression, are correlated with later stage disease and have been shown to lead to poorer prognosis in gastic carcinoma. It has also been shown, in lung cancer specifically, that neoplastic cells with higher levels of the cyclin E/CDK2 complex are more radiosensitive than their lowly expressed counterparts. N/A 2016-11-12 15:50:58 UTC https://civicdb.org/links/evidence_items/1734 https://civicdb.org/links/variants/24 https://civicdb.org/links/genes/11 false CCNE1 898 Amplification Ovarian Serous Cystadenocarcinoma 5746 Akt Inhibitor MK2206,Dinaciclib Combination Predictive Supports D Sensitivity/Response A high throughput compound screen identified synergistic combinations in CCNE1 amplified high grade serous ovarian carcinoma, including dinaciclib and AKT inhibitors 27663592 PubMed Au-Yeung et al., 2016, Clin. Cancer Res. 4 accepted 1735 187 11 19 30302805 30315215 ENST00000262643.3 75 GRCh37 Somatic 2016-11-04 19:33:16 UTC https://civicdb.org/links/evidence_items/1735 https://civicdb.org/links/variants/187 https://civicdb.org/links/genes/11 false EGFR 1956 G719S Lung Non-small Cell Carcinoma 3908 Gefitinib,Erlotinib Substitutes Predictive Supports B Sensitivity/Response This small clinical (n=56) study suggests that patients with minor mutations of EGFR, like G719S, are likely to have a moderate response to Tyrosine kinase inhibitors like Gefitinib and Erlotinib. In this study 44 of 56 patients were treated with either gefitinib or erlotinib. 35 patients had a G719 mutation but the majority of these were G719S (20 with G719S, 9 with G719A, 3 with G719C). 26124334 PubMed Otsuka et al., 2015, Anticancer Res. 3 accepted 1736 134 19 7 55241707 55241707 G A ENST00000275493.2 75 GRCh37 While not as recurrent as the L858R mutation, EGFR G719S has also been shown to be an activating mutation. In lung cancer cell lines, it also confers sensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib. Somatic 2018-01-30 17:20:46 UTC https://civicdb.org/links/evidence_items/1736 https://civicdb.org/links/variants/134 https://civicdb.org/links/genes/19 false STK11 6794 Loss Peutz-Jeghers Syndrome 3852 Predisposing Supports B Positive In a series of 33 patients with Peutz-Jeghers Syndrome, 17 mutations in STK11/LKB1 were observed in exons 1-8 (none in exon 9). 11 of these mutations were predicted to be truncating. These mutations occurred in 10/13 patients with familial PJS and 7/20 patients with sporadic PJS. 12865922 PubMed Lim et al., 2003, Br. J. Cancer 3 accepted 1737 485 5534 19 1205740 1228428 ENST00000326873.7 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/1737 https://civicdb.org/links/variants/485 https://civicdb.org/links/genes/5534 false BRAF 673 G596C Lung Non-small Cell Carcinoma 3908 Dabrafenib,Trametinib Combination Predictive Supports D Sensitivity/Response non-V600 BRAF mutations can be sensitive to clinically relevant doses of Dabrafenib and Trametinib in HEK293T cells, in lung epithelial cellular model (BEAS-2B) and in human cancer cell lines harboring non-V600 BRAF mutations 27577079 PubMed Noeparast et al., 2016, Oncotarget accepted 1738 694 5 7 140453149 140453149 C A ENST00000288602.6 75 GRCh37 Somatic 2021-06-08 01:31:04 UTC https://civicdb.org/links/evidence_items/1738 https://civicdb.org/links/variants/694 https://civicdb.org/links/genes/5 true SMARCB1 6598 Underexpression Synovial Sarcoma 5485 Tazemetostat Predictive Supports D Sensitivity/Response Treatment with tazemetostat , a small-molecule inhibitor of EZH2, results in concentration-dependent cell growth inhibition and cell death specifically in SS18-SSX-positive, SMARCB1-deficient synovial sarcomas. 27391784 PubMed Kawano et al., 2016, PLoS ONE 2 accepted 1739 695 5356 22 24129150 24176703 ENST00000344921.6 75 GRCh37 N/A 2016-11-15 16:47:45 UTC https://civicdb.org/links/evidence_items/1739 https://civicdb.org/links/variants/695 https://civicdb.org/links/genes/5356 false SMARCB1 6598 Deletion Rhabdoid Cancer 3672 Tazemetostat Predictive Supports D Sensitivity/Response EPZ-6438 (Tazemetostat) induces apoptosis and differentiation specifically in SMARCB1-deleted malignant rhabdoid tumors (MRT) cells. This study compared in vitro EPZ-6438 treatment of four SMARCB1-deleted MRT cell lines to three control (wild-type) cell lines. These data demonstrate the dependency of SMARCB1 mutant MRTs on EZH2 enzymatic activity and suggest treatment of these genetically defined cancers with EZH2 inhibitors. 23620515 PubMed Knutson et al., 2013, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 1740 696 5356 22 24129150 24176703 ENST00000344921.6 75 GRCh37 Somatic 2016-11-12 15:53:52 UTC https://civicdb.org/links/evidence_items/1740 https://civicdb.org/links/variants/696 https://civicdb.org/links/genes/5356 false PTEN 5728 Deletion Prostate Cancer 10283 Prognostic Supports B Poor Outcome A meta-analysis of 26 published studies including 8097 prostate cancer patients showed that, compared to patients with normal PTEN, patients with PTEN deletion exhibited a greater aggressive Gleason score (OR: 1.284, 95% CI = 1.145–1.439), pathological stage (OR: 1.628, 95% CI = 1.270–2.087), and risk for recurrence of prostate cancer (HR: 1.738, 95% CI = 1.264–2.390). 27470558 PubMed Gao et al., 2016, Biomed. Pharmacother. 4 accepted 1741 213 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2016-11-11 22:29:36 UTC https://civicdb.org/links/evidence_items/1741 https://civicdb.org/links/variants/213 https://civicdb.org/links/genes/41 false NF2 4771 Loss Thyroid Gland Carcinoma 3963 Selumetinib Predictive Supports D Sensitivity/Response NF2 loss promotes oncogenic RAS-signaling via YAP-dependent transactivation of RAS and sensitizes to MEK inhibition. The authors demonstrate this in (A) isogenic lines derived from C643 cells (HRASG13R, NF2-WT) modified to stably express shNF2, (B) in set of 7 RAS-mutant thyroid cancer cell lines that differ in their NF2 expression levels, and (C) in a Hras-G12V/Nf2-null mouse model. 26359368 PubMed Garcia-Rendueles et al., 2015, Cancer Discov 4 accepted 1742 697 3870 22 29999547 30094587 ENST00000338641.4 75 GRCh37 Somatic 2016-11-12 14:57:15 UTC https://civicdb.org/links/evidence_items/1742 https://civicdb.org/links/variants/697 https://civicdb.org/links/genes/3870 false NF1 4763 Loss Malignant Peripheral Nerve Sheath Tumor 5940 JQ1 Compound Predictive Supports D Sensitivity/Response BRD4 inhibition supressess growth and tumorigenesis of NF1-/-, TP53-/- MPNST cells in mouse xenografts 24373973 PubMed Patel et al., 2014, Cell Rep 3 accepted 1743 698 3867 17 29421945 29704695 ENST00000358273.4 75 GRCh37 Somatic 2016-11-11 22:58:58 UTC https://civicdb.org/links/evidence_items/1743 https://civicdb.org/links/variants/698 https://civicdb.org/links/genes/3867 false SH2B3 10019 RS3184504 Colorectal Cancer 9256 Predisposing Supports B Positive A genome wide association study (GWAS) meta-analysis of 13,265 cancer cases (colorectal cancer and endometrial cancer) and 40,245 controls found this variant to be associated with colorectal cancer (OR = 1.10, P = 7.23 × 10−9). The authors speculated that since this polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, it might influence cancer risk through its role in the immune response. 26621817 PubMed Cheng et al., 2015, Sci Rep 2 accepted 1744 699 7954 12 111884608 111884608 T C ENST00000341259.2 75 GRCh37 Common Germline 2016-11-11 21:52:40 UTC https://civicdb.org/links/evidence_items/1744 https://civicdb.org/links/variants/699 https://civicdb.org/links/genes/7954 false KIF23 9493 EXPRESSION Hepatocellular Carcinoma 684 Prognostic Supports B Better Outcome KIF23 variant 1 was found to be expressed in the cDNA of tumor tissues from a large cohort of HCC patients of chinese descent via PCR. This expression was absent in the normal tissues of these patients for this isoform. Using IHC and custom generated antibody, the overall survival with respect to KIF23 V1 expression was evaluated using the kaplan-meier method with a log rank test. It was found that positive KIF23 V1 staining was correlated with longer overall survival over a period of 5 years (p=.0052). This pattern was seen to a lesser degree over a period of 3 years (p=.1604). KIF23 V1 expression was independent of gender, age, tumor size, or TNM stage (multivariate cox regression). 26674738 PubMed Sun et al., 2015, BMC Cancer 3 accepted 1745 700 7502 15 69706688 69740756 ENST00000260363.4 75 GRCh37 Somatic 2017-02-06 23:10:16 UTC https://civicdb.org/links/evidence_items/1745 https://civicdb.org/links/variants/700 https://civicdb.org/links/genes/7502 false ERBB3 2065 V104M Transitional Cell Carcinoma 2671 Afatinib Predictive Supports B Sensitivity/Response In this phase II trial, patients with metastatic platinum-refractory urothelial carcinoma (UC) received afatinib (40 mg/day). Among the 21 tumors, five of six patients (83.3%) with ERBB2 (HER2) and/or ERBB3 alterations achieved 3-month progression-free survival (PFS3) versus none of 15 patients without alterations (P < .001). Three of three patients with ERBB3 somatic mutations (G284R, V104M, and R103G) achieved PFS3. 27044931 PubMed Choudhury et al., 2016, J. Clin. Oncol. 3 accepted 1746 701 1733 12 56478854 56478854 G A ENST00000267101.3 75 GRCh37 Somatic 2020-11-20 15:48:06 UTC https://civicdb.org/links/evidence_items/1746 https://civicdb.org/links/variants/701 https://civicdb.org/links/genes/1733 false ERBB3 2065 R103G Transitional Cell Carcinoma 2671 Afatinib Predictive Supports B Sensitivity/Response In this phase II trial, patients with metastatic platinum-refractory urothelial carcinoma (UC) received afatinib (40 mg/day). Among the 21 tumors, five of six patients (83.3%) with ERBB2 (HER2) and/or ERBB3 alterations achieved 3-month progression-free survival (PFS3) versus none of 15 patients without alterations (P < .001). Three of three patients with ERBB3 somatic mutations (G284R, V104M, and R103G) achieved PFS3. 27044931 PubMed Choudhury et al., 2016, J. Clin. Oncol. 3 accepted 1747 702 1733 12 56478851 56478851 C G ENST00000267101.3 75 GRCh37 Somatic 2020-11-20 15:48:06 UTC https://civicdb.org/links/evidence_items/1747 https://civicdb.org/links/variants/702 https://civicdb.org/links/genes/1733 false ERBB3 2065 G284R Transitional Cell Carcinoma 2671 Afatinib Predictive Supports B Sensitivity/Response In this phase II trial, patients with metastatic platinum-refractory urothelial carcinoma (UC) received afatinib (40 mg/day). Among the 21 tumors, five of six patients (83.3%) with ERBB2 (HER2) and/or ERBB3 alterations achieved 3-month progression-free survival (PFS3) versus none of 15 patients without alterations (P < .001). Three of three patients with ERBB3 somatic mutations (G284R, V104M, and R103G) achieved PFS3. 27044931 PubMed Choudhury et al., 2016, J. Clin. Oncol. 3 accepted 1748 703 1733 12 56481922 56481922 G A ENST00000267101.3 75 GRCh37 Somatic 2020-11-20 15:48:06 UTC https://civicdb.org/links/evidence_items/1748 https://civicdb.org/links/variants/703 https://civicdb.org/links/genes/1733 false BRAF 673 V600E Melanoma 1909 Vemurafenib Predictive Supports B Sensitivity/Response Multicenter, phase 1, dose-escalation trial of PLX4032 (Vemurafenib). Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients (N=37/48). Patients without the V600E mutation had evidence of tumor regression. 20818844 PubMed Flaherty et al., 2010, N. Engl. J. Med. 4 accepted 1749 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-08-12 05:48:37 UTC https://civicdb.org/links/evidence_items/1749 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600 Melanoma 1909 Trametinib Predictive Supports B Sensitivity/Response Patients who had histologically confirmed, unresectable stage IIIC or IV cutaneous melanoma with a V600E or V600K BRAF mutation were eligible for the study. 322 eligible patients (281 with the V600E mutation, 40 with the V600K mutation, and 1 with both mutations) in a 2:1 ratio to receive oral trametinib (2 mg once daily) or intravenous chemotherapy consisting of either dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter), at the discretion of the investigator, every 3 weeks. The primary end point was progression-free survival; secondary end points included overall survival, overall response rate, duration of response, and safety. Treatment continued until disease progression, death, or withdrawal from the study. In the intention-to-treat population, the median duration of progression-free survival was 4.8 months in the trametinib group as compared with 1.5 months in the chemotherapy group (hazard ratio for progression, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). The 6-month overall survival rate in the intention-to-treat population was 81% in the trametinib group and 67% in the chemotherapy group. 22663011 PubMed Flaherty et al., 2012, N. Engl. J. Med. NCT01245062 3 accepted 1750 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2017-02-14 21:48:25 UTC https://civicdb.org/links/evidence_items/1750 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false GADD45A 1647 rs681673 Ovarian Cancer 2394 Predisposing Supports B Positive GADD45A (1506T>C) association with ovarian cancer was investigated with 258 ovarian cancer patients and 332 age matched healthy women as controls using sequence analysis. A significant difference in genotype distribution was observed between cases and controls (TT vs. TC vs. CC, P = 0.0021). A statistically significant difference in the GADD454A (1506T>C) variant between the controls groups was found in correlation with an increased risk of ovarian cancer (P<0.001, OR = 1.71, 95% CI 1.28–2.29). Presence of the GADD45A (1506T>C) variant was also found to have higher GADD45A mRNA expression, longer ovarian cancer relapse free survival and overall survival. 26422378 PubMed Yuan et al., 2015, PLoS ONE 3 accepted 1751 705 1411 1 68152388 68152388 T C ENST00000370986.4 75 GRCh37 Common Germline 2017-01-31 22:12:55 UTC https://civicdb.org/links/evidence_items/1751 https://civicdb.org/links/variants/705 https://civicdb.org/links/genes/1411 false EWSR1 2130 EWSR1::FLI1 Ewing Sarcoma Of Bone 3368 Diagnostic Supports B Positive A total of 85 unrelated cases of Ewing's sarcoma were examined and 83% we found to harbor the t(11;22)(q24;q12) chromosomal abnormality (EWS/FLI). 3163261 PubMed Turc-Carel et al., 1988, Cancer Genet. Cytogenet. 4 accepted 1752 706 54 22 29664307 29688158 ENST00000414183.2 11 128638013 128683162 ENST00000527786.2 75 GRCh37 In approximately 90% of Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) a translocation t(11;22)(q24; q12) is identified, fusing the 5’ exons (containing the transactivatin domain, at least exon 1-7) of EWSR1, with the 3’ exons (from exon 9, coding the DNA binding domain) of FLI1. Somatic 2016-12-01 15:39:07 UTC https://civicdb.org/links/evidence_items/1752 https://civicdb.org/links/variants/706 https://civicdb.org/links/genes/54 false EWSR1 2130 EWSR1::FLI1 Ewing Sarcoma Of Bone 3368 Diagnostic Supports B Positive The authors propose RT-PCR as a diagnostic test for Ewing sarcoma using FFPE materials. Starting with 40 cases, intact RNA could be isolated from 6, and of these the EWS-FLI event was detected in 2 by nested PCR. Alternative diagnostic assays for this event are also considered. 9741544 PubMed Park et al., 1998, J. Korean Med. Sci. 2 accepted 1753 706 54 22 29664307 29688158 ENST00000414183.2 11 128638013 128683162 ENST00000527786.2 75 GRCh37 In approximately 90% of Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) a translocation t(11;22)(q24; q12) is identified, fusing the 5’ exons (containing the transactivatin domain, at least exon 1-7) of EWSR1, with the 3’ exons (from exon 9, coding the DNA binding domain) of FLI1. Somatic 2016-12-01 15:32:14 UTC https://civicdb.org/links/evidence_items/1753 https://civicdb.org/links/variants/706 https://civicdb.org/links/genes/54 false EWSR1 2130 EWSR1::FLI1 Ewing Sarcoma Of Bone 3368 Diagnostic Supports B Positive An evaluation of alternative strategies for detection of EWS-FLI (FISH break apart, FISH fusion, and RT-PCR). Of the 22 informative EWS/PNETs, 20 cases (91%) were positive by FISH break apart, FISH fusion, or both. 16258512 PubMed Bridge et al., 2006, Mod. Pathol. 3 accepted 1754 706 54 22 29664307 29688158 ENST00000414183.2 11 128638013 128683162 ENST00000527786.2 75 GRCh37 In approximately 90% of Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) a translocation t(11;22)(q24; q12) is identified, fusing the 5’ exons (containing the transactivatin domain, at least exon 1-7) of EWSR1, with the 3’ exons (from exon 9, coding the DNA binding domain) of FLI1. Somatic 2016-12-01 15:38:23 UTC https://civicdb.org/links/evidence_items/1754 https://civicdb.org/links/variants/706 https://civicdb.org/links/genes/54 false MTHFR 4524 A222V Pancreatic Cancer 1793 Prognostic Supports B Better Outcome Study of 1817 PCa cases and 2026 cancer free controls to clarify the association of (MTHFR)c.677C>T (and c.1298A>C ) of pancreatic cancer risk in a population of Han Chinese in Shanghai. Results indicated a lower risk for the heterozygous CT genotype and homozygous TT genotype carriers of (MTHFR)c.677C>T which had a significantly lower risk of developing pancreatic cancer compared with the wild-type CC genotype. 27819322 PubMed Wu et al., 2016, Sci Rep 4 accepted 1756 258 3672 1 11856378 11856378 G A ENST00000376592.1 75 GRCh37 Common Germline 2022-02-24 20:57:03 UTC https://civicdb.org/links/evidence_items/1756 https://civicdb.org/links/variants/258 https://civicdb.org/links/genes/3672 false MTHFR 4524 A222V Rectum Cancer 1993 Fluorouracil Predictive Supports B Sensitivity/Response Patients with the wild type (C/C) MTHFR gene are 2.91 times (95% CI: [1.23, 6.89]) more likely to have a positive response to neoadjuvant CRT and 3.25 times more likely not to experience relapse (95% CI: [1.37, 7.72]) than patients with the heterozygous MTHFR [rs1801133 (C>T)] mutation or the homzygous (T/T). 26693073 PubMed Nikas et al., 2015, Am J Cancer Res 4 accepted 1757 258 3672 1 11856378 11856378 G A ENST00000376592.1 75 GRCh37 Common Germline 2017-07-27 16:19:17 UTC https://civicdb.org/links/evidence_items/1757 https://civicdb.org/links/variants/258 https://civicdb.org/links/genes/3672 false BRCA2 675 TRUNCATING MUTATION Breast Cancer 1612 Predisposing Supports C Uncertain Significance De novo Alu element insertions were identified within the BRCA2 coding sequences in 3 out of 50 Portuguese families. However, the segregation data and mRNA results in this study were conflicting or inconclusive. 16088935 PubMed Teugels et al., 2005, Hum. Mutat. 1 accepted 1758 708 7 Rare Germline 2017-07-27 14:35:11 UTC https://civicdb.org/links/evidence_items/1758 https://civicdb.org/links/variants/708 https://civicdb.org/links/genes/7 false BRCA1 672 Alu insertion Breast Cancer 1612 Predisposing Supports C Likely Pathogenic In a Portuguese family with 6 cases of breast cancer and 1 of ovarian cancer, a 46 year old woman was diagnosed with breast cancer. She was negative for BRCA1/2 mutations using standard methods but a Southern blot identified a ~350bp Alu element (AluYa5 subtype) insertion in exon 3. RT-PCR revealed exon 3 was excluded from the spliced transcript in this patient. Blood samples from 24 family members were collected and the Alu element was identified in the 3 with ovarian or breast cancer that had evaluable samples. 16088935 PubMed Teugels et al., 2005, Hum. Mutat. 3 accepted 1759 709 6 Rare Germline 2017-07-25 20:52:22 UTC https://civicdb.org/links/evidence_items/1759 https://civicdb.org/links/variants/709 https://civicdb.org/links/genes/6 false HOXB13 10481 G84E Prostate Cancer 10283 Predisposing Supports B Uncertain Significance G84E (rs138213197) substitution in HOXB13 is associated with an increased risk for prostate cancer. 49 out of 9012 male patients in the Mayo Clinic Biobank were carriers. 31% of patients were diagnosed with cancer (n=2,595). Cancer diagnosis was more common in G84E carriers than in non-carriers (51.5% vs 30.6%, P = 0.004). G84E was highly prevalent in patients with prostate cancer than those without cancer (P < 0.0001). Evidence also supported a possible link between G84E with bladder cancer (P = 0.06) and leukemia (P = 0.01). Patient family history indicated a history of prostate cancer with a first degree relative was more common when compared to non-carriers (36.2% vs. 16.0%, P = 0.0003). 26108461 PubMed Beebe-Dimmer et al., 2015, Cancer Epidemiol. Biomarkers Prev. 4 accepted 1760 772 8351 17 46805705 46805705 C T ENST00000290295.7 75 GRCh37 Common Germline 2017-02-04 21:35:06 UTC https://civicdb.org/links/evidence_items/1760 https://civicdb.org/links/variants/772 https://civicdb.org/links/genes/8351 false KLLN 100144748 PROMOTER METHYLATION Breast Cancer 1612 Predisposing Supports B Positive 123 patients with Cowden or Cowden-like syndrome (from the IRB8458-PTEN series) and 50 unaffected individuals without PTEN variants were analyzed for germline methylation and expression of PTEN and KILLIN. 45 out of 123 patients (37%; 95% CI, 29%-45%) showed hypermethylation of the bidirectional promoter of PTEN and KILLIN. Individuals with KILLIN-promoter methylation had a 3-fold increased prevalence of breast cancer (35/42 vs 24/64; p<0.0001) over individuals with germline PTEN mutations. 21177507 PubMed Bennett et al., 2010, JAMA 3 accepted 1761 711 32083 N/A 2017-02-15 20:00:10 UTC https://civicdb.org/links/evidence_items/1761 https://civicdb.org/links/variants/711 https://civicdb.org/links/genes/32083 false KLLN 100144748 PROMOTER METHYLATION Renal Cell Carcinoma 4450 Predisposing Supports B Positive 123 patients with Cowden or Cowden-like syndrome (from the IRB8458-PTEN series) and 50 unaffected individuals without PTEN variants were analyzed for germline methylation and expression of PTEN and KILLIN. 45 out of 123 patients (37%; 95% CI, 29%-45%) showed hypermethylation of the bidirectional promoter of PTEN and KILLIN. Individuals with KILLIN-promoter methylation had a greater than 2-fold increase of kidney cancer (4/45 vs 6/155; p=0.004) over individuals with germline PTEN mutations. 21177507 PubMed Bennett et al., 2010, JAMA 3 accepted 1762 711 32083 N/A 2017-02-15 20:00:05 UTC https://civicdb.org/links/evidence_items/1762 https://civicdb.org/links/variants/711 https://civicdb.org/links/genes/32083 false EGFR 1956 D761Y Lung Non-small Cell Carcinoma 3908 Erlotinib,Gefitinib Substitutes Predictive Supports C Resistance D761Y as a secondary mutation was reported to be associated with resistance to gefitinib and erlotinib in NSCLC cells that contain the L858R-EGFR mutation. This mutation combination was observed in a single patient with lung cancer and specifically in a metastatic brain lesion following gefitinib treatment. Functional validation of its role in drug sensitivity was examined in cell lines (293T and Ba/F3 cells). 17085664 PubMed Balak et al., 2006, Clin. Cancer Res. 3 accepted 1763 712 19 7 55242511 55242511 G T ENST00000275493.2 75 GRCh37 Somatic 2017-02-06 22:44:51 UTC https://civicdb.org/links/evidence_items/1763 https://civicdb.org/links/variants/712 https://civicdb.org/links/genes/19 false ERBB2 2064 Amplification Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Emtansine Predictive Supports B Sensitivity/Response In the single arm Phase II study (TDM4258g) breast cancer patients who had progressed on previous anti-HER2 therapy were given transtuzumab emtansine (T-DM1), a HER2 monoclonal antibody and antimicrotubule drug conjugate. 95 trial participants with archival primary tumor were reassessed for HER2 status (positivity defined by FISH or IHC 3+), and 74 patients were confirmed for HER2 positivity and 21 were normal. Overall response rate was 33.8% (95% CI, 23.2% to 44.9%) in patients with confirmed HER2-positive tumors and 4.8% (95% CI, 1.0% to 21.8%) in HER2 normal patients. Median PFS was 8.2 months (95% CI, 4.4 months to not estimable) in patients with confirmed HER2-positive tumors and 2.6 months (95% CI, 1.4 to 3.9 months) in HER2 normal patients. 21172893 PubMed Burris et al., 2011, J. Clin. Oncol. 4 accepted 1764 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2016-12-30 00:39:28 UTC https://civicdb.org/links/evidence_items/1764 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false CDKN2A 1029 Loss Her2-receptor Negative Breast Cancer 0060080 Letrozole,Palbociclib Combination Predictive Supports C Sensitivity/Response A patient with metastatic ER-positive, her2-negative breast cancer with CDKN2A loss experienced a short-lived (~3-month) clinical response to palbociclib when given in combination with letrozole. 26715889 PubMed Gao et al., 2015, Curr Oncol 3 accepted 1765 554 14 9 21967752 21994623 ENST00000579755.1 75 GRCh37 Somatic 2017-01-24 04:20:38 UTC https://civicdb.org/links/evidence_items/1765 https://civicdb.org/links/variants/554 https://civicdb.org/links/genes/14 false CRBN 51185 Mutation Multiple Myeloma 9538 Pomalidomide,Lenalidomide Substitutes Predictive Supports C Resistance A 37 year old, heavily pretreated (including thalidomide and lenalidomide) patient with IgG-kappa multiple myeloma was sequenced following extramedullary relapse. A high number of alterations were observed including 38 rearrangements, 35 translocations, 4 indels, and 271 nonsynonymous point mutations. Two mutations altering CRBN (Q99* and R283K), a gene previously described as being necessary for immunomodulatory drug response, were observed and thought to be responsible for resistance to the pomalidomide and dexamethasone treatment she received but failed to respond to following sequencing. 23480694 PubMed Egan et al., 2013, Br. J. Haematol. 3 accepted 1766 713 11761 3 3191695 3221394 ENST00000231948.4 75 GRCh37 Somatic 2017-08-31 16:54:10 UTC https://civicdb.org/links/evidence_items/1766 https://civicdb.org/links/variants/713 https://civicdb.org/links/genes/11761 false FGFR1 2260 Amplification Estrogen-receptor Positive Breast Cancer 0060075 Ponatinib Predictive Supports D Sensitivity/Response In MDA-MB-134 cells (ER-positive breast cancer cells with amplified FGFR1) ponatinib potently inhibited cell growth with a GI50 value of 23 nmol/L and inhibited FGFR1 phosphorylation with an IC50 value of 7 nmol/L. 22238366 PubMed Gozgit et al., 2012, Mol. Cancer Ther. 3 accepted 1767 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). Somatic 2017-01-24 04:47:11 UTC https://civicdb.org/links/evidence_items/1767 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false TSC1 7248 R1062W Tuberous Sclerosis 13515 Predisposing Supports C Uncertain Significance Deep sequencing of TSC1 and TSC2 was performed on blood from a group of 38 sporadic Tuberous Sclerosis patients who had been previously studied with no mutation identified in TSC1 or TSC2. Five patients had readily observable mutations in these genes, one of which was a previously unidentified TSC1 missense change R1062W. The authors indicate that the mutation may not be pathogenic. 20165957 PubMed Qin et al., 2010, Hum. Genet. 2 accepted 1768 714 46 9 135771933 135771933 G A ENST00000298552.3 75 GRCh37 Rare Germline 2017-02-23 19:17:21 UTC https://civicdb.org/links/evidence_items/1768 https://civicdb.org/links/variants/714 https://civicdb.org/links/genes/46 false STK11 6794 Mutation Peutz-Jeghers Syndrome 3852 Predisposing Supports B Pathogenic Retrospective analysis of the Danish tumor bank. 43 patients with Peutz-Jeghers Syndrome were identified (clinical criteria + STK11 mutations). STK11 mutations were detected in 86% of those tested (18 of 21 probands) and included eight nonsense mutations, five frameshift mutations, two splice site mutations, two large genomic rearrangements, and one missense mutation. 26979979 PubMed Jelsig et al., 2016, Int J Colorectal Dis 4 accepted 1769 715 5534 19 1205740 1223074 ENST00000326873.7 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/1769 https://civicdb.org/links/variants/715 https://civicdb.org/links/genes/5534 false BTK 695 C481S Chronic Lymphocytic Leukemia 1040 Ibrutinib Predictive Supports B Resistance In a trial of 308 patients with chronic lymphocytic leukemia treated with ibrutinib, 31 discontinued treatment due to disease progression (13 CLL progression, 18 Richter’s transformation). 11/13 patients were deep sequenced for BTK and PLCG2. 9 patients were identified with BTK mutations (C481S in 8 patients). In 5 patients, C481S was the sole abnormality. 26182309 PubMed Maddocks et al., 2015, JAMA Oncol NCT01105247,NCT01217749,NCT01578707,NCT01589302 4 accepted 1770 168 65 X 100611165 100611165 A T ENST00000308731.7 75 GRCh37 Somatic 2017-01-23 14:42:11 UTC https://civicdb.org/links/evidence_items/1770 https://civicdb.org/links/variants/168 https://civicdb.org/links/genes/65 false PDGFRA 5156 Amplification Lung Non-small Cell Carcinoma 3908 Sunitinib Predictive Supports D Sensitivity/Response In a high-throughput cell line screen of 637 cell lines, only 2 sunitinib sensitive cell lines were identified. In the sunitinib-sensitive adenosquamous NSCLC cell line (NCI-H1703), PDGFRA expression was associated with focal PDGFRA gene amplification. This alteration was detected in a small fraction of primary squamous cell NSCLC tumor specimens. Focal amplification of PDGFC, the gene encoding the PDGFR ligand, was also detected. 19366796 PubMed McDermott et al., 2009, Cancer Res. 3 accepted 1771 716 38 4 55095264 55164414 ENST00000257290.5 75 GRCh37 Somatic 2020-08-24 21:34:42 UTC https://civicdb.org/links/evidence_items/1771 https://civicdb.org/links/variants/716 https://civicdb.org/links/genes/38 false BRCA1 672 Mutation Ovarian Cancer 2394 Olaparib Predictive Supports B Sensitivity/Response In a study of 63 patients with ovarian cancer, 17 patients had BRCA1 or BRCA2 mutations and 46 patients had no BRCA mutations. Of the BRCA-positive patients, 7/17(41%; 95%CI 22-64) showed objective response to olaparib whereas only 11/46 BRCA-negative patients (24%; 95%CI 14-38) showed objective response to olaparib. 21862407 PubMed Gelmon et al., 2011, Lancet Oncol. NCT00679783 3 accepted 1772 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Rare Germline 2017-01-23 14:46:18 UTC https://civicdb.org/links/evidence_items/1772 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false BRCA2 675 Mutation Ovarian Cancer 2394 Olaparib Predictive Supports B Sensitivity/Response In a study of 63 patients with ovarian cancer, 17 patients had BRCA1 or BRCA2 mutations and 46 patients had no BRCA mutations. Of the BRCA-positive patients, 7/17(41%; 95%CI 22-64) showed objective response to olaparib whereas only 11/46 BRCA-negative patients (24%; 95%CI 14-38) showed objective response to olaparib. 21862407 PubMed Gelmon et al., 2011, Lancet Oncol. NCT00679783 3 accepted 1773 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Rare Germline 2017-01-23 15:04:51 UTC https://civicdb.org/links/evidence_items/1773 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false PDGFRA 5156 FIP1L1::PDGFRA Myeloid And Lymphoid Neoplasms With Eosinophilia And Abnormalities Of PDGFRA, PDGFRB, And FGFR1 0080164 Imatinib Predictive Supports C Sensitivity/Response A patient with monoblastic myeloid sarcoma harbouring a PCR confirmed FIP1L1-PDGFRA rearrangement was treated with imatinib monotherapy. The patient demonstrated a durable response (10 wks) while on therapy which was reversed when the patient discontinued treatment. Imatinib therapy was subsequently restarted, with peripheral blood and BM analyses returning to normal after 4 weeks. 24456122 PubMed Srinivas et al., 2014, Br. J. Haematol. 3 accepted 1774 574 38 4 54243812 54294350 ENST00000337488.6 4 55141008 55164414 ENST00000257290.5 75 GRCh37 Prospective trials of patients with hypereosinophilic syndrome harboring the FIP1L1-PDGFRA fusion identified marked response to imatinib treatment (Gotlib and Cool, Leukemia 2008). Imatinib is FDA approved for the treatment of "adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase" (NDA021588). Somatic 2017-04-13 03:14:41 UTC https://civicdb.org/links/evidence_items/1774 https://civicdb.org/links/variants/574 https://civicdb.org/links/genes/38 false BRCA1 672 Mutation Triple-receptor Negative Breast Cancer 0060081 Olaparib Predictive Supports B Resistance In a study of 26 patients with breast cancer, 10 patients were BRCA-positive and 16 patients were BRCA-negative. Regardless of BRCA status, none showed objective response when treated with olaparib. 21862407 PubMed Gelmon et al., 2011, Lancet Oncol. NCT00679783 3 accepted 1775 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Rare Germline 2017-11-02 18:10:01 UTC https://civicdb.org/links/evidence_items/1775 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false BRCA2 675 Mutation Triple-receptor Negative Breast Cancer 0060081 Olaparib Predictive Does Not Support B Sensitivity/Response In a study of 26 patients with breast cancer, 10 patients were BRCA-positive and 16 patients were BRCA-negative. Regardless of BRCA status, none showed objective response when treated with olaparib. 21862407 PubMed Gelmon et al., 2011, Lancet Oncol. NCT00679783 3 accepted 1776 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Rare Germline 2018-07-18 15:50:24 UTC https://civicdb.org/links/evidence_items/1776 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false PDGFRA 5156 FIP1L1::PDGFRA Myeloid And Lymphoid Neoplasms With Eosinophilia And Abnormalities Of PDGFRA, PDGFRB, And FGFR1 0080164 Ponatinib Predictive Supports D Sensitivity/Response In a FIP1L1-PDGFRA positive eosinophil cell line growth-inhibitory effects were seen with all PDGFR-blocking agents, (ponatinib, sorafenib, masitinib, nilotinib, dasatinib, sunitinib, midostaurin) with ponatinib found to be the most potent compound. 24407160 PubMed Sadovnik et al., 2014, Exp. Hematol. 3 accepted 1777 574 38 4 54243812 54294350 ENST00000337488.6 4 55141008 55164414 ENST00000257290.5 75 GRCh37 Prospective trials of patients with hypereosinophilic syndrome harboring the FIP1L1-PDGFRA fusion identified marked response to imatinib treatment (Gotlib and Cool, Leukemia 2008). Imatinib is FDA approved for the treatment of "adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase" (NDA021588). Somatic 2020-12-03 20:31:29 UTC https://civicdb.org/links/evidence_items/1777 https://civicdb.org/links/variants/574 https://civicdb.org/links/genes/38 false DDIT3 1649 EWSR1::DDIT3 Myxoid Liposarcoma 5363 Diagnostic Supports C Positive Identified two cases of myxoid liposarcoma with translocations (between 12q13 and 22q12) giving rise to EWSR1-DDIT3 (EWS-CHOP) fusions instead of the more common FUS-DDIT3. 8637704 PubMed Panagopoulos et al., 1996, Oncogene 3 accepted 1778 717 1413 22 29664307 29687588 ENST00000414183.2 12 57910376 57911536 ENST00000346473.3 75 GRCh37 Somatic 2017-01-24 05:29:54 UTC https://civicdb.org/links/evidence_items/1778 https://civicdb.org/links/variants/717 https://civicdb.org/links/genes/1413 false PDGFRA 5156 FIP1L1::PDGFRA T674I Myeloid And Lymphoid Neoplasms With Eosinophilia And Abnormalities Of PDGFRA, PDGFRB, And FGFR1 0080164 Ponatinib Predictive Supports D Sensitivity/Response Ba/F3 cells expressing two clinically relevant, imatinib-resistant, mutant forms of FIP1L1-PDGFRA, namely T674I and D842V were tested for growth inhibition by 8 PDGFR-blocking TKIs. Strong inhibitory effects on both mutants were seen only with ponatinib. 24407160 PubMed Sadovnik et al., 2014, Exp. Hematol. 3 accepted 1779 577 38 4 55144547 55144547 C T ENST00000257290.5 75 GRCh37 A case study of relapsed myeloproliferative hypereosinophilic syndrome suggests that a T674I mutation in the PDGFRA split kinase domain of FIP1L1-PDGFRA fusions may confer resistance to imatinib. Somatic 2017-01-30 23:04:04 UTC https://civicdb.org/links/evidence_items/1779 https://civicdb.org/links/variants/577 https://civicdb.org/links/genes/38 false EGFR 1956 G719 Lung Adenocarcinoma 3910 Erlotinib Predictive Supports B Sensitivity/Response In a meta-analysis of 7 clinical trials of erlotinib (some vs placebo or other treatment), 10/24 patients with Exon 18 mutations harbored a G719 variant. These variants were associated with improved progression-free and overall survival. No statistical analysis was reported for this variant and PFS or OS, citing small sample size across the studies. 26773740 PubMed Klughammer et al., 2016, J Thorac Oncol 2 accepted 1780 718 19 7 55241707 55241708 ENST00000275493.2 75 GRCh37 This is a "bucket" variant for evidence that refers generically to missense variants happening at this position such as: G719A, G719D, G719S. Somatic 2021-02-27 00:29:00 UTC https://civicdb.org/links/evidence_items/1780 https://civicdb.org/links/variants/718 https://civicdb.org/links/genes/19 false BRD4 23476 BRD4::NUTM1 NUT Midline Carcinoma 0060463 JQ1 Predictive Supports D Sensitivity/Response Treatment of the patient-derived 797 NMC cell line for 48 hours with JQ1 (500 nM) provoked terminal differentiation which was accompanied by growth arrest and sustained inhibition of proliferation. Non-BRD4-dependent cell lines including a squamous carcinoma cell line (TE10) failed to exhibit differentiation effects when treated with JQ1. 20871596 PubMed Filippakopoulos et al., 2010, Nature 3 accepted 1781 719 9588 Somatic 2017-01-24 04:51:27 UTC https://civicdb.org/links/evidence_items/1781 https://civicdb.org/links/variants/719 https://civicdb.org/links/genes/9588 false EGFR 1956 S720 Lung Adenocarcinoma 3910 Erlotinib Predictive Supports C Resistance Efficacy of erlotinib treatment was evaluated by meta-analysis of results from seven trials and literature review. Two patients with p.S270P, and one patient with p.S720F were observed to have poor survival outcomes. 26773740 PubMed Klughammer et al., 2016, J Thorac Oncol 3 accepted 1782 720 19 7 55241710 55241711 ENST00000275493.2 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1782 https://civicdb.org/links/variants/720 https://civicdb.org/links/genes/19 false ALK 238 Fusion Inflammatory Myofibroblastic Tumor 0050905 Diagnostic Supports C Positive Fluorescence in situ hybridization with a probe flanking the ALK gene at 2p23 and immunohistochemistry revealed ALK expression, suggesting ALK fusions in three cases of IMT. 10383129 PubMed Griffin et al., 1999, Cancer Res. 4 accepted 1783 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2016-12-02 22:00:50 UTC https://civicdb.org/links/evidence_items/1783 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false CYP2D6 1565 Loss-of-function Breast Cancer 1612 Prognostic Does Not Support B Poor Outcome Meta-analysis of 25 studies involving 13,629 women with tamoxifen treated breast cancer. The meta-analysis investigated the association between CYP2D6 genotypes and response to tamoxifen treatment (loss/reduced function vs. unchanged/increased function). The authors examine a prevailing hypothesis that individuals carrying a reduced function CYP2D6 allele have poorer outcomes due to less metabolism of tamoxifen to active metabolites. The study concludes that there is insufficient evidence to support use of CYP2D6 genotyping as a guide for tamoxifen use in breast cancer. 24098545 PubMed Lum et al., 2013, PLoS ONE 4 accepted 1784 721 1342 22 42522501 42526908 ENST00000360608.5 75 GRCh37 Common Germline 2017-01-26 04:56:02 UTC https://civicdb.org/links/evidence_items/1784 https://civicdb.org/links/variants/721 https://civicdb.org/links/genes/1342 false DDIT3 1649 FUS::DDIT3 Myxoid Liposarcoma 5363 Diagnostic Supports A Positive The FUS-DDIT3 fusion is pathognomonic of myxoid liposarcomas. It encompasses parts of the FUS gene on l6pll at its 5’ end and the DDIT3 gene at 12q13 at its 3’ ends 1568170 PubMed Sreekantaiah et al., 1992, Cancer 5 accepted 1785 722 1413 Somatic 2016-12-02 22:12:05 UTC https://civicdb.org/links/evidence_items/1785 https://civicdb.org/links/variants/722 https://civicdb.org/links/genes/1413 false EGFR 1956 K757R Lung Adenocarcinoma 3910 Erlotinib Predictive Supports C Sensitivity/Response In a meta-analysis of 7 clinical trials evaluating the efficacy of erlotinib, one patient was described with the exon 19 mutation K757R from the MERIT study. Progression-free (250 days) and overall (435 days) survival suggested sensitivity in this patient. Literature analysis did not identify additional reports of patients harboring this mutation. 26773740 PubMed Klughammer et al., 2016, J Thorac Oncol 3 accepted 1786 723 19 7 55242500 55242500 A G ENST00000275493.2 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1786 https://civicdb.org/links/variants/723 https://civicdb.org/links/genes/19 false EGFR 1956 E746G Lung Adenocarcinoma 3910 Erlotinib Predictive Supports C Sensitivity/Response In a meta-analysis of 7 clinical trials evaluating the efficacy of erlotinib, one patient was described with the exon 19 mutation E746G from the BeTa study. Progression-free (415 days) and overall (462 days) survival suggested sensitivity in this patient. No statistical analysis was reported for this variant and PFS or OS, citing small sample size across the studies. 26773740 PubMed Klughammer et al., 2016, J Thorac Oncol 1 accepted 1787 724 19 7 55242467 55242467 A G ENST00000275493.2 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1787 https://civicdb.org/links/variants/724 https://civicdb.org/links/genes/19 false MLH1 4292 E13fs Endometrial Cancer 1380 Oncogenic N/A C N/A MLH1 E13fs (c.37del), identified in a case of microsatellite-unstable endometrial cancer, was confirmed to be somatic in a 46 year old female patient (sLS-1) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS. This patient also harbored MLH1 p.G606fs. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1788 725 3532 3 37035075 37035075 G ENST00000231790.2 75 GRCh37 Somatic 2021-03-08 16:53:26 UTC https://civicdb.org/links/evidence_items/1788 https://civicdb.org/links/variants/725 https://civicdb.org/links/genes/3532 false MSH2 4436 R383* Endometrial Cancer 1380 Oncogenic N/A C N/A This variant, identified in two patients was confirmed to be a somatic mutation in both patients' microsatellite-unstable tumors (one endometrial cancer, one ovarian cancer) with suspected Lynch Syndrome (LS). These patients were therefore negative for LS. However, based on this study we can infer that the variant would predispose to LS in a germline setting. LOH of the WT allele was confirmed in the case of ovarian cancer. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1790 727 3628 2 47656951 47656951 C T ENST00000233146.2 75 GRCh37 Somatic 2021-03-05 19:38:31 UTC https://civicdb.org/links/evidence_items/1790 https://civicdb.org/links/variants/727 https://civicdb.org/links/genes/3628 false MLH1 4292 V534R Colorectal Cancer 9256 Oncogenic N/A C N/A MLH1 V534R (c.1600_1601delinsAG), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be a somatic variant in a 27 year old male patient (id: sLS-24) with suspected Lynch syndrome (LS). The patient was therefore negative for LS which is germline by definition. Authors note that this patient's tumor retained MLH1 heterozygosity and wildtype BRAF. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1791 728 3532 3 37081718 37081719 GT AG ENST00000231790.2 75 GRCh37 Somatic 2021-03-09 17:55:47 UTC https://civicdb.org/links/evidence_items/1791 https://civicdb.org/links/variants/728 https://civicdb.org/links/genes/3532 false UGT1A1 54658 UGT1A1*28 Cancer 162 Belinostat Predictive Supports A Adverse Response The FDA approved package insert for Belinostat recommends dose adjustment for UGT1A1*28 allele homozygotes. 26313268 PubMed Goey et al., 2016, J Clin Pharmacol 5 accepted 1792 729 12422 2 234668881 234668882 TATATATATATATA ENST00000305208.5 75 GRCh37 Common Germline 2016-12-02 22:10:17 UTC https://civicdb.org/links/evidence_items/1792 https://civicdb.org/links/variants/729 https://civicdb.org/links/genes/12422 false MLH1 4292 G606FS*2 Endometrial Cancer 1380 Oncogenic N/A C N/A MLH1 G606fs*2 (c.1816_1817del), identified in a case of microsatellite-unstable endometrial cancer, was confirmed to be somatic in a 46 year old female patient (sLS-1) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. This patient also harbored a MLH1 p.E13fs*3 mutation. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1793 730 3532 3 37089094 37089095 GG ENST00000231790.2 75 GRCh37 Somatic 2021-03-06 00:33:32 UTC https://civicdb.org/links/evidence_items/1793 https://civicdb.org/links/variants/730 https://civicdb.org/links/genes/3532 false MLH1 4292 c.790+1G>A Colorectal Cancer 9256 Oncogenic N/A C N/A MLH1 c.790+1G > A, identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 61 year old male patient (sLS-2) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, as the disease is germline by definition. This patient's tumor also harbored a p.K618del mutation and was wildtype for BRAF. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1794 731 3532 3 37056036 37056036 G A ENST00000231790.2 75 GRCh37 Somatic 2021-03-06 17:31:08 UTC https://civicdb.org/links/evidence_items/1794 https://civicdb.org/links/variants/731 https://civicdb.org/links/genes/3532 false UGT1A1 54658 UGT1A1*60 Cancer 162 Belinostat Predictive Supports B Adverse Response In a phase 1 trial belinostat (400-800mg/m2/24h) was administered to 25 patients in combination with cisplatin and etoposide. Endpoints were associations between genotype of UGT1A1 and pharmacokinetics, toxicities and proteine lysine acetylation. Belinostat AUC and half-life was significantly increased in UGT1A1*60 carriers, and they were at greater risk for thrombocytopenia. 26313268 PubMed Goey et al., 2016, J Clin Pharmacol 4 accepted 1795 732 12422 Common Germline 2017-02-16 19:34:09 UTC https://civicdb.org/links/evidence_items/1795 https://civicdb.org/links/variants/732 https://civicdb.org/links/genes/12422 false MLH1 4292 K618DEL Colorectal Cancer 9256 Oncogenic N/A C N/A MLH1 K618del (c.1852_1854del), identified in two cases of microsatellite-unstable colorectal cancer, was confirmed to be somatic in both patients with suspected Lynch Syndrome (LS). Both patients were therefore negative for LS, as it is germline by definition. sLS-2 was a 61 year old male whose tumor harbored MLH1 c.790 + 1G>A concomitantly, retained MLH1 heterozygosity and was wildtype for BRAF. sLS-8 was a 73 year old female whose tumor harbored MLH1 M1L and was wildtype for BRAF. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1796 733 3532 3 37089130 37089132 AAG ENST00000231790.2 75 GRCh37 Somatic 2021-03-06 17:32:11 UTC https://civicdb.org/links/evidence_items/1796 https://civicdb.org/links/variants/733 https://civicdb.org/links/genes/3532 false MLH1 4292 P138T Colorectal Cancer 9256 Oncogenic N/A C N/A This variant, identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be a somatic mutation in a patient with suspected Lynch syndrome (LS). The patient was therefore negative for LS. However, based on this study we can infer that the variant would predispose to LS in a germline setting. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1797 734 3532 Somatic 2021-03-06 18:00:57 UTC https://civicdb.org/links/evidence_items/1797 https://civicdb.org/links/variants/734 https://civicdb.org/links/genes/3532 false MLH1 4292 R687FS Colorectal Cancer 9256 Oncogenic N/A C N/A MLH1 R687fs (c.2059del), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 33 year old male patient (patient id: sLS-3) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS which is germline by definition. Loss of heterozygosity of the wildtype allele was demonstrated. Patient also had a BRAF p.D594G mutation. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1798 735 3532 3 37090464 37090464 C ENST00000231790.2 75 GRCh37 Somatic 2021-03-06 06:02:49 UTC https://civicdb.org/links/evidence_items/1798 https://civicdb.org/links/variants/735 https://civicdb.org/links/genes/3532 false EGFR 1956 V769_D770insASV Lung Adenocarcinoma 3910 Erlotinib Predictive Supports C Sensitivity/Response In this meta-analysis of 7 clinical trials evaluating the efficacy of erlotinib, 1 patient with V769_770insASV had overall and progression-free survival of 642 days. From this and literature review it was concluded that although EGFR exon 20 insertions may confer reduced sensitivity to erlotinib, patients with this particular mutation appeared to benefit from therapy. 26773740 PubMed Klughammer et al., 2016, J Thorac Oncol 3 accepted 1799 736 19 7 55249009 55249010 GCCAGCGTG ENST00000275493.2 75 GRCh37 Somatic 2021-05-11 02:55:11 UTC https://civicdb.org/links/evidence_items/1799 https://civicdb.org/links/variants/736 https://civicdb.org/links/genes/19 false DPYD 1806 DPYD*2A HOMOZYGOSITY Cancer 162 Capecitabine,Tegafur,Fluorouracil Substitutes Predictive Supports A Adverse Response The Clinical Pharmacogenomics Implementation Consortium Guidelines for DPYD genotype and 5-FU dosing does not recommend the use of 5-FU or capecitabine in patients with homozygous DPYD*2A, *13 or rs67376798 and the FDA drug labels warn to use precautions in this patient population. 23988873 PubMed Caudle et al., 2013, Clin. Pharmacol. Ther. 5 accepted 1800 737 1526 1 97915614 97915614 C T ENST00000370192.3 75 GRCh37 Common Germline 2016-12-02 22:01:28 UTC https://civicdb.org/links/evidence_items/1800 https://civicdb.org/links/variants/737 https://civicdb.org/links/genes/1526 false DPYD 1806 DPYD*13 HOMOZYGOSITY Cancer 162 Fluorouracil,Tegafur,Capecitabine Substitutes Predictive Supports A Adverse Response The Clinical Pharmacogenomics Implementation Consortium Guidelines for DPYD genotype and 5-FU dosing does not recommend the use of 5-FU or capecitabine in patients with homozygous DPYD*2A, *13 or rs67376798 and the FDA drug labels warn to use precautions in this patient population. 23988873 PubMed Caudle et al., 2013, Clin. Pharmacol. Ther. 5 accepted 1801 738 1526 1 97981343 97981343 A C ENST00000370192.3 75 GRCh37 Common Germline 2016-12-02 22:01:45 UTC https://civicdb.org/links/evidence_items/1801 https://civicdb.org/links/variants/738 https://civicdb.org/links/genes/1526 false FOS 2353 TRUNCATING FUSION Bone Epithelioid Hemangioma 6610 Diagnostic Supports C Positive FOS was found fused with 3 different genes in 3 cases of bone epithelioid hemangioma. The fusion partners were not recurrent, respectively MBNL1, VIM and a lincRNA. The truncation of the FOS gene would result in the loss of the transactivation domain (TAD) in all three cases. Extension of this analysis identified FOS rearrangements in 5/7 additional classic epithelioid hemangiomas of bone. 26173738 PubMed van IJzendoorn et al., 2015, Genes Chromosomes Cancer 3 accepted 1802 739 1955 14 75745477 75748127 ENST00000303562.4 75 GRCh37 Somatic 2021-05-25 22:59:34 UTC https://civicdb.org/links/evidence_items/1802 https://civicdb.org/links/variants/739 https://civicdb.org/links/genes/1955 false DPYD 1806 RS67376798 HOMOZYGOSITY Cancer 162 Fluorouracil,Tegafur,Capecitabine Substitutes Predictive Supports A Adverse Response The Clinical Pharmacogenomics Implementation Consortium Guidelines for DPYD genotype and 5-FU dosing does not recommend the use of 5-FU or capecitabine in patients with homozygous DPYD*2A, *13 or rs67376798 and the FDA drug labels warn to use precautions in this patient population. 23988873 PubMed Caudle et al., 2013, Clin. Pharmacol. Ther. 5 accepted 1803 740 1526 Common Germline 2016-12-02 22:01:54 UTC https://civicdb.org/links/evidence_items/1803 https://civicdb.org/links/variants/740 https://civicdb.org/links/genes/1526 false MLH1 4292 R100* Colorectal Cancer 9256 Oncogenic N/A C N/A R100* (c.298C > T), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 46 year old female patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. Loss of heterozygosity of the wildtype allele was confirmed. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1804 741 3532 3 37042536 37042536 C T ENST00000231790.2 75 GRCh37 Somatic 2021-03-05 18:00:51 UTC https://civicdb.org/links/evidence_items/1804 https://civicdb.org/links/variants/741 https://civicdb.org/links/genes/3532 false WWTR1 25937 WWTR1::CAMTA1 Malignant Epithelioid Hemangioendothelioma 0080190 Diagnostic Supports B Positive Performed a systematic molecular analysis of 17 epithelioid hemangioendothelioma (EHE) and compared to 13 epithelioid hemangiomas, five epithelioid angiosarcomas, and four epithelioid sarcoma-like EHE. A FISH positional cloning strategy, and RT-PCR analysis identified WWTR1-CAMTA1 in all EHE cases and none of the other benign or malignant epithelioid vascular tumors examined. 21584898 PubMed Errani et al., 2011, Genes Chromosomes Cancer 4 accepted 1805 742 9952 3 149235022 149290787 ENST00000465804.1 1 7721786 7829766 ENST00000303635.7 75 GRCh37 Somatic 2020-08-12 05:52:21 UTC https://civicdb.org/links/evidence_items/1805 https://civicdb.org/links/variants/742 https://civicdb.org/links/genes/9952 false MLH1 4292 T117M Colorectal Cancer 9256 Oncogenic N/A C N/A MLH1 T117M (c.350C > T), identified in three cases of microsatellite-unstable colorectal cancer, was confirmed to be somatic in patients with suspected Lynch Syndrome (LS). The patients were therefore negative for LS, as the disease is germline by definition. Patient sLS-6 was a 59 year old female whose tumor harbored BRAF V600E and had loss of heterozygosity of MLH1. Patient sLS-19 was a 62 year old female whose tumor harbored loss of heterozygosity at MLH1 and wildtype BRAF. Patient sLS-20 was a 65 year old male whose tumor harbored concomitant MLH1 I68S and BRAF wildtype. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1806 743 3532 3 37045935 37045935 C T ENST00000231790.2 75 GRCh37 Somatic 2021-03-06 05:37:28 UTC https://civicdb.org/links/evidence_items/1806 https://civicdb.org/links/variants/743 https://civicdb.org/links/genes/3532 false MLH1 4292 Q426FS Colorectal Cancer 9256 Oncogenic N/A C N/A MLH1 Q426fs (c.1276del), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be a somatic mutation in a 46 year old male patient (patient id: sLS-5) with suspected Lynch syndrome (LS). The patient was therefore negative for LS as it is a germline disease, by definition. Loss of heterozygosity of the wildtype allele and wildtype BRAF was observed. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1807 744 3532 3 37067365 37067365 C ENST00000231790.2 75 GRCh37 Somatic 2021-03-09 18:44:16 UTC https://civicdb.org/links/evidence_items/1807 https://civicdb.org/links/variants/744 https://civicdb.org/links/genes/3532 false MLH1 4292 V49A Colorectal Cancer 9256 Oncogenic N/A C N/A MLH1 V49A (c.146 T > C), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 68 year old female patient (id: sLS-7) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS as the disease is germline by definition. The patient also harbored a second MLH1 mutation (p.D667fs) which demonstrated loss of heterozygosity and BRAF wildtype. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1808 745 3532 3 37038139 37038139 T C ENST00000231790.2 75 GRCh37 Somatic 2021-03-06 17:24:36 UTC https://civicdb.org/links/evidence_items/1808 https://civicdb.org/links/variants/745 https://civicdb.org/links/genes/3532 false EGFR 1956 Exon 20 Insertion Lung Adenocarcinoma 3910 Afatinib Predictive Supports B Resistance In retrospective analysis of trials, afatinib conferred limited clinical benefit to patients with EGFR exon 20 insertion mutations (N=23). Only 2 patients had objective responses. 26051236 PubMed Yang et al., 2015, Lancet Oncol. NCT00525148,NCT00949650,NCT01121393 3 accepted 1809 726 19 7 55248991 55249022 ENST00000275493.2 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1809 https://civicdb.org/links/variants/726 https://civicdb.org/links/genes/19 false MLH1 4292 D667FS Colorectal Cancer 9256 Oncogenic N/A C N/A This variant (D667fs), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 68 year old female patient (id: sLS-7) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. Loss of heterozygosity leading to primarily the D667fs allele detected (90% VAF). This patient also harbored a heterozygous p.V49A variant. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1810 746 3532 3 37090406 37090406 C ENST00000231790.2 75 GRCh37 Somatic 2021-03-06 00:36:54 UTC https://civicdb.org/links/evidence_items/1810 https://civicdb.org/links/variants/746 https://civicdb.org/links/genes/3532 false MLH1 4292 M1L Colorectal Cancer 9256 Oncogenic N/A C N/A MLH1 M1L (c.1A>T), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 73 year old female patient (patient id: sLS-8) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. Loss of heterozygosity resulting in overrepresentation of the M1L allele was observed. Additionally, this patient's tumor harbored a heterozygous MLH1 p.K618del mutation and was wildtype for BRAF. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1811 747 3532 3 37035039 37035039 A T ENST00000231790.2 75 GRCh37 Somatic 2021-03-06 00:34:19 UTC https://civicdb.org/links/evidence_items/1811 https://civicdb.org/links/variants/747 https://civicdb.org/links/genes/3532 false MLH1 4292 *757L Villous Adenoma Oncogenic N/A C N/A MLH1 *757 L (c.2270A > T), identified in a case of microsatellite-unstable villous adenoma, was confirmed to be somatic in a 39 year old male patient (id: sLS-9) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, as the disease is germline by definition. The patient also harbored an MLH1 c.453+1G > A mutation. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1812 748 3532 3 37092143 37092143 A T ENST00000231790.2 75 GRCh37 Somatic 2021-09-10 01:04:27 UTC https://civicdb.org/links/evidence_items/1812 https://civicdb.org/links/variants/748 https://civicdb.org/links/genes/3532 true MLH1 4292 R265G Colorectal Cancer 9256 Oncogenic N/A C N/A MLH1 R265G (c.793C > G), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 65 year old female patient (id: sLS-10) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, as the disease is germline by definition. Loss of heterozygosity of the wildtype allele and BRAF wildtype was observed. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1813 749 3532 3 37058999 37058999 C G ENST00000231790.2 75 GRCh37 Somatic 2021-03-06 17:02:31 UTC https://civicdb.org/links/evidence_items/1813 https://civicdb.org/links/variants/749 https://civicdb.org/links/genes/3532 false MLH1 4292 V213FS Colorectal Cancer 9256 Oncogenic N/A C N/A This variant (V213fs), identified in two cases of microsatellite-unstable colorectal cancer, was confirmed to be somatic in both patients (40 year-old female & 70 year-old male) with suspected Lynch Syndrome (LS). The patients were therefore negative for LS, which is by definition a germline disorder. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1814 750 3532 3 37053551 37053551 T ENST00000231790.2 75 GRCh37 Somatic 2021-03-08 16:58:24 UTC https://civicdb.org/links/evidence_items/1814 https://civicdb.org/links/variants/750 https://civicdb.org/links/genes/3532 false MLH1 4292 N551T Colorectal Cancer 9256 Oncogenic N/A C N/A MLH1 N551T (c.1652A > C) identified in a case of microsatellite-unstable colorectal cancer was confirmed to be somatic in a 51 year old female patient (id: sLS-12) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS as the disease is germline by definition. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1815 751 3532 3 37081770 37081770 A C ENST00000231790.2 75 GRCh37 Somatic 2021-03-09 17:57:03 UTC https://civicdb.org/links/evidence_items/1815 https://civicdb.org/links/variants/751 https://civicdb.org/links/genes/3532 false MLH1 4292 A424T Colorectal Cancer 9256 Oncogenic N/A C N/A MLH1 A424T (c.1270G>A), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 45 year old male patient (id: sLS-13) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS which is germline by definition. Patient also harbored a BRAF V600E mutation. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1816 752 3532 3 37067359 37067359 G A ENST00000231790.2 75 GRCh37 Somatic 2021-03-09 17:56:24 UTC https://civicdb.org/links/evidence_items/1816 https://civicdb.org/links/variants/752 https://civicdb.org/links/genes/3532 false MLH1 4292 Q149* Colorectal Cancer 9256 Oncogenic N/A C N/A MLH1 Q149* (c.445C > T), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 65 year old female patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is a germline disease by definition. This patient also harbored MLH1 p.R226* and MSH6 p.I972F mutations at similar variant allele frequencies. Authors note that the tumor retained MLH1 heterozygosity, was wildtype for BRAF, and harbored two pathogenic variants in MMR. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1817 753 3532 3 37048546 37048546 C T ENST00000231790.2 75 GRCh37 Somatic 2021-03-06 17:00:07 UTC https://civicdb.org/links/evidence_items/1817 https://civicdb.org/links/variants/753 https://civicdb.org/links/genes/3532 false MLH1 4292 R226* Colorectal Cancer 9256 Oncogenic N/A C N/A MLH1 R226* (c.676C > T), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 65 year old female patient (sLS-14) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. This patient also harbored MLH1 p.Q149* and MSH6 p.I972F mutations as similar variant allele frequencies. Authors note that the tumor of this patient was wildtype for BRAF. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1818 754 3532 3 37053589 37053589 C T ENST00000231790.2 75 GRCh37 Somatic 2021-03-06 00:22:37 UTC https://civicdb.org/links/evidence_items/1818 https://civicdb.org/links/variants/754 https://civicdb.org/links/genes/3532 false MLH1 4292 P536FS Colorectal Cancer 9256 Oncogenic N/A C N/A This variant (P536fs), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 59 year-old female patient (sLS-17) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. Loss of heterozygosity of the wildtype allele was demonstrated resulting in higher mutated allele representation (80% variant allele frequency). 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1820 756 3532 3 37081726 37081726 T ENST00000231790.2 75 GRCh37 Somatic 2021-03-08 17:04:55 UTC https://civicdb.org/links/evidence_items/1820 https://civicdb.org/links/variants/756 https://civicdb.org/links/genes/3532 false MLH1 4292 G67R Colorectal Cancer 9256 Oncogenic N/A C N/A This variant (G67R), identified in a case of microsatellite-unstable colorectal cancer was confirmed to be somatic in a 61 year-old male patient (sLS-18) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. Loss of heterozygosity of the wildtype allele was demonstrated. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1821 757 3532 3 37038192 37038192 G A ENST00000231790.2 75 GRCh37 Somatic 2021-03-08 17:10:11 UTC https://civicdb.org/links/evidence_items/1821 https://civicdb.org/links/variants/757 https://civicdb.org/links/genes/3532 false MLH1 4292 I68S Colorectal Cancer 9256 Oncogenic N/A C N/A MLH1 I68S (c.203 T > G), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 65 year old male patient (id: sLS-20) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, as the disease is germline by definition. Loss of heterozygosity leading to p.I68S at 77% variant allele frequency was demonstrated. The patient also harbored a heterozygous MLH1 p.T117M mutation (38% VAF). 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1822 758 3532 3 37038196 37038196 T G ENST00000231790.2 75 GRCh37 Somatic 2021-03-06 17:28:30 UTC https://civicdb.org/links/evidence_items/1822 https://civicdb.org/links/variants/758 https://civicdb.org/links/genes/3532 false MLH1 4292 G65D Colorectal Cancer 9256 Oncogenic N/A C N/A This variant (G65D), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 71 year-old male patient (sLS-21) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. This patient also had loss of heterozygosity. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1823 759 3532 3 37038187 37038187 G A ENST00000231790.2 75 GRCh37 Somatic 2021-03-08 17:11:21 UTC https://civicdb.org/links/evidence_items/1823 https://civicdb.org/links/variants/759 https://civicdb.org/links/genes/3532 false MLH1 4292 A681V Colorectal Cancer 9256 Oncogenic N/A C N/A This variant (A681V), identified in a case of microsatellite-unstable colorectal cancer was confirmed to be somatic in a 52 year-old male patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. Loss of heterozygosity (wildtype allele loss) was also demonstrated. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1824 760 3532 3 37090447 37090447 C T ENST00000231790.2 75 GRCh37 Somatic 2021-03-08 17:12:04 UTC https://civicdb.org/links/evidence_items/1824 https://civicdb.org/links/variants/760 https://civicdb.org/links/genes/3532 false MSH6 2956 P138T Colorectal Cancer 9256 Oncogenic N/A C N/A This variant, identified in a case of microsatellite-unstable colorectal cancer was confirmed to be somatic in a patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1825 761 2478 2 48018217 48018217 C A ENST00000234420.5 75 GRCh37 Somatic 2021-03-06 00:16:00 UTC https://civicdb.org/links/evidence_items/1825 https://civicdb.org/links/variants/761 https://civicdb.org/links/genes/2478 false MSH2 4436 V273FS Colorectal Cancer 9256 Oncogenic N/A C N/A This variant (V273fs), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be a somatic mutation in a 61 year-old male patient (sLS-27) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. LOH of the WT allele was demonstrated. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1826 762 3628 2 47641433 47641433 T ENST00000233146.2 75 GRCh37 Somatic 2021-03-08 17:42:55 UTC https://civicdb.org/links/evidence_items/1826 https://civicdb.org/links/variants/762 https://civicdb.org/links/genes/3628 false MSH2 4436 E28FS Colorectal Cancer 9256 Oncogenic N/A C N/A This variant (E28fs), identified in a case of microsatellite-unstable colorectal cancer was confirmed to be somatic in a 66 year-old male patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which by definition is a germline condition.. This patient had two somatic mutations in MSH2 (E28fs, K172*). 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1827 763 3628 2 47630413 47630414 G ENST00000233146.2 75 GRCh37 Somatic 2021-03-08 17:44:30 UTC https://civicdb.org/links/evidence_items/1827 https://civicdb.org/links/variants/763 https://civicdb.org/links/genes/3628 false VHL 7428 E55FS (c.163_164delGA) Renal Cell Carcinoma 4450 Oncogenic N/A C N/A In a 54 year old male patient with sporadic renal cell carcinoma, VHL c.163_164delGA causing a p.Glu55 Stop at 130 frameshift mutation was observed. Loss of heterozygosity analysis was non-informative. This result suggests a potential oncogenic role for VHL c.163_164delGA in Renal Cell Carcinoma. 10408776 PubMed Gallou et al., 1999, Hum. Mutat. 1 accepted 1828 764 58 3 10183694 10183695 GA ENST00000256474.2 75 GRCh37 Somatic 2021-06-21 18:59:48 UTC https://civicdb.org/links/evidence_items/1828 https://civicdb.org/links/variants/764 https://civicdb.org/links/genes/58 false MSH6 2956 I891FS Colorectal Cancer 9256 Oncogenic N/A C N/A This variant (I891fs), identified in a case of microsatellite-unstable colorectal cancer was confirmed to be somatic in a 79 year-old male patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1829 765 2478 2 48027794 48027795 TC ENST00000234420.5 75 GRCh37 Somatic 2021-03-08 12:52:09 UTC https://civicdb.org/links/evidence_items/1829 https://civicdb.org/links/variants/765 https://civicdb.org/links/genes/2478 false VHL 7428 E55RfsTer11 (c.163delG) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance This is a frameshift mutation that results in a stop at codon 66. Family 3682 in this publication, variant segregates with disease. VHL Type 1 disease is reported: CNS tumors, retinal angioma, renal cell carcinoma but no pheochromocytoma 8956040 PubMed Zbar et al., 1996, Hum. Mutat. 3 accepted 1830 766 58 3 10183694 10183694 G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/1830 https://civicdb.org/links/variants/766 https://civicdb.org/links/genes/58 false MSH6 2956 R1242H Colorectal Cancer 9256 Oncogenic N/A C N/A This variant (R1242H), identified in a case of microsatellite-unstable colorectal cancer was confirmed to be somatic in a 79 year-old male patient (sLS-37) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1831 767 2478 2 48033421 48033421 G A ENST00000234420.5 75 GRCh37 Somatic 2021-03-08 18:01:32 UTC https://civicdb.org/links/evidence_items/1831 https://civicdb.org/links/variants/767 https://civicdb.org/links/genes/2478 false PMS2 5395 R315* Endometrial Cancer 1380 Oncogenic N/A C N/A This variant, identified in a case of microsatellite-unstable endometrial cancer was confirmed to be somatic in a patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS. This patient also harbored MLH1 p.M490T, MSH2 p.E483G, and MSH6 p.V352I mutations. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1832 768 4371 7 6031649 6031649 G A ENST00000265849.7 75 GRCh37 Somatic 2021-03-06 18:01:20 UTC https://civicdb.org/links/evidence_items/1832 https://civicdb.org/links/variants/768 https://civicdb.org/links/genes/4371 false MLH1 4292 M490T Endometrial Cancer 1380 Oncogenic N/A C N/A This variant (M490T), identified in a case of microsatellite-unstable endometrial cancer was confirmed to be somatic in a 69 year-old female patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which by definition is a germline condition. The patient also harbored PMS2 R315*, MSH2 p.E483G and MSH6 p.V352I mutations. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1833 769 3532 3 37070334 37070334 T C ENST00000231790.2 75 GRCh37 Somatic 2021-03-08 18:03:53 UTC https://civicdb.org/links/evidence_items/1833 https://civicdb.org/links/variants/769 https://civicdb.org/links/genes/3532 false MSH2 4436 K172* Colorectal Cancer 9256 Oncogenic N/A C N/A MSH2 K172*, identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 66 year old male patient (id: sLS-32) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS. This patient had two somatic mutations in MSH2 (E28fs, K172*). 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1834 770 3628 2 47637380 47637380 A T ENST00000233146.2 75 GRCh37 Somatic 2021-03-09 17:38:34 UTC https://civicdb.org/links/evidence_items/1834 https://civicdb.org/links/variants/770 https://civicdb.org/links/genes/3628 false VHL 7428 A56FS (c.164_165insG) Von Hippel-Lindau Disease 14175 Pheochromocytoma,Renal cell carcinoma,Retinal capillary hemangioma,Hemangioblastoma Predisposing Supports C Uncertain Significance c.164insG causes a framehift and truncation allele. One family is described with this allele segregating with disease; 10 affected individuals: 2 patients with renal cell carcinoma, 3 with pheochromocytoma, 7 with retinal angioma, 3 with central nervous system hemangioma. ACMG evidence codes supported by this paper are possibly PVS1 and PP1. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 1835 771 58 3 10183695 10183696 G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/1835 https://civicdb.org/links/variants/771 https://civicdb.org/links/genes/58 false HOXB13 10481 G84E Prostate Cancer 10283 Predisposing Supports B Positive Meta-analysis of prostate cancer with sixteen case-control studies including 50,048 cases and 123,211 controls. In a random effect model the pooled OR (3.38 (95% CI: 2.45–4.66)) of the studies supported the link between HOXB13 G84E variant and a susceptibility to prostate cancer. 27626483 PubMed Zhang et al., 2016, Oncotarget 4 accepted 1836 772 8351 17 46805705 46805705 C T ENST00000290295.7 75 GRCh37 Rare Germline 2017-01-17 01:32:06 UTC https://civicdb.org/links/evidence_items/1836 https://civicdb.org/links/variants/772 https://civicdb.org/links/genes/8351 false MSH2 4436 E483G Endometrial Cancer 1380 Oncogenic N/A C N/A MSH2 E483G (c.1448A > G), identified in a case of microsatellite-unstable endometrial cancer was confirmed to be somatic in a 69 year old female patient (sLS-39) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, as LS is a germline condition by definition. This patient also harbored PMS2 p.R315*, MLH1 p.M490T and MSH6 p.V352I mutations. Authors note that this patient's tumor harbored wildtype BRAF. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1837 773 3628 2 47690231 47690231 A G ENST00000233146.2 75 GRCh37 Somatic 2021-03-06 05:56:17 UTC https://civicdb.org/links/evidence_items/1837 https://civicdb.org/links/variants/773 https://civicdb.org/links/genes/3628 false PDGFRA 5156 TNKS2::PDGFRA Myeloid And Lymphoid Neoplasms With Eosinophilia And Abnormalities Of PDGFRA, PDGFRB, And FGFR1 0080164 Imatinib Predictive Supports C Sensitivity/Response A patient harbouring a novel TNKS2–PDGFRA fusion in a myeloid neoplasm with eosinophilia demonstrated a dramatic and durable response upon treatment with Imatinib mono therapy. 25658984 PubMed Chalmers et al., 2015, Blood Cancer J 3 accepted 1838 774 38 10 93558069 93619405 ENST00000371627.4 4 55141008 55164414 ENST00000257290.5 75 GRCh37 Somatic 2017-01-24 04:56:07 UTC https://civicdb.org/links/evidence_items/1838 https://civicdb.org/links/variants/774 https://civicdb.org/links/genes/38 false MSH6 2956 V352I Endometrial Cancer 1380 Oncogenic N/A C N/A This variant, identified in a case of microsatellite-unstable endometrial cancer was confirmed to be somatic in a patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS. This patient also harbored PMS2 p.R315*, MLH1 p.M490T and MSH2 p.E483G mutations. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1839 775 2478 2 48026176 48026176 G A ENST00000234420.5 75 GRCh37 Somatic 2021-03-05 19:49:09 UTC https://civicdb.org/links/evidence_items/1839 https://civicdb.org/links/variants/775 https://civicdb.org/links/genes/2478 false MSH6 2956 R1242C Colorectal Cancer 9256 Oncogenic N/A C N/A MSH6 R1242C (c.3724C > T), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 53 year old male patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, as LS is a germline condition by definition. The authors note that this patient's tumor was not deficient in mismatch repair (MMR) protein and retained heterozygosity in MSH6. 25111426 PubMed Geurts-Giele et al., 2014, J. Pathol. 1 accepted 1840 776 2478 2 48033420 48033420 C T ENST00000234420.5 75 GRCh37 Somatic 2021-03-06 06:34:36 UTC https://civicdb.org/links/evidence_items/1840 https://civicdb.org/links/variants/776 https://civicdb.org/links/genes/2478 false SLCO1B1 10599 RS4149056 Cancer 162 Methotrexate Predictive Supports B Adverse Response 499 children from ALL trials treated with methotrexate were genotyped for 8 SNPs in 5 genes. The SLCO1B1 rs4149056 variant was significantly associated with MTX AUC0-48h and as such associated with increased toxicity. 23652803 PubMed Radtke et al., 2013, Blood 3 accepted 1841 777 8450 12 21331549 21331549 T C ENST00000256958.2 75 GRCh37 Common Germline 2017-01-23 15:07:04 UTC https://civicdb.org/links/evidence_items/1841 https://civicdb.org/links/variants/777 https://civicdb.org/links/genes/8450 false SLCO1B1 10599 N130D Cancer 162 Methotrexate Predictive Supports B Adverse Response 499 children from ALL trials treated with methotrexate were genotyped for 8 SNPs in 5 genes. The SLCO1B1 RS2306283 variant was significantly associated with MTX AUC0-48h and as such associated with increased toxicity. 23652803 PubMed Radtke et al., 2013, Blood 3 accepted 1842 778 8450 12 21329738 21329738 A G ENST00000256958.2 75 GRCh37 Common Germline 2017-01-23 15:07:24 UTC https://civicdb.org/links/evidence_items/1842 https://civicdb.org/links/variants/778 https://civicdb.org/links/genes/8450 false TYMS 7298 RS34743033 Cancer 162 Methotrexate Predictive Supports B Adverse Response 499 children from ALL trials treated with methotrexate were genotyped for 8 SNPs in 5 genes. The TYMS rs34743033 tandem repeat polymorphism was the only significant predictor of stomatitis in a multiple regression model considering sex, age, MRD class, WBC, MTX AUC0-48h, and genotypes as independent variables (B = −0.48; 95% CI, −0.84, −0.12; R2 = 0.018; P = .009). Stomatitis toxicity was reduced with increasing *3 (3R) alleles as the *2/*2 (2R/2R) genotype displayed the highest incidence of stomatitis, *2/*3 (2R/3R) showed intermediate toxicity, and *3/*3 (3R/3R) had the lowest incidence of stomatitis. 23652803 PubMed Radtke et al., 2013, Blood 3 accepted 1843 779 5971 18 657646 657646 C T ENST00000323274.10 75 Common Germline 2021-04-14 17:41:07 UTC https://civicdb.org/links/evidence_items/1843 https://civicdb.org/links/variants/779 https://civicdb.org/links/genes/5971 false GLI1 2735 ACTB::GLI1 Pericytoma With T(7;12) 0080896 Diagnostic Supports B Positive Pericytoma with t(7;12) is a soft tissue tumor characterized by fusion of the ACTB and GLI genes through the translocation t(7;12)(p22;q13). In this study the genomic breakpoints of 5 cases were characterized. 15555571 PubMed Dahlén et al., 2004, Biochem. Biophys. Res. Commun. 3 accepted 1844 780 2279 Fusion of the hedgehog pathway component gene GLI1 to the β-actin gene (ACTB) has been described as a mechanism of GLI1,and by extension hedgehog pathway, activation. These fusions have been described in histologically distinctive soft tissue tumours showing a pericytic phenotype. Gene fusions retain the DNA-binding zinc finger domains of GLI1 and it is likely that the replacement of the promoter region of GLI1with that of the ubiquitously expressed ACTB gene leads to deregulation of GLI expression and its downstream target genes. Somatic 2021-05-06 12:42:55 UTC https://civicdb.org/links/evidence_items/1844 https://civicdb.org/links/variants/780 https://civicdb.org/links/genes/2279 false ERBB3 2065 V855A Lung Non-small Cell Carcinoma 3908 Pertuzumab,Afatinib Substitutes Predictive Supports D Sensitivity/Response Case report on a novel V855A mutation located in exon 21 of the HER3 tyrosine kinase domain and found in the tumor specimen of an adolescent patient with a chemotherapy-resistant advanced NSCLC. Protein alignments indicated this mutation was analogous to EGFR-L858R and BRAF-L597V. Co-expression of wildtype HER2 and HER3-V855A in Ba/F3 cells led to sensitivity to afatinib and pertuzumab. 26689995 PubMed Umelo et al., 2016, Oncotarget 2 accepted 1845 781 1733 12 56491672 56491672 T C ENST00000267101.3 75 GRCh37 Somatic 2017-02-06 22:37:17 UTC https://civicdb.org/links/evidence_items/1845 https://civicdb.org/links/variants/781 https://civicdb.org/links/genes/1733 false FGFR2 2263 FGFR2::BICC1 Cholangiocarcinoma 4947 Diagnostic Supports B Positive Massively parallel whole transcriptome sequencing in eight specimens from cholangiocarcinoma patients identified two fusion kinase genes, FGFR2-AHCYL1 and FGFR2-BICC1. In RT-PCR screening, the FGFR2 fusion was detected in nine patients with cholangiocarcinoma (9/102), exclusively in the intrahepatic subtype (9/66, 13.6%). 24122810 PubMed Arai et al., 2014, Hepatology 4 accepted 1846 782 22 10 123239371 123357917 ENST00000457416.2 10 60461834 60591195 ENST00000373886.3 75 GRCh37 Somatic 2017-01-26 04:04:15 UTC https://civicdb.org/links/evidence_items/1846 https://civicdb.org/links/variants/782 https://civicdb.org/links/genes/22 false FGFR2 2263 FGFR2::AHCYL1 Cholangiocarcinoma 4947 Diagnostic Supports B Positive Massively parallel whole transcriptome sequencing in eight specimens from cholangiocarcinoma patients identified two fusion kinase genes, FGFR2-AHCYL1 and FGFR2-BICC1. In RT-PCR screening, the FGFR2 fusion was detected in nine patients with cholangiocarcinoma (9/102), exclusively in the intrahepatic subtype (9/66, 13.6%). 24122810 PubMed Arai et al., 2014, Hepatology 4 accepted 1847 783 22 10 123239371 123357917 ENST00000457416.2 1 110554984 110566357 ENST00000369799.5 75 GRCh37 Somatic 2020-12-03 20:32:29 UTC https://civicdb.org/links/evidence_items/1847 https://civicdb.org/links/variants/783 https://civicdb.org/links/genes/22 false CDKN2B 1030 METHYLATION Acute Promyelocytic Leukemia 0060318 Prognostic Supports B Poor Outcome This study analyses 45 new acute promyelocytic leukemia patients (22 male and 23 female). CDKN2B was found to be a negative prognostic biomarker for disease free survival (DFS). The 5-year DFS was 9.6% in methylated and 62.5% in unmethylated samples. While methylation also associated with young age, a multivariate analysis found CDKN2B methylation to be the only independent marker with significance (P=0.008) for DFS. 16307009 PubMed Chim et al., 2006, Leukemia 4 accepted 1848 784 916 9 22009121 22009172 ENST00000276925.6 75 GRCh37 Somatic 2017-02-14 17:45:41 UTC https://civicdb.org/links/evidence_items/1848 https://civicdb.org/links/variants/784 https://civicdb.org/links/genes/916 false CHEK2 11200 1100DELC Prostate Cancer 10283 Predisposing Supports B Positive Meta-analysis linking CHEK2 1100delC to a higher risk of prostate cancer (OR 3.29; 95% confidence interval: 1.85-5.85; P = 0.00). 26629066 PubMed Wang et al., 2015, Int J Clin Exp Med 3 accepted 1850 785 8950 22 29091857 29091857 G ENST00000328354.6 75 GRCh37 Rare Germline 2017-02-15 03:39:27 UTC https://civicdb.org/links/evidence_items/1850 https://civicdb.org/links/variants/785 https://civicdb.org/links/genes/8950 false FGFR2 2263 FGFR2::BICC1 Cholangiocarcinoma 4947 Infigratinib,PD173074 Substitutes Predictive Supports D Sensitivity/Response Expression of the FGFR2-BICC1 fusion kinase in NIH3T3 cells demonstrated transforming ability that was effectively suppressed with the fibroblast growth factor receptor (FGFR) kinase inhibitors BGJ398 and PD173074. 24122810 PubMed Arai et al., 2014, Hepatology 3 accepted 1851 782 22 10 123239371 123357917 ENST00000457416.2 10 60461834 60591195 ENST00000373886.3 75 GRCh37 Somatic 2017-05-31 15:24:35 UTC https://civicdb.org/links/evidence_items/1851 https://civicdb.org/links/variants/782 https://civicdb.org/links/genes/22 false CHEK2 11200 I157T Prostate Cancer 10283 Predisposing Supports B Uncertain Significance Meta-analysis of 4 retrospective studies linked CHEK2 I157T to a higher risk of prostate cancer (OR 1.80; 95% confidence interval: 1.51-2.14; P = 0.00). 26629066 PubMed Wang et al., 2015, Int J Clin Exp Med 3 accepted 1852 787 8950 22 29121087 29121087 A G ENST00000328354.6 75 GRCh37 Rare Germline 2017-07-25 20:34:35 UTC https://civicdb.org/links/evidence_items/1852 https://civicdb.org/links/variants/787 https://civicdb.org/links/genes/8950 false FGFR2 2263 FGFR2::AHCYL1 Cholangiocarcinoma 4947 Infigratinib,PD173074 Substitutes Predictive Supports D Sensitivity/Response Expression of the FGFR2-AHCYL1 fusion kinase in NIH3T3 cells demonstrated transforming ability that was effectively suppressed with the fibroblast growth factor receptor (FGFR) kinase inhibitors BGJ398 and PD173074. 24122810 PubMed Arai et al., 2014, Hepatology 3 accepted 1853 783 22 10 123239371 123357917 ENST00000457416.2 1 110554984 110566357 ENST00000369799.5 75 GRCh37 Somatic 2017-05-31 15:23:36 UTC https://civicdb.org/links/evidence_items/1853 https://civicdb.org/links/variants/783 https://civicdb.org/links/genes/22 false CHEK2 11200 IVS2+1G>A Prostate Cancer 10283 Predisposing Does Not Support B Uncertain Significance Meta-analysis of 2 studies of CHEK2 and prostate cancer showing that the IVS2+1G>A mutation is irrelevant as a predictor of prostate cancer. 26629066 PubMed Wang et al., 2015, Int J Clin Exp Med 2 accepted 1854 788 8950 Rare Germline 2017-07-25 20:36:37 UTC https://civicdb.org/links/evidence_items/1854 https://civicdb.org/links/variants/788 https://civicdb.org/links/genes/8950 false PTPRD 5789 V253I Ewing Sarcoma Of Bone 3368 Teprotumumab,Cixutumumab Substitutes Predictive Supports C Sensitivity/Response Report of complete response to IGF1-R antibody, with or without mTOR inhibitor tensirolimus in 2/3 Ewing Sarcoma patients with germline PTPRD mutations (V253I and W775*, R995C). The third patient had stable disease (T781A mutant). Four wildtype patients had stable or progressive disease. 23800680 PubMed Jiang et al., 2013, Oncotarget 4 accepted 1856 792 4692 9 8521481 8521481 C T ENST00000381196.4 75 GRCh37 Rare Germline 2017-02-23 19:40:03 UTC https://civicdb.org/links/evidence_items/1856 https://civicdb.org/links/variants/792 https://civicdb.org/links/genes/4692 false VHL 7428 A56fs (c.164_165insA) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A variants resulting in A56G frameshift (with stop introduced at position 131) was observed in a single patient of a VHL family. (family #146 in the publication). Neither the VHL phenotype details or segregation data were provided by this publication. Since this is a frameshift occurring early in the protein sequence we can assign an ACMG evidence code of 'PVS1'. 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 2 accepted 1857 793 58 3 10183695 10183696 A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/1857 https://civicdb.org/links/variants/793 https://civicdb.org/links/genes/58 false VHL 7428 E55= (c.165G>A) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance c.165G>A results in synonymous change Glu55Glu. This is family V5 in the paper (VHL Type 1, no phechromocytoma). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 2 accepted 1858 794 58 3 10183696 10183696 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/1858 https://civicdb.org/links/variants/794 https://civicdb.org/links/genes/58 false RRM1 6240 Overexpression Pancreatic Cancer 1793 Gemcitabine Predictive Supports D Resistance The mRNA expression level of RRM1 was analyzed by RT-PCR in 3 human pancreatic cancer cell lines cultured in incrementally increased concentrations of gemcitabine. Expression levels of RRM1 progressively increased during the development of gemcitabine resistance. 17224927 PubMed Nakano et al., 2007, Br. J. Cancer 2 accepted 1859 795 5051 11 4116039 4160106 ENST00000300738.5 75 GRCh37 N/A 2017-02-06 23:05:08 UTC https://civicdb.org/links/evidence_items/1859 https://civicdb.org/links/variants/795 https://civicdb.org/links/genes/5051 false RRM2 6241 OVEREXPRESSION Pancreatic Cancer 1793 Gemcitabine Predictive Supports D Resistance The mRNA expression level of RRM2 was analyzed by RT-PCR in 3 human pancreatic cancer cell lines cultured in incrementally increased concentrations of gemcitabine. Expression levels of RRM2 progressively increased during the development of gemcitabine resistance. 17224927 PubMed Nakano et al., 2007, Br. J. Cancer 2 accepted 1860 796 5052 2 10262455 10271545 ENST00000360566.2 75 GRCh37 N/A 2017-05-31 15:22:15 UTC https://civicdb.org/links/evidence_items/1860 https://civicdb.org/links/variants/796 https://civicdb.org/links/genes/5052 false POLE 5426 Mutation Glioblastoma 3068 Pembrolizumab Predictive Supports C Sensitivity/Response Case report of a patient with glioblastoma multiforme and POLE germline mutation. The patient was treated with pembrolizumab and lymphocyte infiltration was noted after resection of a spinal metastasis. An objective radiographic response was noted in the intracranial lesion. A high neoantigen load was identified. 27683556 PubMed Johanns et al., 2016, Cancer Discov 3 accepted 1861 797 4386 12 133202900 133256623 ENST00000320574.5 75 GRCh37 Rare Germline 2017-01-24 22:21:47 UTC https://civicdb.org/links/evidence_items/1861 https://civicdb.org/links/variants/797 https://civicdb.org/links/genes/4386 false POLE 5426 Mutation Endometrial Cancer 1380 Pembrolizumab Predictive Supports C Sensitivity/Response Case report of a patient with endometrial cancer and exceptional response to pembrolizumab (maintained at 14 months). POLE mutations V411L (exonuclease domain) and R114* were identified in the primary tumor as well as a resected lymph node metastasis. The tumor harbored a high mutational load as assessed by panel sequencing. Analysis of TCGA RNA-seq data revealed an association between POLE mutations and high immune marker expression. 27159395 PubMed Mehnert et al., 2016, J. Clin. Invest. 3 accepted 1862 797 4386 12 133202900 133256623 ENST00000320574.5 75 GRCh37 Somatic 2017-02-17 08:37:04 UTC https://civicdb.org/links/evidence_items/1862 https://civicdb.org/links/variants/797 https://civicdb.org/links/genes/4386 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Afatinib Predictive Supports B Resistance Patients with advanced NSCLC and acquired resistance to EGFR TKI (gefitinib or erlotinib) were analyzed for T790M mutations. Of the 70 patients analyzed, 36 (51%) had the T790M mutation and 34 (49%) were T790M-negative. There was no significant difference in the median post-progression or overall survival between patients with T790M mutation and without T790M mutation for initial TKI treatment. However, subsequent treatment with afatinib showed partial response in six patients where 1/21(5%) were in the T790M-positive group and 5/13 (38%) were in the T790M-negative group (P=0.01). 24035188 PubMed Sun et al., 2013, Lung Cancer 4 accepted 1863 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2017-01-01 21:00:15 UTC https://civicdb.org/links/evidence_items/1863 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false MET 4233 D1228V Lung Non-small Cell Carcinoma 3908 Cabozantinib Predictive Supports C Sensitivity/Response Case report of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET. After progression on erlotinib the patient was treated with combined type I MET (savolitinib) and EGFR (osimertinib) inhibition and responded. When resistance developed, a new MET kinase domain mutation, D1228V, was detected. Drug binding predictions and in vitro studies demonstrated that the D1228V mutation induces resistance to type I but not type II MET TKIs. The patient was treated with erlotinib (EGFR TKI) combined with cabozantinib, a type II MET inhibitor, and had a response which continued at the time of report (5 months). 27694386 PubMed Bahcall et al., 2016, Cancer Discov 4 accepted 1864 798 52 7 116423408 116423408 A T ENST00000397752.3 75 GRCh37 Somatic 2017-02-13 13:27:44 UTC https://civicdb.org/links/evidence_items/1864 https://civicdb.org/links/variants/798 https://civicdb.org/links/genes/52 false MET 4233 D1228V Lung Non-small Cell Carcinoma 3908 Savolitinib Predictive Supports C Resistance Case report of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET. After progression on erlotinib the patient was treated with combined type I MET (savolitinib) and EGFR (osimertinib) inhibition and responded. When resistance developed, a new MET kinase domain mutation, D1228V, was detected. Drug binding predictions and in vitro studies demonstrated that the D1228V mutation induces resistance to type I but not type II MET TKIs. The patient was treated with erlotinib (EGFR TKI) combined with cabozantinib, a type II MET inhibitor, and had a response which continued at the time of report (5 months). 27694386 PubMed Bahcall et al., 2016, Cancer Discov 4 accepted 1865 798 52 7 116423408 116423408 A T ENST00000397752.3 75 GRCh37 Somatic 2017-02-13 13:27:18 UTC https://civicdb.org/links/evidence_items/1865 https://civicdb.org/links/variants/798 https://civicdb.org/links/genes/52 false RB1 5925 Mutation Lung Small Cell Carcinoma 5409 Chemotherapy Predictive Supports B Sensitivity/Response Study evaluated a total of 50 small cell lung cancer patients with extensive stage disease. Multivariate analysis identified RB1 as a factor in predicting response to first-line chemotherapy (odds ratio 5.58 compared to WT, p=.038). Kaplan-Meier survival analysis revealed patients with RB1 mutations exhibited better overall survival (p = .04, 11.7 versus 9.1 months, CI = 1.1-28.2). 26802149 PubMed Dowlati et al., 2016, Ann. Oncol. 2 accepted 1866 799 4795 13 48877911 49056122 ENST00000267163.4 75 GRCh37 Somatic 2017-02-06 17:41:28 UTC https://civicdb.org/links/evidence_items/1866 https://civicdb.org/links/variants/799 https://civicdb.org/links/genes/4795 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Osimertinib Predictive Supports A Sensitivity/Response Randomized, international, open-label, phase 3 trial (NCT02151981) in 419 patients with T790M-positive advanced NSCLC and disease progression after first-line EGFR-TKI therapy. Patients were randomized, in a 2:1 ratio, to oral osimertinib or chemotherapy (pemetrexed plus either carboplatin or cisplatin every 3 weeks for up to six cycles, maintenance pemetrexed was allowed). Primary end point was PFS, which was significantly longer with osimertinib than with chemotherapy (10.1 months vs. 4.4 months; HR 0.30; 95% CI: 0.23 to 0.41; P<0.001). Objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with chemotherapy (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). 27959700 PubMed Mok et al., 2016, N. Engl. J. Med. NCT02151981 5 accepted 1867 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2017-01-19 19:59:33 UTC https://civicdb.org/links/evidence_items/1867 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false NTRK1 4914 SQSTM1::NTRK1 Lung Non-small Cell Carcinoma 3908 Entrectinib Predictive Supports C Sensitivity/Response In 1378 cases of NSCLC screened for NTRK1 rearrangements, 2 were identified (frequency 0.1%). One patient with SQSTM1-NTRK1 was treated with entrectinib in a phase 1 study. The patient had resolution of prior dyspnea and pain within 3 weeks. CT scans showed a partial response and complete resolution of brain metastases. The patient has continued treatment for over 6 months with ongoing PR. 26565381 PubMed Farago et al., 2015, J Thorac Oncol NCT02097810 3 accepted 1868 800 3983 Somatic 2017-04-14 16:51:40 UTC https://civicdb.org/links/evidence_items/1868 https://civicdb.org/links/variants/800 https://civicdb.org/links/genes/3983 false NTRK3 4916 ETV6::NTRK3 Mammary Analogue Secretory Carcinoma 0080808 Entrectinib Predictive Supports C Sensitivity/Response Case report of a patient with mammary analogue secretory carcinoma (MASC) harboring an ETV6-NTRK3 fusion. The patient was treated with entrectinib and exhibited a partial response for 7 months followed by disease progression. 26884591 PubMed Drilon et al., 2016, Ann. Oncol. NCT02097810 3 accepted 1869 801 3985 12 11802788 12022903 ENST00000396373.4 15 88483984 88418230 ENST00000394480.2 75 GRCh37 Somatic 2022-01-11 17:46:50 UTC https://civicdb.org/links/evidence_items/1869 https://civicdb.org/links/variants/801 https://civicdb.org/links/genes/3985 false NTRK3 4916 ETV6::NTRK3 Mammary Analogue Secretory Carcinoma 0080808 Crizotinib Predictive Does Not Support C Sensitivity/Response Case report of a patient with mammary analogue secretory carcinoma (MASC) harboring an ETV6-NTRK3 fusion. The patient was treated with crizotinib and had stable disease but disease progression after 18 weeks. The patient was subsequently treated with entrectinib and exhibited a partial response for 7 months followed by disease progression. 26884591 PubMed Drilon et al., 2016, Ann. Oncol. NCT02097810 2 accepted 1870 801 3985 12 11802788 12022903 ENST00000396373.4 15 88483984 88418230 ENST00000394480.2 75 GRCh37 Somatic 2022-01-11 17:45:50 UTC https://civicdb.org/links/evidence_items/1870 https://civicdb.org/links/variants/801 https://civicdb.org/links/genes/3985 false RUNX1 861 K83E Acute Myeloid Leukemia 9119 Predisposing Supports C Likely Pathogenic A pedigree of 48 individuals with multiple instances of bleeding and platelet disorders and 8 cases of leukemia showed an A>G substitution in RUNX1 exon 3 which segregated with Familial Platelet Disorder and Acute Myeloid Leukemia. The mutation was not present in 188 unrelated control chromosomes. Functional assay suggested the mutant RUNX1 transcription factor had impaired DNA binding. 11830488 PubMed Michaud et al., 2002, Blood 4 accepted 1871 802 43 21 36259163 36259163 T C ENST00000344691.4 75 GRCh37 Rare Germline 2019-08-08 16:25:47 UTC https://civicdb.org/links/evidence_items/1871 https://civicdb.org/links/variants/802 https://civicdb.org/links/genes/43 false RUNX1 861 Y260* Acute Myeloid Leukemia 9119 Predisposing Supports C Uncertain Significance A pedigree (Pedigree number 3) with 24 members with multiple instances of bleeding disorder and three cases of familial leukemia showed a C>A substitution in exon 7B of the transcription factor RUNX1. This mutation resulted in a nonsense mutation, and the mutation segregated with familial platelet disorder and acute myeloid leukemia in the pedigree. 11830488 PubMed Michaud et al., 2002, Blood 3 accepted 1872 803 43 21 36171704 36171704 G T ENST00000344691.4 75 GRCh37 Rare Germline 2019-08-08 16:24:49 UTC https://civicdb.org/links/evidence_items/1872 https://civicdb.org/links/variants/803 https://civicdb.org/links/genes/43 false RUNX1 861 R135FSX177 Acute Myeloid Leukemia 9119 Predisposing Supports C Likely Pathogenic A pedigree (Pedigree number 2) with familial platelet disorder and acute myeloid leukemia (FPD/AML) was studied and a one-base deletion was found in RUNX1 splice donor site. This resulted in use of a cryptic donor splice site and a novel transcript with frameshift, 41 novel amino acids and termination at codon 177. This mutation segregated with FDP/AML and was not found in 184 unrelated control chromosomes. 11830488 PubMed Michaud et al., 2002, Blood 4 accepted 1873 804 43 Rare Germline 2017-08-31 19:23:34 UTC https://civicdb.org/links/evidence_items/1873 https://civicdb.org/links/variants/804 https://civicdb.org/links/genes/43 false NTRK3 4916 ETV6::NTRK3 G623R Mammary Analogue Secretory Carcinoma 0080808 Entrectinib Predictive Supports C Resistance Case report of a patient with mammary analogue secretory carcinoma (MASC) harboring an etv6-ntrk3 fusion. The patient was treated with entrectinib and exhibited a partial response for 7 months followed by disease progression. A NTRK3 exon 16 G623R (c.1867G>A) mutation was identified in the progressive tumor. Cell line and structural models revealed that this mutation conferred relative resistance to entrectinib. 26884591 PubMed Drilon et al., 2016, Ann. Oncol. NCT02097810 4 accepted 1874 805 3985 15 88476265 88476265 C T ENST00000394480.2 75 GRCh37 Somatic 2022-01-11 17:45:13 UTC https://civicdb.org/links/evidence_items/1874 https://civicdb.org/links/variants/805 https://civicdb.org/links/genes/3985 false RUNX1 861 D198Y Acute Myeloid Leukemia 9119 Predisposing Supports C Uncertain Significance In a pedigree with familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) spanning three generations, five members of generation II were sequenced at exons 3, 4 and 5 of the RUNX1 (or CBFA2) gene and the D198Y mutation (in the DNA binding RUNT domain) was found in 3/5 of the individuals with FPD/AML but not in 2/5 without FPD/AML. The mutation was not found in 108 control subjects. 11675361 PubMed Buijs et al., 2001, Blood 3 accepted 1875 806 43 21 36231792 36231792 C A ENST00000300305.3 75 GRCh37 D198Y was observed in a pedigree with a history of Familial platelet disorder with predisposition to acute myeloid leukemia. It occurs within the Runt domain of RUNX1, known to be associated with the disease. Rare Germline 2017-07-25 19:02:42 UTC https://civicdb.org/links/evidence_items/1875 https://civicdb.org/links/variants/806 https://civicdb.org/links/genes/43 false RUNX1 861 A107P Acute Myeloid Leukemia 9119 Predisposing Supports C Positive A pedigree of 3 generations and 8 individuals with familial platelet disease with propensity to acute myeloid leukemia (FPD/AML) was assessed for mutation in RUNX1 exons 3, 4, 5 and 6. Mutation was found in DNA binding RUNT domain at amino acid 107 from alanine to proline. This mutation was found in 5/8 individuals with FPD/AML but not in 3/8 unaffected individuals as well as 10 unrelated control samples. 12060124 PubMed Walker et al., 2002, Br. J. Haematol. 5 accepted 1876 807 43 21 36252962 36252962 C G ENST00000344691.4 75 GRCh37 Rare Germline 2017-02-14 20:40:22 UTC https://civicdb.org/links/evidence_items/1876 https://civicdb.org/links/variants/807 https://civicdb.org/links/genes/43 false MSH2 4436 Loss Transitional Cell Carcinoma 2671 Anti-PD-1 Monoclonal Antibody MEDI0680,Durvalumab Combination Predictive Supports C Sensitivity/Response Case report of a 45-year old woman of Japanese descent with recurrent urothelial carcinoma. The patient was identified to harbor mutations in MSH2 (A913fs*2, E226*, E580*) and in MSH6 (R361H) by panel sequencing as well as loss of expression of these genes as confirmed by IHC. Testing also revealed a high mutational load as well as 2+ PD-L1 expression in 80% of the cells. The patient was treated with anti-PD-L1 inhibitor MEDI4736 and MEDI0680 in a phase 1 trial and had a complete remission within 2 months of treatment that was ongoing after 11 months. 26674132 PubMed Castro et al., 2015, J Immunother Cancer NCT00938834 3 accepted 1877 808 3628 2 47630108 47710367 ENST00000233146.2 75 GRCh37 Somatic 2020-11-20 15:48:06 UTC https://civicdb.org/links/evidence_items/1877 https://civicdb.org/links/variants/808 https://civicdb.org/links/genes/3628 false MSH6 2956 LOSS Transitional Cell Carcinoma 2671 Durvalumab,Anti-PD-1 Monoclonal Antibody MEDI0680 Combination Predictive Supports C Sensitivity/Response Case report of a 45-year old woman of Japanese descent with recurrent urothelial carcinoma. The patient was identified to harbor mutations in MSH2 (A913fs*2, E226*, E580*) and in MSH6 (R361H) by panel sequencing as well as loss of expression of these genes as confirmed by IHC. Testing also revealed a high mutational load as well as 2+ PD-L1 expression in 80% of the cells. The patient was treated with anti-PD-L1 inhibitor MEDI4736 and MEDI0680 in a phase 1 trial and had a complete remission within 2 months of treatment that was ongoing after 11 months. 26674132 PubMed Castro et al., 2015, J Immunother Cancer NCT00938834 3 accepted 1878 809 2478 2 48010221 48037240 ENST00000234420.5 75 GRCh37 Somatic 2020-11-20 15:48:06 UTC https://civicdb.org/links/evidence_items/1878 https://civicdb.org/links/variants/809 https://civicdb.org/links/genes/2478 false CDKN2A 1029 Loss Ewing Sarcoma 3369 Linsitinib,Palbociclib Substitutes Predictive Supports D Sensitivity/Response A patient-derived xenograft (PDX) from a patient with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion positive Ewing's sarcoma was created. The PDX was treated in four cohorts (each N=6) with control, doxorubicin, CDK4/6 inhibitor palbociclib or IGF-1R inhibitor linsitinib. Both linsitinib and palbociclib cohorts were significantly more effective than control and doxorubicin. Doxorubicin was part of the patient's treatment (Neoadjuvant chemotherapy with DOX, vincristine, and cyclophosphamide) and was noted by authors as failing to control tumor growth. 27286459 PubMed Murakami et al., 2016, Oncotarget 2 accepted 1879 554 14 9 21967752 21994623 ENST00000579755.1 75 GRCh37 Somatic 2017-07-25 20:39:26 UTC https://civicdb.org/links/evidence_items/1879 https://civicdb.org/links/variants/554 https://civicdb.org/links/genes/14 false CDKN2B 1030 Loss Ewing Sarcoma 3369 Linsitinib,Palbociclib Substitutes Predictive Supports D Sensitivity/Response A patient-derived xenograft (PDX) from a patient with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion positive Ewing's sarcoma was created. The PDX was treated in four cohorts (each N=6) with control, doxorubicin, CDK4/6 inhibitor palbociclib or IGF-1R inhibitor linsitinib. Both linsitinib and palbociclib cohorts were significantly more effective than control and doxorubicin. Doxorubicin was part of the patient's treatment (Neoadjuvant chemotherapy with DOX, vincristine, and cyclophosphamide) and was noted by authors as failing to control tumor growth. 27286459 PubMed Murakami et al., 2016, Oncotarget 2 accepted 1880 555 916 9 22002902 22009362 ENST00000276925.6 75 GRCh37 Somatic 2017-02-07 17:53:10 UTC https://civicdb.org/links/evidence_items/1880 https://civicdb.org/links/variants/555 https://civicdb.org/links/genes/916 false CDKN2A 1029 Loss Dermatofibrosarcoma Protuberans 3507 Palbociclib Predictive Supports D Sensitivity/Response An imatinib-resistant cell line, DFSP105, was established from a dermatofibrosarcoma protuberans which had progressed to a high-grade fibrosarcomatous DFSP. The disease-associated COL1A1-PDGFB fusion was consistent with the most common form, a supernumerary ring chromosome. Genetic characterization of the cell line with a SNP array identified a homozygous CDKN2A/B deletion. Treatment of this cell line with CDK4/6 inhibitor palbociclib led to growth inhibition and reduced RB1 phosphorylation in vitro and in-vivo. 25852058 PubMed Eilers et al., 2015, Mol. Cancer Ther. 2 accepted 1881 554 14 9 21967752 21994623 ENST00000579755.1 75 GRCh37 Unknown 2020-08-25 00:28:38 UTC https://civicdb.org/links/evidence_items/1881 https://civicdb.org/links/variants/554 https://civicdb.org/links/genes/14 false RUNX1 861 T148HFSX9 Acute Myeloid Leukemia 9119 Predisposing Supports C Uncertain Significance A 2 year old male presented with easy bruising and bleeding. At 6 years old he was diagnosed with AML. The patients mother showed mile thrombocytopenia. Sequencing of RUNX1 exons 3-6 revealed an 8 bp deletion which was hypothesized to result in a null allele. The mutation was found in the mother and son. The patient's maternal grandparents were haematologicaly normal. Relevant ACMG codes from this paper are 'PVS1' (frameshift/null variant) and 'PP1' (limited segregation data). 18478040 PubMed Béri-Dexheimer et al., 2008, Eur. J. Hum. Genet. 2 accepted 1882 810 43 21 36252913 36252920 GCTGCGGT ENST00000300305.3 75 GRCh37 Rare Germline 2017-02-11 22:47:20 UTC https://civicdb.org/links/evidence_items/1882 https://civicdb.org/links/variants/810 https://civicdb.org/links/genes/43 false DDX41 51428 R164W Hematologic Cancer 2531 Predisposing Supports C Positive Eight members of larger pedigree spanning four generations with inherited hematological cancers were sequenced with whole exome sequencing or sanger sequencing of DDX41 exons 5 and 6. A mutation c.490C>T or R164W was found in 5/5 members with Non Hodkin's lymphoma, Hodgkin lymphoma, or multiple myeloma but not in 3/3 unaffected individuals. The site of mutation is reported to potentially be important for DDX41 helicase activity. 26712909 PubMed Lewinsohn et al., 2016, Blood 3 accepted 1887 814 11932 5 176942767 176942767 G A ENST00000507955.1 75 GRCh37 Rare Germline 2017-01-26 05:08:01 UTC https://civicdb.org/links/evidence_items/1887 https://civicdb.org/links/variants/814 https://civicdb.org/links/genes/11932 false ERBB2 2064 Y772_A775DUP Lung Adenocarcinoma 3910 Afatinib Predictive Supports C Sensitivity/Response A Phase II study for use of Afatinib in non- or light smokers with lung adenocarcinoma. Three patients with metastatic lung adenocarcinomas bearing mutations in the kinase domain of HER2 gene were identified (Y772_A775dup, G776L, and G778_P780dup). Objective response was observed in all three of these patients. The patient with Y772_A775dup (Case 1 in the paper), maintained a metabolic complete response for 3 months, ultimately received a total of 9 months of Afatinib, and survived one year from study entry. 22325357 PubMed De Grève et al., 2012, Lung Cancer NCT00730925 3 accepted 1888 414 20 17 37880996 37880997 TACGTGATGGCT ENST00000269571.5 75 GRCh37 Mutations in the HER2 kinase domain occur at a 2-4% frequency in lung adenocarcinomas, the majority of which are in exon 20 as in-frame duplications or insertions in a small 8 codon region (774-781 or 775-782). These are analogous to the exon 20 alterations found in EGFR TK domain. The M774 insertion, M774insAYVM, represents 62.5% of all HER2 kinase domain mutations identified (when combined with the A775insYVMA mutations as they translate to the identical amino acid sequence changes). As demonstrated in mouse models (Perrera et al., PNAS 2009) and subsequent clinical trials in human lung adenocarcinoma with these insertions, HER2 YVMA mutants predict response to several targeted HER2 agonists such as afatinib, trastuzumab, neratinib and TDM-1 (trastuzumab emtansine) as monotherapy or combined with specific chemotherapies. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1888 https://civicdb.org/links/variants/414 https://civicdb.org/links/genes/20 false ERBB2 2064 G776L Lung Adenocarcinoma 3910 Afatinib Predictive Supports C Sensitivity/Response A Phase II study for use of Afatinib in non- or light smokers with lung adenocarcinoma. Three patients with metastatic lung adenocarcinomas bearing mutations in the kinase domain of HER2 gene were identified (Y772_A775dup, G776L, and G778_P780dup). Objective response was observed in all three of these patients. The patient with G776L (Case 2 in the paper) achieved a partial response after two months of afatinib (50 mg/day). The time to progression of this single agent was four months. The patient was also noted to have a EGFR kinase domain (exon 21: p.Ala859Thr) mutation. 22325357 PubMed De Grève et al., 2012, Lung Cancer NCT00730925 3 accepted 1889 816 20 17 37880997 37880998 GG CT ENST00000269571.5 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1889 https://civicdb.org/links/variants/816 https://civicdb.org/links/genes/20 false ERBB2 2064 G778_P780DUP Lung Adenocarcinoma 3910 Afatinib Predictive Supports C Sensitivity/Response A Phase II study for use of Afatinib in non- or light smokers with lung adenocarcinoma. Three patients with metastatic lung adenocarcinomas bearing mutations in the kinase domain of HER2 gene were identified (Y772_A775dup, G776L, and G778_P780dup). Objective response was observed in all three of these patients. The patient with G778_P780dup (Case 3 in the paper), had a rapid clinical and symptomatic response to Afatinib and stable disease which lasted for 3 months. Progressive disease at 4 months led to the addition of paclitaxel, resulting in partial response. Total Afatinib treatment was 15 months (11 in combination) at which time the patient developed a brain metastasis but no other progressive disease. 22325357 PubMed De Grève et al., 2012, Lung Cancer NCT00730925 3 accepted 1890 817 20 17 37881011 37881012 GGCTCCCCA ENST00000269571.5 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/1890 https://civicdb.org/links/variants/817 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Lung Non-small Cell Carcinoma 3908 Dacomitinib Predictive Does Not Support B Sensitivity/Response Phase 2 trial of ERBB-inhibitor dacomitinib in stage IIIB/IV lung cancers with HER2 mutations or amplification. 4 patients with HER2 amplified NSCLC were enrolled in the trial, no one among them had a response. 25899785 PubMed Kris et al., 2015, Ann. Oncol. NCT00818441 3 accepted 1891 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. N/A 2017-01-23 15:20:10 UTC https://civicdb.org/links/evidence_items/1891 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 G778_P780DUP Lung Non-small Cell Carcinoma 3908 Dacomitinib Predictive Supports C Sensitivity/Response Phase 2 trial of ERBB-inhibitor dacomitinib in stage IIIB/IV lung cancers with HER2 mutations or amplification. Two patients were identified with identical HER2 p.G778_P780dup mutations (p. P780_Y781insGSP, c. 2339_2340ins GGCTCCCCA) and no amplification. Both had a confirmed partial response lasting 11 and 14 months. Only 3/30 patients on this trial had a partial response (no complete responses). 25899785 PubMed Kris et al., 2015, Ann. Oncol. NCT00818441 3 accepted 1892 817 20 17 37881011 37881012 GGCTCCCCA ENST00000269571.5 75 GRCh37 Somatic 2017-02-06 17:16:31 UTC https://civicdb.org/links/evidence_items/1892 https://civicdb.org/links/variants/817 https://civicdb.org/links/genes/20 false ERBB2 2064 Y772_A775DUP Lung Non-small Cell Carcinoma 3908 Dacomitinib Predictive Does Not Support B Sensitivity/Response Phase 2 trial of ERBB-inhibitor dacomitinib in stage IIIB/IV lung cancers with HER2 mutations or amplification (N=30). Thirteen tumors harbored identical 12 base pair exon 20 insertions [A775_G776insYVMA, alternative nomenclature p.Y772_A775dup(c.2313_2324dup)]. No partial responses were found in this subgroup even though some were on study treatment for >2 years and 3 patients with other HER2 mutations achieved PRs. 25899785 PubMed Kris et al., 2015, Ann. Oncol. NCT00818441 2 accepted 1893 414 20 17 37880996 37880997 TACGTGATGGCT ENST00000269571.5 75 GRCh37 Mutations in the HER2 kinase domain occur at a 2-4% frequency in lung adenocarcinomas, the majority of which are in exon 20 as in-frame duplications or insertions in a small 8 codon region (774-781 or 775-782). These are analogous to the exon 20 alterations found in EGFR TK domain. The M774 insertion, M774insAYVM, represents 62.5% of all HER2 kinase domain mutations identified (when combined with the A775insYVMA mutations as they translate to the identical amino acid sequence changes). As demonstrated in mouse models (Perrera et al., PNAS 2009) and subsequent clinical trials in human lung adenocarcinoma with these insertions, HER2 YVMA mutants predict response to several targeted HER2 agonists such as afatinib, trastuzumab, neratinib and TDM-1 (trastuzumab emtansine) as monotherapy or combined with specific chemotherapies. Somatic 2018-06-05 21:34:23 UTC https://civicdb.org/links/evidence_items/1893 https://civicdb.org/links/variants/414 https://civicdb.org/links/genes/20 false ERBB2 2064 M774DELINSWLV Lung Non-small Cell Carcinoma 3908 Dacomitinib Predictive Supports C Sensitivity/Response Phase 2 trial of ERBB-inhibitor dacomitinib in stage IIIB/IV lung cancers with HER2 mutations or amplification (N=30). One patient was found to harbor a unique Exon 20 indel (p. M774delinsWLV, c.2320A>TGGCT GG; p. M774delinsWLV, c.2320delins TGGCTGG) and was among the three patients that had a partial response. 25899785 PubMed Kris et al., 2015, Ann. Oncol. NCT00818441 3 accepted 1894 818 20 17 37880991 37880991 A TGGCTGG ENST00000269571.5 75 GRCh37 Somatic 2017-02-07 18:08:40 UTC https://civicdb.org/links/evidence_items/1894 https://civicdb.org/links/variants/818 https://civicdb.org/links/genes/20 false PTPRB 5787 Loss-of-function Angiosarcoma 0001816 Sunitinib,Vatalanib Substitutes Predictive Supports D Sensitivity/Response The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harbored truncating mutations in 10 of 39 angiosarcomas (26%) which correlated with MYC amplifications. In HUVEC cell line model, silencing of PTPRB induced features of angiogenesis which were abolished in the presence of sunitinib or vatalinib, inhibitors of VEGFR. 24633157 PubMed Behjati et al., 2014, Nat. Genet. 3 accepted 1895 819 4690 12 70910630 71031220 ENST00000334414.6 75 GRCh37 Somatic 2022-01-07 20:09:40 UTC https://civicdb.org/links/evidence_items/1895 https://civicdb.org/links/variants/819 https://civicdb.org/links/genes/4690 false VHL 7428 A149S (c.445G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Study of a large kindred with von Hippel-Lindau disease (VHLD) and pheochromocytoma (spread over four generations). 25 proven cases of VHLD and 17 cases with pheochromocytoma were identified. Mutation analysis was performed in 14 family members (7 affected, 7 unaffected). 11 cases had the same mutation resulting in a predicted amino acid substitution of A149S. The cases with mutation that appeared unaffected were all very young (before the likely age of onset). The three cases without the mutation that appeared unaffected were aged 18, 54, and 69. ACMG evidence codes: 'PP1' based on segregation results, 'PM5' because the authors describe a prior report of a similar mutation at the same site (A149T), 'PP2' because they observe a missense variant in gene where missense variants are common mechanism of disease, and 'PP4' because the patients phenotypes and family history are highly specific for a disease with single genetic etiology. 9435426 PubMed Atuk et al., 1998, J. Clin. Endocrinol. Metab. 4 accepted 1896 820 58 3 10188302 10188302 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/1896 https://civicdb.org/links/variants/820 https://civicdb.org/links/genes/58 false BRCA1 672 Mutation Ovarian Cancer 2394 Rucaparib Predictive Supports B Sensitivity/Response A phase 2 trial on patients with relapsed, platinum-sensitive high grade ovarian, fallopian tube or primary peritoneal carcinoma (ARIEL2 Part1, NCT01891344) was held to assess PARP inhibitor rucaparib on 3 genetically defined subsets of patients. Out of 40 BRCA mutant (BRCA1 or BRCA2) patients, 14 had homozygous somatic BRCA1 mutation or deletion. Confirmed objective response was seen in 71% (10/14) of the somatic BRCA1 mutant subgroup. Authors note that response rate was similar regardless of whether the BRCA mutation was somatic or germline, in BRCA 1 or BRCA 2. In a BRCA wild-type subgroup, with low levels of loss of heterozygosity (LOH), confirmed objective response was observed in 10% (7/70) of the patients. Patients with BRCA mutant tumors experienced significantly longer median progression free survival than patients with BRCA wildtype, LOH low tumors (12.8 vs 5.2 mo, HR: 0.27, P<0.0001). 27908594 PubMed Swisher et al., 2017, Lancet Oncol. NCT01891344 3 accepted 1897 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Somatic 2020-08-27 23:03:29 UTC https://civicdb.org/links/evidence_items/1897 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false KRAS 3845 G12D Colorectal Cancer 9256 Therapeutic Tumor Infiltrating Lymphocytes Predictive Supports C Sensitivity/Response A patient with metastatic colorectal cancer was enrolled in a phase 2 clinical trial (NCT01174121). 24 cultures of tumor-infiltrating lymphocytes were expanded from 3 lung metastasis resections. After cultures were tested for reactivity, the patient was infused with 1.48 x 10^11 tumor-infiltrating lymphocytes (75% CD8+ T cells) that were specifically reactive to KRAS G12D. All 7 metastatic lung lesions regressed 40 days after therapy, and the patient had a 9-month partial response. 27959684 PubMed Tran et al., 2016, N. Engl. J. Med. 3 accepted 1898 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2017-01-31 17:24:06 UTC https://civicdb.org/links/evidence_items/1898 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false HLA-C 3107 COPY-NEUTRAL LOSS OF HETEROZYGOSITY Colorectal Cancer 9256 Therapeutic Tumor Infiltrating Lymphocytes Predictive Supports C Resistance A patient with metastatic colorectal cancer was enrolled in a phase 2 clinical trial (NCT01174121). 24 cultures of tumor-infiltrating lymphocytes were expanded from 3 lung metastasis resections. After cultures were tested for reactivity, the patient was infused with 1.48 x 10^11 tumor-infiltrating lymphocytes (75% CD8+ T cells) that were specifically reactive to KRAS G12D and HLA-C*08:02. A single lesion that progressed after 9 months still expressed the KRAS G12D mutation. Whole-exome analysis revealed copy-neutral loss of heterozygosity at chromosome 6, encoding the HLA locus and resulting in loss of the targeted HLA-C*08:02 allele. 27959684 PubMed Tran et al., 2016, N. Engl. J. Med. 3 accepted 1899 821 2608 Somatic 2017-02-06 22:35:27 UTC https://civicdb.org/links/evidence_items/1899 https://civicdb.org/links/variants/821 https://civicdb.org/links/genes/2608 false JAK1 3716 S703I Hepatocellular Carcinoma 684 Ruxolitinib Predictive Supports D Sensitivity/Response A JAK1 S703I mutation was found to activate the JAK-STAT signaling pathway in vitro and in vivo in hepatocellular carcinoma. Ruxolitinib causes the suppression of JAK-STAT signaling pathway in PDX models bearing JAK1 S703I mutation and delays tumor progression. 26701727 PubMed Yang et al., 2016, Oncotarget 4 accepted 1900 822 3090 1 65311203 65311203 C A ENST00000342505.4 75 GRCh37 Somatic 2017-02-02 21:56:24 UTC https://civicdb.org/links/evidence_items/1900 https://civicdb.org/links/variants/822 https://civicdb.org/links/genes/3090 false EPCAM 4072 3' EXON DELETION Lynch Syndrome 3883 Predisposing Supports B Uncertain Significance Rare but recurring germline truncating mutations of the 3’ end of EPCAM, were reported for 27 independent families, shown to lead to epigenetic silencing of a neighbouring gene, MSH2, and suggested to cause Lynch syndrome. 21309036 PubMed Kuiper et al., 2011, Hum. Mutat. 4 accepted 1901 823 3364 2 47612305 47614173 ENST00000263735 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/1901 https://civicdb.org/links/variants/823 https://civicdb.org/links/genes/3364 false BRAF 673 V600E Colorectal Cancer 9256 Irinotecan,Cetuximab,Vemurafenib Combination Predictive Supports B Sensitivity/Response Phase 1b study of vemurafenib, cetuximab and irinotecan in 19 patients with colorectal cancer (1 with appendiceal cancer). Six of 17 evaluable patients achieved an objective response, 15 patients total had either stable disease or radiographic response (the patient with appendiceal cancer had disease progression). Estimated median PFS was 7.7 months. Effect of the combined treatment was also observed in xenograft and cell line studies. 27729313 PubMed Hong et al., 2016, Cancer Discov NCT01787500 4 accepted 1902 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2017-02-14 21:10:27 UTC https://civicdb.org/links/evidence_items/1902 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false ARAF 369 S490T Colorectal Cancer 9256 Vemurafenib,Irinotecan,Cetuximab Combination Predictive Supports C Resistance Phase 1b study of vemurafenib, cetuximab and irinotecan in 19 BRAF V600E mutant colorectal cancer patients. cfDNA panel sequencing was performed in 10 patients after disease progression. One patient had an acquired ARAF S490T mutation that was not identified before treatment initiation. 27729313 PubMed Hong et al., 2016, Cancer Discov NCT01787500 1 accepted 1905 825 3 X 47429340 47429340 T A ENST00000377045.4 75 GRCh37 Somatic 2017-08-31 19:47:16 UTC https://civicdb.org/links/evidence_items/1905 https://civicdb.org/links/variants/825 https://civicdb.org/links/genes/3 false GNAS 2778 R201C Colorectal Cancer 9256 Vemurafenib,Irinotecan,Cetuximab Combination Predictive Supports C Resistance Phase 1b study of vemurafenib, cetuximab and irinotecan in 19 BRAF V600E mutant colorectal cancer patients. cfDNA panel sequencing was performed in 10 patients after disease progression. One patient acquired a novel GNAS1 R201C mutation at disease progression. 27729313 PubMed Hong et al., 2016, Cancer Discov NCT01787500 2 accepted 1906 826 2319 20 57484420 57484420 C T ENST00000371085.3 75 GRCh37 Somatic 2017-07-20 14:51:41 UTC https://civicdb.org/links/evidence_items/1906 https://civicdb.org/links/variants/826 https://civicdb.org/links/genes/2319 false ATM 472 Mutation Mantle Cell Lymphoma 0050746 Olaparib Predictive Supports D Sensitivity/Response Two ATM deficient mantle cell lymphoma (MCL) cell lines were more sensitive to PARP-1 inhibition with olaparib or PJ-34 than 4 other MCL cell lines. shRNA mediated ATM knockdown in a cell line increased sensitivity to olaparib. These results were confirmed in a xenograft model. 20124459 PubMed Williamson et al., 2010, Mol. Cancer Ther. 3 accepted 1907 178 69 11 108093559 108239826 ENST00000278616.4 75 GRCh37 Somatic 2017-07-25 17:38:36 UTC https://civicdb.org/links/evidence_items/1907 https://civicdb.org/links/variants/178 https://civicdb.org/links/genes/69 false FGFR1 2260 Amplification Lung Squamous Cell Carcinoma 3907 Infigratinib Predictive Supports B Sensitivity/Response Phase 1 study of FGFR-inhibitor BGJ398 (infigratinib) in advanced cancer with FGFR-aberrations (n=132). In the subgroup of FGFR1-amplified squamous NSCLC (as classified by FISH), 36 patients were treated at doses >100mg continuously and disease control was achieved in 50% of patients (4 PR and 14 SD) with 6 patients receiving treatment after 16 weeks. Of the 27 patients who had evaluable pre- and post- treatment target lesion assessments, 11 had reduced tumor burden. 27870574 PubMed Nogova et al., 2017, J. Clin. Oncol. 3 accepted 1908 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). Somatic 2021-01-25 23:27:05 UTC https://civicdb.org/links/evidence_items/1908 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false FGFR1 2260 Amplification Breast Cancer 1612 Infigratinib Predictive Does Not Support B Resistance Phase 1 study of FGFR-inhibitor BGJ398 (infigratinib) in advanced cancer with FGFR-aberrations (n=132). Among the 21 continuously treated (>100mg) patients with breast cancer and FGFR1 amplification (as classified by FISH), 9 had a best response of SD, three of which experienced reductions in tumor burden. 27870574 PubMed Nogova et al., 2017, J. Clin. Oncol. 2 accepted 1909 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). Somatic 2020-12-03 21:13:01 UTC https://civicdb.org/links/evidence_items/1909 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false FGFR3 2261 Mutation Bladder Carcinoma 4007 Infigratinib Predictive Supports B Sensitivity/Response Phase 1 study evaluated 132 patients who had advanced cancer with FGFR-aberrations treated with FGFR-inhibitor BGJ398. In the subgroup of eight patients with FGFR3-mutated bladder/urothelial cancer treated at doses ≥ 100 mg, the disease control rate (SD + PR) was 75%. Three patients achieved partial response and 3 patients had stable disease. Of the six patients with disease control, the time on treatment ranged from 15.1 to ≥ 101 weeks, with one ongoing at data cutoff. 27870574 PubMed Nogova et al., 2017, J. Clin. Oncol. 3 accepted 1910 827 23 4 1795039 1810599 ENST00000340107.4 75 GRCh37 Somatic 2021-01-04 21:16:09 UTC https://civicdb.org/links/evidence_items/1910 https://civicdb.org/links/variants/827 https://civicdb.org/links/genes/23 false FGFR1 2260 Amplification Bladder Carcinoma 4007 Infigratinib Predictive Does Not Support C Sensitivity/Response Phase 1 study of FGFR-inhibitor BGJ398 in advanced cancer with FGFR-aberrations. Of the eight patients with FGFR3-mutated bladder/urothelial cancer, one patient with FGFR1 amplification was treated with 125 mg and progressed rapidly in cycle 1 after 11 days of treatment. 27870574 PubMed Nogova et al., 2017, J. Clin. Oncol. 2 accepted 1911 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). N/A 2021-08-25 21:13:51 UTC https://civicdb.org/links/evidence_items/1911 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false FGFR2 2263 Mutation Cholangiocarcinoma 4947 Infigratinib Predictive Supports C Sensitivity/Response Phase 1 study of FGFR-inhibitor BGJ398 in advanced cancer with FGFR-aberrations. Among three patients with cholangiocarcinoma and FGFR2 aberrations (2 fusions, 1 mutation), all three had stable disease with a reduced tumor burden. 27870574 PubMed Nogova et al., 2017, J. Clin. Oncol. 2 accepted 1912 511 22 10 123239371 123357917 ENST00000457416.2 75 GRCh37 Somatic 2017-06-09 23:47:41 UTC https://civicdb.org/links/evidence_items/1912 https://civicdb.org/links/variants/511 https://civicdb.org/links/genes/22 false FGFR2 2263 Fusion Cholangiocarcinoma 4947 Infigratinib Predictive Supports C Sensitivity/Response Phase 1 study of FGFR-inhibitor BGJ398 (infigratinib) in advanced cancer with FGFR-aberrations (n=132). Two cholangiocarcinoma patients harbored FGFR2 fusions. Both were treated at BGJ398 doses >100mg and saw stable disease. One patient had an unknown FGFR2 fusion partner and saw 20.2% reduction in target lesion size. The other patient harbored FGFR2 BICC1 fusion, and saw a 9.8% reduction in target lesion size. 27870574 PubMed Nogova et al., 2017, J. Clin. Oncol. 2 accepted 1913 2202 22 Somatic 2020-10-19 19:11:51 UTC https://civicdb.org/links/evidence_items/1913 https://civicdb.org/links/variants/2202 https://civicdb.org/links/genes/22 false VHL 7428 M54IFS (c.162_166delGGAGG) Clear Cell Renal Cell Carcinoma 4467 Oncogenic N/A C N/A A study of sporadic renal cell carcinoma identified this frameshift confirmed somatic variant along with LOH of the VHL gene in a case with clear cell renal carcinoma (case #152 in the study). 8187067 PubMed Shuin et al., 1994, Cancer Res. 1 accepted 1914 829 58 3 10183693 10183697 GGAGG ENST00000256474.2 75 GRCh37 Somatic 2021-03-05 17:13:05 UTC https://civicdb.org/links/evidence_items/1914 https://civicdb.org/links/variants/829 https://civicdb.org/links/genes/58 false FGFR2 2263 FGFR2::BICC1 Transitional Cell Carcinoma 2671 Erdafitinib Predictive Supports C Sensitivity/Response Phase 1 study of pan-FGFR inhibitor JNJ-42756493 in patients with solid tumors. No responses were seen 36 patients without known FGFR pathway aberrations. Among 23 patients with FGFR pathway aberrations, 4 partial responses as well as 16 with stable disease were seen. In patients with FGFR2-BICC1 fusions, 1 patient with urothelial cancer harboring FGFR2-BICC1/FGFR2-CASP7 fusions had a PR. 26324363 PubMed Tabernero et al., 2015, J. Clin. Oncol. NCT01703481 3 accepted 1917 782 22 10 123239371 123357917 ENST00000457416.2 10 60461834 60591195 ENST00000373886.3 75 GRCh37 Somatic 2020-11-20 15:48:06 UTC https://civicdb.org/links/evidence_items/1917 https://civicdb.org/links/variants/782 https://civicdb.org/links/genes/22 false FGFR2 2263 Fusion Cancer 162 Erdafitinib Predictive Supports B Sensitivity/Response Phase 1 study of pan-FGFR inhibitor JNJ-42756493 in patients with solid tumors. No responses were seen 36 patients without FGFR pathway aberrations. Among 23 patients with FGFR pathway aberrations, 4 partial responses as well as 16 with stable disease were seen. In patients with FGFR2 fusions, 1 patient with urothelial cancer had a PR harbored FGFR2-BICC1/FGFR2-CASP7 fusions, a patient with endometrial cancer and synchronous FGFR3-TACC3 and FGFR2-BICC1/FGFR2-OFD1 fusions had a PR, and tumor shrinkage was observed in a patient with adrenal carcinoma and FGFR3-TACC3/FGFR2-CCDC6 fusions. 26324363 PubMed Tabernero et al., 2015, J. Clin. Oncol. NCT01703481 3 accepted 1918 2202 22 Somatic 2020-10-19 19:11:51 UTC https://civicdb.org/links/evidence_items/1918 https://civicdb.org/links/variants/2202 https://civicdb.org/links/genes/22 false FGFR3 2261 FGFR3::TACC3 Cancer 162 Erdafitinib Predictive Supports B Sensitivity/Response Phase 1 study of pan-FGFR inhibitor JNJ-42756493 in patients with solid tumors. No responses were seen 36 patients without FGFR pathway aberrations. Among 23 patients with FGFR pathway aberrations, 5 partial responses (PR) and 16 with stable disease were seen. In patients harboring FGFR3-TACC3, there were 2 urothelial cancer patients with PRs, 1 endometrial cancer patient with PR (also had FGFR2-BICC1/FGFR2-OFD1 fusions), and tumor shrinkage in a patient with adrenal carcinoma (also had FGFR2-CCDC6 fusion). 26324363 PubMed Tabernero et al., 2015, J. Clin. Oncol. NCT01703481 3 accepted 1919 830 23 4 1795039 1808661 ENST00000340107.4 4 1741429 1746898 ENST00000313288.4 75 GRCh37 Somatic 2019-07-31 15:34:30 UTC https://civicdb.org/links/evidence_items/1919 https://civicdb.org/links/variants/830 https://civicdb.org/links/genes/23 false FGFR2 2263 FGFR2::BICC1 Endometrial Cancer 1380 Erdafitinib Predictive Supports C Sensitivity/Response Phase 1 study of pan-FGFR inhibitor JNJ-42756493 in patients with solid tumors. No responses were seen 36 patients without FGFR pathway aberrations. Among 23 patients with FGFR pathway aberrations, 4 partial responses as well as 16 with stable disease were seen. A patient with endometrial cancer with synchronous FGFR3-TACC3 and FGFR2-BICC1/FGFR2-OFD1 fusions had a PR. 26324363 PubMed Tabernero et al., 2015, J. Clin. Oncol. NCT01703481 3 accepted 1920 782 22 10 123239371 123357917 ENST00000457416.2 10 60461834 60591195 ENST00000373886.3 75 GRCh37 Somatic 2017-03-13 08:33:57 UTC https://civicdb.org/links/evidence_items/1920 https://civicdb.org/links/variants/782 https://civicdb.org/links/genes/22 false TSC1 7248 R1062W Tuberous Sclerosis 13515 Predisposing Supports D Uncertain Significance The authors used a transfection based immunoblot assay to assess the impact of TSC1 (and TSC2) variants. Numerous variants were tested independently across 4 replicates and the mean and s.e.m. were plotted relative to wild type TSC1. The R1062W variant does not display a significant functional impact relative to the wildtype. The authors state that SIFT (an in-silico missense functional prediction program) predicts the variant is tolerated. 21309039 PubMed Hoogeveen-Westerveld et al., 2011, Hum. Mutat. 3 accepted 1921 714 46 9 135771933 135771933 G A ENST00000298552.3 75 GRCh37 Rare Germline 2017-02-23 16:53:09 UTC https://civicdb.org/links/evidence_items/1921 https://civicdb.org/links/variants/714 https://civicdb.org/links/genes/46 false AKT3 10000 Overexpression Breast Cancer 1612 Akt Inhibitor MK2206 Predictive Supports D Resistance Upregulation of AKT3 due to epigenetic reprogramming may confer acquired resistance to AKT inhibitor (MK2206) in breast cancer preclinical model. 27297869 PubMed Stottrup et al., 2016, Mol. Cancer Ther. 4 accepted 1922 1301 7936 N/A 2017-05-13 18:18:28 UTC https://civicdb.org/links/evidence_items/1922 https://civicdb.org/links/variants/1301 https://civicdb.org/links/genes/7936 false AKT3 10000 Overexpression Triple-receptor Negative Breast Cancer 0060081 Pan-AKT Kinase Inhibitor GSK690693 Predictive Supports E Sensitivity/Response AKT3 was found to be preferentially required for the proliferation and tumor growth of TNBC. It was found to be upregulated in a set of TNBC cell lines compared to other breast cancer types. Depletion of AKT3 in TNBC sensitizes cells to the pan-Akt inhibitor GSK690693. It was found that depletion of Akt3 potentially inhibits the growth of TNBC cell lines in three-dimensional (3D) spheroid cultures and in mouse xenograft models, which imply that therapeutic targeting of AKT3 may provide a new treatment option for TNBCs. 24335962 PubMed Chin et al., 2014, Cancer Res. 4 accepted 1923 1301 7936 N/A 2017-05-13 18:17:44 UTC https://civicdb.org/links/evidence_items/1923 https://civicdb.org/links/variants/1301 https://civicdb.org/links/genes/7936 false BRCA1 672 Loss-of-function Breast Cancer 1612 Pidnarulex,Quarfloxin Substitutes Predictive Supports D Sensitivity/Response The authors show that in the CX-5461 and CX-3543, G-quadruplex stabilizing agents, demonstrate specific toxicity against BRCA deficient breast cancer derived cells and polyclonal patient-derived xenograft models. Xenografts harbored both a germline BRCA and a somatic BRCA mutation leading to disruption of both. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. 28211448 PubMed Xu et al., 2017, Nat Commun NCT02719977 4 accepted 1924 131 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 BRCA1 loss of function mutations have been shown to increase risk of breast and ovarian cancer in those carrying the allele in their germline. Treating BRCA mutant patients with PARP inhibitors such as Olaparib has led to significant response. Unknown 2017-10-21 23:07:09 UTC https://civicdb.org/links/evidence_items/1924 https://civicdb.org/links/variants/131 https://civicdb.org/links/genes/6 false BRCA2 675 Loss-of-function Breast Cancer 1612 Pidnarulex,Quarfloxin Substitutes Predictive Supports D Sensitivity/Response The authors show that in the CX-5461 and CX-3543, G-quadruplex stabilizing agents, demonstrate specific toxicity against BRCA deficient breast cancer derived cells and polyclonal patient-derived xenograft models. The BRCA and NHE J pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. 28211448 PubMed Xu et al., 2017, Nat Commun NCT02719977 4 accepted 1925 132 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 BRCA2 loss of function mutations have been shown to increase risk of breast and ovarian cancer in those carrying the allele in their germline. Treating BRCA mutant patients with PARP inhibitors such as Olaparib has led to significant response. Unknown 2018-07-12 18:17:28 UTC https://civicdb.org/links/evidence_items/1925 https://civicdb.org/links/variants/132 https://civicdb.org/links/genes/7 false PTEN 5728 R173C Cancer 162 Predisposing Supports D Uncertain Significance Han et al functionally tested the R173C mutation in PTEN using an expression vector construct, assessing phosphatase activity of the mutant construct with two phosphoinositide substrates ("with[ PtdIns(3,4,5)P3] or without[ Ins(1,3,4,5)P4] a diacylglycerol chain"). R173C resides in the NH2-terminal phosphatase domain of PTEN. R173C was one of four mutations (out of 42 tested) that displayed no significant phosphatase activity against either substrate, indicating, by this assay, that the mutation negatively impacts the function of PTEN. However this mutation did not affect the ability of PTEN to bind lipid membranes in-vivo. This data justifies PS3 level evidence for pathogenicity according to ACMG guidelines. 10866302 PubMed Han et al., 2000, Cancer Res. 3 accepted 1930 838 41 10 89711899 89711899 C T ENST00000371953.3 75 GRCh37 N/A 2017-05-11 16:56:31 UTC https://civicdb.org/links/evidence_items/1930 https://civicdb.org/links/variants/838 https://civicdb.org/links/genes/41 false PTEN 5728 Mutation Glioblastoma 3068 Diagnostic Supports C Positive Rasheed et al. identified that PTEN mutations occur with significantly greater frequency in adults with high-grade gliomas (42 adult glioblastoma multiforme and 13 adult anaplastic astrocytoma) compared to low-grade and child gliomas (68 others, varied). Mutation analysis performed using SSCP. No further testing was done. 9331072 PubMed Rasheed et al., 1997, Cancer Res. 2 accepted 1931 510 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2017-05-18 15:50:53 UTC https://civicdb.org/links/evidence_items/1931 https://civicdb.org/links/variants/510 https://civicdb.org/links/genes/41 false PTEN 5728 R173C Endometrial Hyperplasia 0080365 Oncogenic N/A C N/A Maxwell et al identified R173C in 1 subject (of 51 endometrial hyperplasias assayed for mutations in PTEN), and identified 10 mutations of 51 in PTEN overall (20%). No additional functional testing or clinical description was given. 9635567 PubMed Maxwell et al., 1998, Cancer Res. 1 accepted 1934 838 41 10 89711899 89711899 C T ENST00000371953.3 75 GRCh37 Somatic 2021-03-06 00:19:22 UTC https://civicdb.org/links/evidence_items/1934 https://civicdb.org/links/variants/838 https://civicdb.org/links/genes/41 false PTEN 5728 R173C PTEN Hamartoma Tumor Syndrome 0080191 Venous malformation,Chylothorax,Dyspnea Predisposing N/A C N/A Hopman et al presents a case study with an affected proband carrying PTEN R173C, and meeting the pediatric criteria for PTEN testing of Tan et al (2011). The proband died at 2 years due to a fatal chylothorax, having been seen at 1 year with progressive dyspnoea and displaying extensive lymphatic and venus malformations that displaced the right lung, as well as osteolytic lesions of the bones. Proband's mother and two siblings (one 7 years and one 7 months) also carried the PTEN R173C mutation and were thus far asymptomatic. The mother's parents did not carry the R173C mutation. PP4 ACMG evidence criteria are met as PTEN hamartoma tumor syndrome is a disease with a single genetic etiology. 22628360 PubMed Hopman et al., 2012, Am. J. Med. Genet. A 3 accepted 1935 838 41 10 89711899 89711899 C T ENST00000371953.3 75 GRCh37 Rare Germline 2021-07-10 19:21:51 UTC https://civicdb.org/links/evidence_items/1935 https://civicdb.org/links/variants/838 https://civicdb.org/links/genes/41 false ALK 238 Alternative Transcript (ATI) Skin Melanoma 8923 Crizotinib Predictive Supports C Sensitivity/Response Expression of an alternative ALK transcript (ATI), encompassing exons 20–29 preceded by ~400 base pairs (bp) of intron 19, but not exons 1–19 was identified in three samples of thyroid cancer and melanoma. In TCGA samples, ALK ATI was expressed in approx. 11% of melanoma samples. Functional activity of ALK ATI was shown in-vitro. In vivo studies confirmed oncogenic activity of ALK ATI similar to other ALK mutations or fusions and sensitivity to crizotinib. A patient with metastatic melanoma and ALK ATI expression but no MET or ALK aberrations identified with FISH and a 341-gene panel sequencing was treated with crizotinib and had symptomatic improvement and tumor shrinkage within 6 weeks of therapy 26444240 PubMed Wiesner et al., 2015, Nature 4 accepted 1936 839 1 This novel ALK transcript (alternative isoform) initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19. N/A 2017-06-15 19:16:58 UTC https://civicdb.org/links/evidence_items/1936 https://civicdb.org/links/variants/839 https://civicdb.org/links/genes/1 false EGFR 1956 Mutation Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports B Sensitivity/Response This open label Phase 3 Trial performed across 36 centers in Japan (WJTOG3405) assessed patients with postoperative recurrent or stage IIIB/IV NSCLC and activating EGFR mutations (Exon 19 deletion and L858R). 88 patients were treated with EGFR inhibitor gefitinib, while 89 were treated with cisplatin/docetaxel. Progression free survival was significantly longer with gefitinib treatment with a median of 9.2 months vs. 6.3 with cisplatin/docetaxel (HR 0.48; 95% CI 0.336-0.710; p<0.0001). Difference in response to gefitinib between the two EGFR mutation types was not observed. 20022809 PubMed Mitsudomi et al., 2010, Lancet Oncol. 5 accepted 1937 442 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2017-09-08 19:21:13 UTC https://civicdb.org/links/evidence_items/1937 https://civicdb.org/links/variants/442 https://civicdb.org/links/genes/19 false BRAF 673 V600E Colorectal Cancer 9256 Prognostic Supports B Poor Outcome In a study of 468 colorectal cancer samples, 61 patients had micro-satellite instability and there was a statistically significantly better prognosis for BRAF WT patients relative to BRAF (V600E)-mutated patients (Log-rank P=0.0903). 27302369 PubMed Schell et al., 2016, Nat Commun 4 accepted 1940 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-01-22 18:08:41 UTC https://civicdb.org/links/evidence_items/1940 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false VHL 7428 Exon 1-3 Deletion Von Hippel-Lindau Disease 14175 Hemangioblastoma,Retinal capillary hemangioma,Renal cyst,Hepatic cysts,Pancreatic cysts,Renal cell carcinoma Predisposing N/A C N/A Mutation detected in 4 separate cases. Two cases show CNS hemangioblastoma, pancreatic/hepatic/renal cysts, and renal cell carcinoma. One case shows CNS hemangioblastoma, pancreatic cysts, and Grawitz One shows CNS HB, pancreatic/renal cysts and retinal angioma. ACMG evidence codes: 'PVS1' based on deletion of all exons, 'PP1' based on segregation results, 'PP4' because the patients phenotypes are highly specific for a disease with single genetic etiology. 20151405 PubMed Nordstrom-O'Brien et al., 2010, Hum. Mutat. 4 accepted 1942 843 58 3 10183532 10191649 ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/1942 https://civicdb.org/links/variants/843 https://civicdb.org/links/genes/58 false VHL 7428 Exon 1 Deletion Von Hippel-Lindau Disease 14175 Hemangioblastoma Predisposing Supports C Pathogenic Mutation detected in one case. Case shows CNS hemangioblastoma. ACMG evidence codes: 'PVS1' for a single exon deletion, 'PP1' based on segregation results, 'PP4' because patients phenotypes are highly specific for a disease with single genetic etiology. 20151405 PubMed Nordstrom-O'Brien et al., 2010, Hum. Mutat. 3 accepted 1943 844 58 3 10183532 10183871 ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/1943 https://civicdb.org/links/variants/844 https://civicdb.org/links/genes/58 false VHL 7428 Exon 1-2 Deletion Von Hippel-Lindau Disease 14175 Renal cell carcinoma Predisposing Supports C Uncertain Significance Mutation detected in one case. Case shows renal cell carcinoma. ACMG evidence codes:Mutation detected in one case. Case shows renal cell carcinoma. ACMG evidence codes: 'PVS1' based on deletion of exon 1+2, 'PP4' since the patients phenotypes are highly specific for a disease with single genetic etiology. 20151405 PubMed Nordstrom-O'Brien et al., 2010, Hum. Mutat. 3 accepted 1944 845 58 3 10183532 10188320 ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/1944 https://civicdb.org/links/variants/845 https://civicdb.org/links/genes/58 false VHL 7428 M1FS (c.1_17del17) Chromophobe Renal Cell Carcinoma 4471 Oncogenic N/A C N/A This somatic mutation was detected in two samples from a single patient with chromophobe renal cell carcinoma (a 74 year old male). The tumor also harbored a silent T157= (c.471T>A) somatic variant. 15932632 PubMed van Houwelingen et al., 2005, BMC Cancer 1 accepted 1945 846 58 3 10183532 10183548 ATGCCCCGGAGGGCGGA ENST00000256474.2 75 GRCh37 Somatic 2021-03-05 18:00:13 UTC https://civicdb.org/links/evidence_items/1945 https://civicdb.org/links/variants/846 https://civicdb.org/links/genes/58 false VHL 7428 M1? (c.1-1_20del21) Von Hippel-Lindau Disease 14175 Oncogenic N/A C N/A This variant was detected in a single case with clear-cell renal cell carcinoma. The tumor had two somatic variants (c.1-1_20del21 and c.291_310del20). Either of these variants is predicted to be quite deleterious. While they were observed in a somatic context in an RCC, we can infer that they could be predisposing for VHL in a germline context. 15932632 PubMed van Houwelingen et al., 2005, BMC Cancer 1 accepted 1946 847 58 3 10183531 10183551 AATGCCCCGGAGGGCGGAGAA ENST00000256474.2 75 GRCh37 Somatic 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/1946 https://civicdb.org/links/variants/847 https://civicdb.org/links/genes/58 false VHL 7428 M1? (c.3G>A) Clear Cell Renal Cell Carcinoma 4467 Oncogenic N/A C N/A Mutation detected in one case. Case shows clear-cell renal cell carcinoma. This case also harbored a second somatic variant in VHL: 209-210delAG (Stop130). 11505222 PubMed Gallou et al., 2001, Pharmacogenetics 1 accepted 1947 848 58 3 10183534 10183534 G A ENST00000256474.2 75 GRCh37 Somatic 2021-03-05 19:43:24 UTC https://civicdb.org/links/evidence_items/1947 https://civicdb.org/links/variants/848 https://civicdb.org/links/genes/58 false VHL 7428 N7D (c.19A>G) Renal Cell Carcinoma 4450 Oncogenic N/A C N/A A somatic mutation detected in one case, a 79ya patient with renal cell carcinoma (case '1VT'). The patient had a second in-frame deletion of 5 amino acids (41-45), but the author speculate that it could be an inherited polymorphism. 11536052 PubMed Ma et al., 2001, Oncogene 1 accepted 1948 849 58 3 10183550 10183550 A G ENST00000256474.2 75 GRCh37 Somatic 2021-03-06 00:13:48 UTC https://civicdb.org/links/evidence_items/1948 https://civicdb.org/links/variants/849 https://civicdb.org/links/genes/58 false VHL 7428 P25L (c.74C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Mutation was detected in three unaffected members of Polish VHL families. Described as being in the non-conserved portion of the VHL coding region where mutations are not typically seen according to these authors. Possibly benign but appears to have fairly low global mutation allele frequency. 12114495 PubMed Cybulski et al., 2002, J. Med. Genet. 3 accepted 1949 850 58 3 10183605 10183605 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/1949 https://civicdb.org/links/variants/850 https://civicdb.org/links/genes/58 false VHL 7428 P59fs (c.173_174insC) Von Hippel-Lindau Disease 14175 Neoplasm of the central nervous system,Pancreatic endocrine tumor,Pancreatic cysts,Hemangioblastoma,Renal cyst Predisposing Supports C Uncertain Significance Mutation was detected in one patient. Patient shows CNS hemangioblastoma and pancreatic neuroendocrine tumors, renal and pancreatic cysts, or central nervous system tumors. ACMG evidence codes: 'PVS1' because the variant is an early frameshift and 'PP4' because the patients phenotypes and family history are highly specific for a disease with single genetic etiology. 19270817 PubMed Cho et al., 2009, J. Korean Med. Sci. 3 accepted 1950 851 58 3 10183704 10183705 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/1950 https://civicdb.org/links/variants/851 https://civicdb.org/links/genes/58 false VHL 7428 Y98FS (c.291_310del20) Clear Cell Renal Cell Carcinoma 4467 Oncogenic N/A C N/A This variant was detected in a single case with clear-cell renal cell carcinoma. The tumor had two somatic variants (c.1-1_20del21 and c.291_310del20). Either of these variants is predicted to be quite deleterious. 15932632 PubMed van Houwelingen et al., 2005, BMC Cancer 1 accepted 1951 852 58 3 10183822 10183841 CTACCCAACGCTGCCGCCTG ENST00000256474.2 75 GRCh37 Somatic 2021-03-05 19:55:37 UTC https://civicdb.org/links/evidence_items/1951 https://civicdb.org/links/variants/852 https://civicdb.org/links/genes/58 false GNA11 2767 Mutation Uveal Melanoma 6039 Sotrastaurin Acetate,Mirdametinib Combination Predictive Supports D Sensitivity/Response Preclinical study in uveal melanoma. Increased PKC activity was found in uveal melanoma cell lines with GNA11 or GNAQ mutations (n=6) compared to GNA wt cell lines (n=4) and could be induced by introducing these mutations into wt cell lines. Cell lines carrying GNA mutations were more sensitive to PKC inhibition with AEB071 and AHT956 in vitro and in vivo. Combined inhibition of MEK and PKC with AEB071 and PD0325901led to sustained MAPK-signalling blockade and induced apoptosis. 24141786 PubMed Chen et al., 2014, Oncogene 3 accepted 1952 506 2308 19 3094408 3124002 ENST00000078429.4 75 GRCh37 Somatic 2017-07-20 16:08:33 UTC https://civicdb.org/links/evidence_items/1952 https://civicdb.org/links/variants/506 https://civicdb.org/links/genes/2308 false GNAQ 2776 Mutation Uveal Melanoma 6039 Mirdametinib,Sotrastaurin Acetate Combination Predictive Supports D Sensitivity/Response Preclinical study in uveal melanoma. Increased PKC activity was found in uveal melanoma cell lines with GNA11 or GNAQ mutations (n=6) compared to GNA wt cell lines (n=4) and could be induced by introducing these mutations into wt cell lines. Cell lines carrying GNA mutations were more sensitive to PKC inhibition with AEB071 and AHT956 in vitro and in vivo. Combined inhibition of MEK and PKC with AEB071 and PD0325901led to sustained MAPK-signalling blockade and induced apoptosis. 24141786 PubMed Chen et al., 2014, Oncogene 4 accepted 1953 505 2317 9 80331003 80646374 ENST00000286548.4 75 GRCh37 Somatic 2017-07-20 14:49:48 UTC https://civicdb.org/links/evidence_items/1953 https://civicdb.org/links/variants/505 https://civicdb.org/links/genes/2317 false NF1 4763 Mutation Plexiform Neurofibroma 5151 Selumetinib Predictive Supports B Sensitivity/Response Treatment with selumetinib (NCT01362803) resulted in confirmed partial, long term responses in 17 of the 24 children with NF1 associated plexiform fibromas (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). 28029918 PubMed Dombi et al., 2016, N. Engl. J. Med. NCT01362803 3 accepted 1958 587 3867 17 29421945 29704695 ENST00000358273.4 75 GRCh37 Rare Germline 2017-07-25 19:31:10 UTC https://civicdb.org/links/evidence_items/1958 https://civicdb.org/links/variants/587 https://civicdb.org/links/genes/3867 false ATM 472 Mutation Prostate Cancer 10283 Olaparib Predictive Supports C Sensitivity/Response Response to olaparib was observed in 4 of 5 with prostate cancer patients with ATM aberrations (2 germline). 26510020 PubMed Mateo et al., 2015, N. Engl. J. Med. NCT01682772 3 accepted 1960 178 69 11 108093559 108239826 ENST00000278616.4 75 GRCh37 Rare Germline 2017-04-05 15:38:56 UTC https://civicdb.org/links/evidence_items/1960 https://civicdb.org/links/variants/178 https://civicdb.org/links/genes/69 false PALB2 79728 Biallelic Inactivation Prostate Cancer 10283 Olaparib Predictive Supports C Sensitivity/Response From 14 prostate cancer patients (88%) who had a response to olaparib, 7 patients had BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations), 4 of 5 with had ATM aberrations and one had a biallelic inactivation of PALB2 (frameshift mutation and deletion). 26510020 PubMed Mateo et al., 2015, N. Engl. J. Med. NCT01682772 3 accepted 1963 532 15013 16 23614491 23652631 ENST00000261584.4 75 GRCh37 Somatic 2018-09-17 19:43:11 UTC https://civicdb.org/links/evidence_items/1963 https://civicdb.org/links/variants/532 https://civicdb.org/links/genes/15013 false MET 4233 Amplification Colorectal Cancer 9256 Anti-EGFR Monoclonal Antibody Predictive Supports D Resistance Functional studies show that MET activation confers resistance to anti-EGFR therapy both in vitro and in vivo. Notably, in patient-derived colorectal cancer xenografts, MET amplification correlated with resistance to EGFR blockade, which could be overcome by MET kinase inhibitors. 23729478 PubMed Bardelli et al., 2013, Cancer Discov 3 accepted 1971 270 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 Somatic 2017-03-16 10:13:58 UTC https://civicdb.org/links/evidence_items/1971 https://civicdb.org/links/variants/270 https://civicdb.org/links/genes/52 false NTRK1 4914 Overexpression Neuroblastoma 769 Prognostic Supports B Better Outcome A high level of expression of the TRK proto-oncogene in a neuroblastoma is strongly predictive of a favorable outcome. A tumor with a functional nerve growth factor receptor may be dependent on the neurotrophin nerve growth factor for survival and may regress in its absence. 8441429 PubMed Nakagawara et al., 1993, N. Engl. J. Med. 4 accepted 1972 860 3983 1 156830686 156851434 ENST00000524377.1 75 GRCh37 N/A 2020-10-24 06:42:20 UTC https://civicdb.org/links/evidence_items/1972 https://civicdb.org/links/variants/860 https://civicdb.org/links/genes/3983 false PDGFRA 5156 P577S Melanoma 1909 Imatinib,Crenolanib Substitutes Predictive Supports D Sensitivity/Response PDGFRA mutations (exon 12, 14, 18) were assessed in 351 melanoma patient samples. 18 different mutations were detected in 4,6% of samples (all without chronic sun-induced damage and mainly in acral and mucosal melanoma, mutually exclusive with KIT). 12 novel missense mutations were tested for functional significance (western blot of autophosphorylation in transduced 293T cell line). Five PDGFRA Mutations (P577S, V658A, R841K, H845Y, and G853D) resulted in strong autophosphorylation of PDGFRA. Crenolanib showed higher potency than imatinib in inhibiting the kinase activity of PDGFRA. Except for the imatinib-resistant V658A mutation, all the other mutations were sensitive to both imatinib and crenolanib. 24132921 PubMed Dai et al., 2013, Clin. Cancer Res. 3 accepted 1974 862 38 4 55141083 55141083 C T ENST00000257290.5 75 GRCh37 Somatic 2020-10-05 23:03:48 UTC https://civicdb.org/links/evidence_items/1974 https://civicdb.org/links/variants/862 https://civicdb.org/links/genes/38 false PDGFRA 5156 R841K Melanoma 1909 Imatinib,Crenolanib Substitutes Predictive Supports D Sensitivity/Response PDGFRA mutations (exon 12, 14, 18) were assessed in 351 melanoma patient samples. 18 different mutations were detected in 4.6% of samples (all without chronic sun-induced damage and mainly in acral and mucosal melanoma, mutually exclusive with KIT). 12 novel missense mutations were tested for functional significance (western blot of autophosphorylation in transduced 293T cell line). PDGFRA R841K was detected in one sample of mucosal melanoma. In vitro, PDGFRA R841K expressed in IL-3 dependent Ba/F3 cells resulted in strong auto-phosphorylation and cell growth of PDGFRA independent of the presence of IL-3, suggesting oncogenicity. Crenolanib showed higher potency than imatinib in inhibiting the kinase activity of PDGFRA and cell proliferation. The authors concluded that PDGFRA R841K is sensitive to imatinib and crenolanib. 24132921 PubMed Dai et al., 2013, Clin. Cancer Res. 3 accepted 1975 863 38 4 55152090 55152090 G A ENST00000257290.5 75 GRCh37 Somatic 2020-10-05 22:58:47 UTC https://civicdb.org/links/evidence_items/1975 https://civicdb.org/links/variants/863 https://civicdb.org/links/genes/38 false PDGFRA 5156 H845Y Melanoma 1909 Crenolanib,Imatinib Substitutes Predictive Supports D Sensitivity/Response PDGFRA mutations (exon 12, 14, 18) were assessed in 351 melanoma patient samples. 18 different mutations were detected in 4,6% of samples (all without chronic sun-induced damage and mainly in acral and mucosal melanoma, mutually exclusive with KIT). 12 novel missense mutations were tested for functional significance (western blot of autophosphorylation in transduced 293T cell line). Five PDGFRA Mutations (P577S, V658A, R841K, H845Y, and G853D) resulted in strong autophosphorylation of PDGFRA. Crenolanib showed higher potency than imatinib in inhibiting the kinase activity of PDGFRA. Except for the imatinib-resistant V658A mutation, all the other mutations were sensitive to both imatinib and crenolanib. 24132921 PubMed Dai et al., 2013, Clin. Cancer Res. 3 accepted 1976 864 38 4 55152101 55152101 C T ENST00000257290.5 75 GRCh37 Somatic 2020-10-05 23:04:15 UTC https://civicdb.org/links/evidence_items/1976 https://civicdb.org/links/variants/864 https://civicdb.org/links/genes/38 false PDGFRA 5156 G853D Melanoma 1909 Imatinib,Crenolanib Substitutes Predictive Supports D Sensitivity/Response PDGFRA mutations (exon 12, 14, 18) were assessed in 351 melanoma patient samples. 18 different mutations were detected in 4,6% of samples (all without chronic sun-induced damage and mainly in acral and mucosal melanoma, mutually exclusive with KIT). 12 novel missense mutations were tested for functional significance (western blot of autophosphorylation in transduced 293T cell line). Five PDGFRA Mutations (P577S, V658A, R841K, H845Y, and G853D) resulted in strong autophosphorylation of PDGFRA. Crenolanib showed higher potency than imatinib in inhibiting the kinase activity of PDGFRA. Except for the imatinib-resistant V658A mutation, all the other mutations were sensitive to both imatinib and crenolanib. 24132921 PubMed Dai et al., 2013, Clin. Cancer Res. 3 accepted 1977 865 38 4 55152126 55152126 G A ENST00000257290.5 75 GRCh37 Somatic 2020-10-05 23:04:34 UTC https://civicdb.org/links/evidence_items/1977 https://civicdb.org/links/variants/865 https://civicdb.org/links/genes/38 false MET 4233 Amplification Colorectal Cancer 9256 Crizotinib,Cetuximab Combination Predictive Supports D Sensitivity/Response Functional studies show that MET activation confers resistance to anti-EGFR therapy both in vitro and in vivo. Notably, in patient-derived colorectal cancer xenografts, MET amplification correlated with resistance to EGFR blockade, which could be overcome by MET kinase inhibitors. 23729478 PubMed Bardelli et al., 2013, Cancer Discov 3 accepted 1979 270 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 Somatic 2017-03-20 19:27:54 UTC https://civicdb.org/links/evidence_items/1979 https://civicdb.org/links/variants/270 https://civicdb.org/links/genes/52 false MTAP 4507 Underexpression Breast Cancer 1612 Pyrimidine Antagonist Predictive Supports D Sensitivity/Response MTAP and CDKN2A gene (RT-qPCR) and protein (western-blotting) expression as well as promoter methylation status were analyzed in breast cancer patients and seven breast cancer cell lines. Knockdown of MTAP in one cell line with strong endogenous MTAP expression (MDA-MB-435) increased sensitivity to inhibitors of de novo adenine synthesis (5-FU, AZA and MTX), mainly 5-FU. 26751376 PubMed de Oliveira et al., 2016, PLoS ONE 1 accepted 1980 867 3659 Somatic 2021-01-20 19:00:09 UTC https://civicdb.org/links/evidence_items/1980 https://civicdb.org/links/variants/867 https://civicdb.org/links/genes/3659 false VPS37A 137492 Underexpression Ovarian Cancer 2394 Cetuximab Predictive Supports D Resistance Vps37A-deficient ovarian cancer cells become irresponsive to inhibition by the therapeutic antibody cetuximab in-vitro. 22016507 PubMed Wittinger et al., 2011, Clin. Cancer Res. 3 accepted 1981 868 18353 8 17104080 17155533 ENST00000324849.4 75 GRCh37 Somatic 2018-07-06 21:29:55 UTC https://civicdb.org/links/evidence_items/1981 https://civicdb.org/links/variants/868 https://civicdb.org/links/genes/18353 false EGFR 1956 Expression Chordoma 3302 Lapatinib Predictive Supports B Sensitivity/Response 18 advanced progressing chordoma patients that were positive for EGFR by at least one technique (immunohistochemistry and/or phospho-arrays, real-time polymerase chain reaction for EGFR ligands, FISH) entered this phase 2 study investigating the efficacy of lapatinib (median age: 61 years; disease extent: metastatic 72% and locally advanced 28%). Of the 25 patients screened, three tested negative for EGFR. Six (33.3%) patients had PR and 7 (38.9%) SD, as their best Choi responses, corresponding to RECIST SD in all cases. Median PFS by Choi was 6 [interquartile (IQ) range 3-8] months. Median PFS by RECIST was 8 (IQ range 4-12) months, with a 22% CBR. This phase II study showed a modest antitumor activity of lapatinib in chordoma 23559153 PubMed Stacchiotti et al., 2013, Ann. Oncol. 2 accepted 1984 354 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 N/A 2020-05-22 05:07:39 UTC https://civicdb.org/links/evidence_items/1984 https://civicdb.org/links/variants/354 https://civicdb.org/links/genes/19 false BTK 695 T316A Chronic Lymphocytic Leukemia 1040 Ibrutinib Predictive Supports C Resistance Case report of a patient with CLL and Richter-transformed relapse under ibrutinib (after an initial partial response for 10 months). Sequencing of sequential samples of this patient revealed a novel BTK T316 mutation at relapse (allele frequency of 75%). Characterization of this mutation showed that is was located on the SH2 domain, not associated with Ibrutinib binding. Introduction of this mutation in an Ibrutinib-sensitive lymphoma cell line showed resistance comparable to the known C481 resistance mutations, which was also confirmed by absence of downstream signaling. 27626698 PubMed Sharma et al., 2016, Oncotarget 4 accepted 1985 870 65 X 100613633 100613633 T C ENST00000308731.7 75 GRCh37 Somatic 2017-07-27 14:38:24 UTC https://civicdb.org/links/evidence_items/1985 https://civicdb.org/links/variants/870 https://civicdb.org/links/genes/65 false ERBB2 2064 T862A Stomach Carcinoma 5517 Lapatinib Predictive Supports D Sensitivity/Response Cell proliferation analysis showed that the ERBB2-H878Y mutant had the highest sensitivity against lapatinib among all mutations tested. Another mutation, ERBB2-V777L also remained sensitive to lapatinib with a cellular IC50 value similar to that of wild type ERBB2. Remaining mutations showed a shift towards significant higher cellular IC50 values compared to the wild type receptor. Since levels of up to 1 µM of lapatinib may be achieved in patients, ERBB2-V773A, ERBB2-T862A and ERBB2-N857S mutations might respond to higher doses of lapatinib. In contrast, ERBB2-L755S, ERBB2-L755P and ERBB2-T798M caused strong lapatinib resistance. 22046346 PubMed Kancha et al., 2011, PLoS ONE 3 accepted 1986 871 20 17 37881392 37881392 A G ENST00000269571.5 75 GRCh37 Somatic 2017-05-15 19:35:31 UTC https://civicdb.org/links/evidence_items/1986 https://civicdb.org/links/variants/871 https://civicdb.org/links/genes/20 false ERBB2 2064 V773A Breast Cancer 1612 Lapatinib Predictive Supports D Sensitivity/Response The IC90 of ERBB2-V773A cell lines was approximately 0.5 µM and was considered as lapatinib-sensitive. Since levels of up to 1 µM of lapatinib may be achieved in patients, ERBB2-T773A might respond to higher doses of lapatinib. 22046346 PubMed Kancha et al., 2011, PLoS ONE 1 accepted 1987 872 20 17 37880989 37880989 T C ENST00000269571.5 75 GRCh37 Somatic 2021-09-01 23:26:45 UTC https://civicdb.org/links/evidence_items/1987 https://civicdb.org/links/variants/872 https://civicdb.org/links/genes/20 false ERBB2 2064 N857S Breast Cancer 1612 Lapatinib Predictive Supports D Sensitivity/Response The IC90 of ERBB2-N857S cell lines was approximately 0.5 µM and was considered as lapatinib-sensitive. Since levels of up to 1 µM of lapatinib may be achieved in patients, ERBB2-N857S might respond to higher doses of lapatinib. 22046346 PubMed Kancha et al., 2011, PLoS ONE 1 accepted 1988 873 20 17 37881378 37881378 A G ENST00000269571.5 75 GRCh37 Somatic 2021-08-30 20:19:37 UTC https://civicdb.org/links/evidence_items/1988 https://civicdb.org/links/variants/873 https://civicdb.org/links/genes/20 false ERBB2 2064 H878Y Hepatocellular Carcinoma 684 Lapatinib Predictive Supports D Sensitivity/Response Cell proliferation analysis of ERBB2 mutant expressing cell lines showed that the ERBB2-H878Y mutant, which is observed in 11% of hepatocellular carcinoma patients, had the highest sensitivity against lapatinib among all mutations tested (IC50<30nM). 22046346 PubMed Kancha et al., 2011, PLoS ONE 1 accepted 1989 874 20 17 37881440 37881440 C T ENST00000269571.5 75 GRCh37 Somatic 2021-08-30 19:25:41 UTC https://civicdb.org/links/evidence_items/1989 https://civicdb.org/links/variants/874 https://civicdb.org/links/genes/20 false FGFR2 2263 Amplification Stomach Carcinoma 5517 FGFR Inhibitor AZD4547 Predictive Supports B Sensitivity/Response Nine patients with FGFR2-amplified gastroesophageal cancer were treated with AZD4547. Of these 9 patients, 3 showed confirmed responses to AZD4547. Median progression-free survival was 6.6 months (range=6.2-10.5). Two additional patients had a response in day 15 using FDG-PET but were not considered complete responders by RECIST criteria. High-level FGFR2-amplified (arbitrarily defined as FISH-ratio > 5) cancers had a higher likelihood of response and were associated with a substantially higher expression of both FGFR2 mRNA and FGFR2 protein (IHC). In vitro and in PDX models, FGFR2-amplified cell lines were sensitive to FGFR inhibition. Further preclinical analyses suggested, that FGFR2 amplification mainly signals via the PI3K pathway. 27179038 PubMed Pearson et al., 2016, Cancer Discov 3 accepted 1990 629 22 10 123239371 123357917 ENST00000457416.2 75 GRCh37 N/A 2017-07-27 20:12:17 UTC https://civicdb.org/links/evidence_items/1990 https://civicdb.org/links/variants/629 https://civicdb.org/links/genes/22 false FGFR1 2260 Amplification Breast Cancer 1612 FGFR Inhibitor AZD4547 Predictive Supports C Sensitivity/Response Activity of the FGFR-selective inhibitor AZD4547 in FGFR1-amplified breast cancer and FGFR2-amplified gastroesophageal cancer was analyzed in this study. 341 patients with advanced cancer were screened by FISH, identifying FGFR1 amplification in 18% of advanced HER2-negative breast cancers and FGFR2 amplification in 9% of advanced gastroesophageal cancer. 1 patient had a confirmed response among 8 patients treated with FGFR1-amplified breast cancer. In a preclinical model, FGFR1 amplification in breast cancer cell lines was less pronounced than FGFR2-amplifications in gastroesophageal cancers, which also had a higher response rate in the trial, indicating that high level amplification is associated with response and less common in FGFR1-amplified breast cancer. 27179038 PubMed Pearson et al., 2016, Cancer Discov 2 accepted 1991 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). N/A 2017-07-20 14:39:47 UTC https://civicdb.org/links/evidence_items/1991 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false ERBB2 2064 Overexpression Head And Neck Squamous Cell Carcinoma 5520 Lapatinib Predictive Supports C Sensitivity/Response Case report of a 60-year old patient with p16 positive tumor of the tonsil with lung metastases after primary radiochemotherapy. The metastases were analyzed using a commercial molecular analysis and overexpression of HER2 was identified (IHC, 95% of cells, with high intensity 3+ staining) which was confirmed on RNA-level. The patient was treated with single-agent lapatinib. A locally recurrent tumor was excised (and found HER2-negative) and the patient continued on lapatinib (for 2 years) as well as 5 cycles 5-FU and irinotecan. All lung metastases decreased in size within 3 months of lapatinib mono therapy initiation. The patient remains free of local or distant disease 5 years after starting lapatinib. 28061634 PubMed Seim et al., 2017, Ann. Otol. Rhinol. Laryngol. 2 accepted 1992 875 20 N/A 2020-11-24 07:11:19 UTC https://civicdb.org/links/evidence_items/1992 https://civicdb.org/links/variants/875 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance We identified 142 patients with metastatic colorectal cancer whose tumors harbored both wild-type exons 2, 3, and 4 in KRAS and NRAS, and wild-type exon 15 in BRAF. All patients received cetuximab after oxaliplatin, irinotecan, and fluoropyrimidine failure. HER2 status was determined using immunohistochemistry and silver in situ hybridization and correlated with cetuximab efficacy. Of 142 RAS and BRAF wild-type tumors, we observed 7 cases (4.9%) of HER2 amplification by SISH. After a median follow-up of 13.2 months (range, 1.4-78.1 months), median progression-free survival (PFS) was significantly different according to HER2 status: 3.1 months in patients with HER2 amplification compared with 5.6 months in those with non-amplified HER2 (HR = 2.73; 95% CI = 1.18-6.31; P = 0.019). Overall survival (OS) was not significantly different between groups, although there was a tendency towards shorter OS in patients with HER2-amplified tumors (HR = 0.31; 95% CI = 0.61-2.82; 10.1 vs. 13.5 months; P = 0.488). 28223103 PubMed Jeong et al., 2017, Clin Colorectal Cancer 3 accepted 1993 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2017-06-16 20:15:21 UTC https://civicdb.org/links/evidence_items/1993 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false GNAS 2778 R201 Pseudomyxoma Peritonei 3559 Prognostic Supports B Poor Outcome Significantly shorter median progression-free survival was observed in relapsed pseudomyxoma peritonei patients with GNAS mutations (N=9; 5.3 months) as compared to wild-type (N=6; not reached; p < 0.007). The results were externally validated on a previous series of 11 peritoneal pseudomyxoma patients (5.1 vs 13 months; HR for progression 11.26, 95 % CI 3.62–35.06; log-rank test p < 0.0001). 14/15 patients evaluated also harbored KRAS exon 2 mutations but no NRAS or BRAF mutations. 27154293 PubMed Pietrantonio et al., 2016, J Transl Med 3 accepted 1994 876 2319 Somatic 2017-05-11 16:43:56 UTC https://civicdb.org/links/evidence_items/1994 https://civicdb.org/links/variants/876 https://civicdb.org/links/genes/2319 false GNAS 2778 c.393T>C Lung Non-small Cell Carcinoma 3908 Gefitinib,Erlotinib Substitutes Predictive Supports B Resistance The disease control rate of patients with GNAS1 T393C CC genotype was lower than that of patients with variant genotype (TT or CT) (46.2% vs 73.8%, P=0.039). Univariate analysis identified gender, smoking history, histology and GNAS1 T393C polymorphism as predictive marker of PFS (P=0.04, P<0.001, P<0.001 and P=0.005). Multivariate analysis of factors, including smoking history, performance status score, histology, GNAS1 T393C polymorphism demonstrated that GNAS1 T393C polymorphism was correlated independently with PFS (P=0.007). The data suggests the role of GNAS1 T393C CC genotype as a poor predictive marker both of DCR and PFS in advanced NSCLC patients treated with tyrosine kinase inhibitor. 24758907 PubMed Hong et al., 2014, Zhongguo Fei Ai Za Zhi 2 accepted 1995 877 2319 20 57428713 57428713 T C ENST00000371100.4 75 GRCh37 Common Germline 2017-05-11 15:46:04 UTC https://civicdb.org/links/evidence_items/1995 https://civicdb.org/links/variants/877 https://civicdb.org/links/genes/2319 false GNAS 2778 c.393T>C Intrahepatic Cholangiocarcinoma 4928 Prognostic Supports B Poor Outcome Intrahepatic cholangiocarcinomas of patients with homozygous TT genotypes revealed a higher proliferation rate and a lower apoptotic rate.This study demonstrated a significant association of both disease-specific OS and recurrence-free survival with the homozygous TT genotype of the GNAS1 gene (hazard ratio = 2.47; 95% CI = 1.03–7.28). Patients with T393 homozygosity exhibit a decreased survival time regardless of their resection status and show earlier tumor recurrence. 17356712 PubMed Schmitz et al., 2007, Neoplasia 3 accepted 1996 877 2319 20 57428713 57428713 T C ENST00000371100.4 75 GRCh37 Common Germline 2017-12-20 19:08:08 UTC https://civicdb.org/links/evidence_items/1996 https://civicdb.org/links/variants/877 https://civicdb.org/links/genes/2319 false GNAS 2778 c.393T>C Breast Carcinoma 3459 Prognostic Supports B Poor Outcome This study showed that the carriers of the T allele had a significantly less favourable course of the disease when compared to carriers of the homozygous CC genotype. GNAS 393C homozygous patients of pT2-4 stages displayed a significantly lower risk for death than T393 homozygous patients, with heterozygous patients being at intermediate risk. Ten-year survival rates were 63% for CC, 40% for TC and 23% for TT genotypes, respectively. 17186357 PubMed Otterbach et al., 2007, Breast Cancer Res. Treat. 4 accepted 1997 877 2319 20 57428713 57428713 T C ENST00000371100.4 75 GRCh37 Common Germline 2017-05-11 15:47:11 UTC https://civicdb.org/links/evidence_items/1997 https://civicdb.org/links/variants/877 https://civicdb.org/links/genes/2319 false PIK3CA 5290 C420R Colorectal Cancer 9256 Cetuximab Predictive Does Not Support C Resistance One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored PIK3CA C420R and was wildtype for KRAS, BRAF and NRAS. This patient was was a 60 year old female treated with cetuximab monotherapy as 5th line therapy who experienced partial response and had PFS of 31 weeks and OS of 59 weeks. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 1999 931 37 3 178927980 178927980 T C ENST00000263967.3 75 GRCh37 Somatic 2020-11-25 22:33:55 UTC https://civicdb.org/links/evidence_items/1999 https://civicdb.org/links/variants/931 https://civicdb.org/links/genes/37 false KRAS 3845 G12V Colorectal Cancer 9256 Selumetinib,Dactolisib Combination Predictive Supports D Sensitivity/Response In 28 out of 40 (70%) metastatic colorectal cancer tumors harboring KRAS, NRAS, BRAF, or PIK3CA mutations and implanted into mice, the therapeutic combination of the MEK inhibitor AZD6244 and the PI3K/mTor inhibitor BEZ235 resulted in disease stabilization. Mean tumor growth was lower in the tumors treated with AZD6244+ BEZ235 (+77% vs. +267%, P=1E-6) compared to AZD6244 alone and (+77% vs. +222%, P=0.0014) BEZ235 alone. 32/40 tumors harbored KRAS mutations including 8 G12V mutations (3 with PIK3CA mutations) where progressive disease occurred in only 1 tumor upon doublet treatment but 6 tumors in monotherapy. 22392911 PubMed Migliardi et al., 2012, Clin. Cancer Res. 3 accepted 2001 425 30 12 25398284 25398284 C A ENST00000256078.4 75 GRCh37 KRAS mutations are the most common mutations in pancreatic cancer occurring in > 90% of cases. Of these the G12D activating mutation is the most prevalent and results in a loss of GTPase activity which in turn leads to a constitutively active form of KRAS. This is enough to cause pre-cancerous pancreatic intraepithelial lesions Somatic 2017-07-21 15:56:41 UTC https://civicdb.org/links/evidence_items/2001 https://civicdb.org/links/variants/425 https://civicdb.org/links/genes/30 false NRAS 4893 G12D Colorectal Cancer 9256 Cetuximab,Irinotecan Combination Predictive Supports C Resistance One patient participating in a large retrospective trial of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored NRAS G12D and was wild type for KRAS, PIK3CA, and BRAF. This patient was a 64 year old male treated with cetuximab and irinotecan as 5th line therapy who experienced stable disease and had PFS of 64 weeks and OS of 84 weeks. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 2002 878 36 1 115258747 115258747 C T ENST00000369535.4 75 GRCh37 Somatic 2020-11-10 22:24:15 UTC https://civicdb.org/links/evidence_items/2002 https://civicdb.org/links/variants/878 https://civicdb.org/links/genes/36 false KRAS 3845 G12/G13 Colorectal Cancer 9256 Panitumumab Predictive Supports B Resistance In a retrospective study of 427 chemotherapy-refractory metastatic colorectal patients treated with either panitumumab monotherapy or best supportive care (BSC), KRAS codon 12 or 13 mutations were observed in 43% of the tumor samples. The effect of panitumumab on PFS in the KRAS wt group was significantly greater than in the KRAS mutant group (HR:0.45, 95% CI:0.34-0.59 vs HR:0.99, 95% CI:0.73-1.36; P<0.0001). None of the 84 panitumumab-treated patients with KRAS mutant tumors responded to treatment (100% positive predictive value for nonresponse in mutant group). In the KRAS wt group treated with panitumumab (n=124), 21 patients had partial response (17%), 42 experienced stable disease (34%). Additionally, patients with KRAS mutations showed no significant improvement between treatment with panitumumab and BSC alone (PFS: 7.4 wk vs 7.3 wk). The authors concluded that their findings support the hypothesis that KRAS mutations confer primary resistance to anti-EGFR antibodies and recommend that KRAS status be evaluated prior to panitumumab administration. 18316791 PubMed Amado et al., 2008, J. Clin. Oncol. NCT00113763,NCT00113776 3 accepted 2004 77 30 12 25398280 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2020-09-03 22:09:42 UTC https://civicdb.org/links/evidence_items/2004 https://civicdb.org/links/variants/77 https://civicdb.org/links/genes/30 false KRAS 3845 G12A Lung Cancer 1324 Gefitinib Predictive Supports B Resistance In recurrent lung cancer patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib, patients with KRAS mutations had a lower frequency of partial response (PR) and stable disease (SD) and a higher rate of progressive disease (PD) (PR:0, SD:1, PD:15 vs. PR:24, SD:8, PD:14; P=0.0274) compared to wildtype KRAS patients. Patients with KRAS mutations also had a shorter overall survival compared to wildtype KRAS patients (HR:2.542, 95% CI:1.048-6.168, P=0.0390). 17409929 PubMed Endoh et al., 2006, J Thorac Oncol 2 accepted 2008 148 30 12 25398284 25398284 C G ENST00000256078.4 75 GRCh37 KRAS G12A, like EGFR T790M, has been shown to be capable of driving acquired resistance to tyrosine kinase inhibitors in lung adenocarcinoma. Somatic 2017-04-11 19:51:04 UTC https://civicdb.org/links/evidence_items/2008 https://civicdb.org/links/variants/148 https://civicdb.org/links/genes/30 false KRAS 3845 G12A Multiple Myeloma 9538 Melphalan Predictive Supports B Resistance In a study of patients receiving melphalan-based therapy, those with KRAS codon 12 mutations were less likely to have a positive response than those with wildtype KRAS (26.9% vs. 58.3%, P=0.015). 19284554 PubMed Greco et al., 2009, J. Exp. Clin. Cancer Res. 2 accepted 2009 148 30 12 25398284 25398284 C G ENST00000256078.4 75 GRCh37 KRAS G12A, like EGFR T790M, has been shown to be capable of driving acquired resistance to tyrosine kinase inhibitors in lung adenocarcinoma. Somatic 2018-07-18 15:21:47 UTC https://civicdb.org/links/evidence_items/2009 https://civicdb.org/links/variants/148 https://civicdb.org/links/genes/30 false KRAS 3845 G12A Multiple Myeloma 9538 Melphalan Predictive Supports D Resistance In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. 11050000 PubMed Rowley et al., 2000, Blood 2 accepted 2012 148 30 12 25398284 25398284 C G ENST00000256078.4 75 GRCh37 KRAS G12A, like EGFR T790M, has been shown to be capable of driving acquired resistance to tyrosine kinase inhibitors in lung adenocarcinoma. Somatic 2017-07-21 11:22:53 UTC https://civicdb.org/links/evidence_items/2012 https://civicdb.org/links/variants/148 https://civicdb.org/links/genes/30 false KRAS 3845 G12A Multiple Myeloma 9538 Melphalan Predictive Supports D Resistance In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. 12483530 PubMed Rowley et al., 2002, Oncogene 2 accepted 2013 148 30 12 25398284 25398284 C G ENST00000256078.4 75 GRCh37 KRAS G12A, like EGFR T790M, has been shown to be capable of driving acquired resistance to tyrosine kinase inhibitors in lung adenocarcinoma. Somatic 2017-07-21 11:25:21 UTC https://civicdb.org/links/evidence_items/2013 https://civicdb.org/links/variants/148 https://civicdb.org/links/genes/30 false KRAS 3845 G12A Multiple Myeloma 9538 Melphalan Predictive Supports D Resistance In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. 16497971 PubMed Hoang et al., 2006, Blood 2 accepted 2014 148 30 12 25398284 25398284 C G ENST00000256078.4 75 GRCh37 KRAS G12A, like EGFR T790M, has been shown to be capable of driving acquired resistance to tyrosine kinase inhibitors in lung adenocarcinoma. Somatic 2017-07-21 11:25:12 UTC https://civicdb.org/links/evidence_items/2014 https://civicdb.org/links/variants/148 https://civicdb.org/links/genes/30 false IDH1 3417 R132 High Grade Glioma 3070 Sunitinib,Bevacizumab Substitutes Predictive Supports B Sensitivity/Response In a clinical study of 63 recurrent glioma patients, the combined cohort of patients treated with either bevacizumab or sunitinib showed that those harboring IDH1 codon 132 mutation were associated with improved overall survival (OS 7.53 vs. 4.83 months; P=0.04), as compared to patients with wild-type IDH1. 22199315 PubMed Lv et al., 2011, Anticancer Res. 2 accepted 2020 58 26 2 209113111 209113113 ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes, IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2020-02-07 00:36:33 UTC https://civicdb.org/links/evidence_items/2020 https://civicdb.org/links/variants/58 https://civicdb.org/links/genes/26 false PIK3CA 5290 E542K Her2-receptor Positive Breast Cancer 0060079 Pictilisib Predictive Supports D Sensitivity/Response This preclinical study tested the efficacy on several breast cancer cell lines of GDC-0941 (pictilisib), a selective inhibitor of all four isoforms of class I PI3-kinases at a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. HCC202 is a HER2 positive, ER/PR negative breast cancer cell line harboring PIK3CA E542K, and it had an IC50 of 0.80uM. Authors further note that HER2 amplified cell lines were generally more sensitive, regardless of mutation, to pictilisib than basal-like cell lines (p=0.002). 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 2 accepted 2022 103 37 3 178936082 178936082 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K variants are the second most recurrent PIK3CA mutations in breast cancer and are highly recurrent mutations in many other cancer types. Colorectal cancer patients with the PIK3CA E545K variant, and possibly other variants in the E545 region, may indicate poor prognosis relative to patients with other PIK3CA variants or wild-type PIK3CA. The literature also suggests that E545/E542 variants may confer resistance to EGFR inhibitors (e.g., cetuximab). An FDA approved treatment regimen including a targeted PIK3CA inhibitor is available for specific subtypes of breast cancer. While PIK3CA variants are highly prevalent in many other cancer types, targeted therapies for PIK3CA variants are still in early clinical trial phases in other cancer types. Somatic 2021-02-11 00:24:36 UTC https://civicdb.org/links/evidence_items/2022 https://civicdb.org/links/variants/103 https://civicdb.org/links/genes/37 false PIK3CA 5290 Mutation Breast Cancer 1612 Prognostic Supports B Better Outcome Prognostic significance of PIK3CA mutations was evaluated in a retrospective study of 590 patients with surgically resected invasive breast cancer. Patients with tumors harboring PIK3CA mutations (n=192, 32.5%; 14.9% with H1047R; 4.2% with E542K; 4.9% with E545K; 8.5% across all other variants) experienced longer PFS, OS, and breast cancer specific survival than patients with PIK3CA wt tumors (p=0.06; p=0.03; p=0.004). PIK3CA mutations were positively associated with lymph node negativity, lower tumor stage, hormone receptor positivity, and HER2 negativity. Patients with PIK3CA mutated tumors experienced a 2 fold decrease in death due to breast cancer at 5 and 10 years. Tumors with hot spot mutations (E542K, E545K, H10447), were strongly correlated with lower grade (2), ER-positive, PR-positive, HR-positive, HER2-negative compared to PIK3CA wt tumors. 19671852 PubMed Kalinsky et al., 2009, Clin. Cancer Res. 3 accepted 2025 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2020-10-28 00:38:46 UTC https://civicdb.org/links/evidence_items/2025 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PIK3CA 5290 E542K Breast Cancer 1612 Pictilisib Predictive Supports D Sensitivity/Response This preclinical study tested the efficacy on several breast cancer cell lines of GDC-0941 (pictilisib), which is a selective inhibitor of all four isoforms of class I PI3-kinases over a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. KPL-1 is a luminal-like breast cancer cell line harboring PIK3CA E542K, and it had an IC50 of 0.72uM. Authors note that luminal-like cell lines were generally more sensitive, regardless of mutation, to pictilisib than basal-like cell lines (p=0.02). 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 2 accepted 2026 103 37 3 178936082 178936082 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K variants are the second most recurrent PIK3CA mutations in breast cancer and are highly recurrent mutations in many other cancer types. Colorectal cancer patients with the PIK3CA E545K variant, and possibly other variants in the E545 region, may indicate poor prognosis relative to patients with other PIK3CA variants or wild-type PIK3CA. The literature also suggests that E545/E542 variants may confer resistance to EGFR inhibitors (e.g., cetuximab). An FDA approved treatment regimen including a targeted PIK3CA inhibitor is available for specific subtypes of breast cancer. While PIK3CA variants are highly prevalent in many other cancer types, targeted therapies for PIK3CA variants are still in early clinical trial phases in other cancer types. Somatic 2021-02-11 00:27:56 UTC https://civicdb.org/links/evidence_items/2026 https://civicdb.org/links/variants/103 https://civicdb.org/links/genes/37 false PIK3CA 5290 E545K Breast Cancer 1612 Pictilisib Predictive Supports D Sensitivity/Response This preclinical study tested the efficacy on several breast cancer cell lines of GDC-0941 (pictilisib), a selective inhibitor of all four isoforms of class I PI3-kinases over a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. MCF7 is a luminal type breast cancer cell line harboring PIK3CA E545K, and it had an IC50 of 0.34uM. To evaluate in vivo efficacy, MCF7 cells were injected in the mammary fat pad of SCID mice and allowed to grow. Mice treated with 100mg/kg pictilisib experienced a 62% tumor reduction, and those treated with 150mg/kg experienced a 70% tumor reduction, with respect to untreated control. Authors note that pictilisib was well tolerated and observed no toxicities or significant weight loss. Authors further note that luminal-like cell lines were generally more sensitive, regardless of mutation, to pictilisib than basal-like (p=0.02). 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 2 accepted 2034 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2021-02-11 00:30:10 UTC https://civicdb.org/links/evidence_items/2034 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false PTEN 5728 Loss Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Supports B Resistance In a retrospective study of 111 HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapy, PTEN loss (as measured by IHC) was associated with shorter survival as measured from initiation of trastuzumab (HR = 1.92, P = 0.017) and diagnosis of first metastasis (HR = 1.69, P = 0.047). 21594665 PubMed Razis et al., 2011, Breast Cancer Res. Treat. 2 accepted 2035 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2019-01-26 23:08:38 UTC https://civicdb.org/links/evidence_items/2035 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PIK3CA 5290 E545K Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Emtansine Predictive Does Not Support D Resistance As part of a pre-clinical experiment, the efficacy of ado-trastuzumab emtansine (T-DM1) was compared to that of trastuzumab against various HER2 positive cell lines. MCF7-neo/HER2 cell line harboring PIK3CA E545K was associated with similar sensitivity to T-DM1 as PIK3CA wild-type cell line SK-BR-3; reduced cell viability was observed at concentrations >0.01 ug/mL in both cell lines. Conversely, the cell line harboring PIK3CA E545K was resistant to trastuzumab in vitro at all concentrations tested (0-10 ug/mL). Further, treatment with T-DM1 on nude mice xenografted with PIK3CA E545K-harboring cells resulted in inhibition of tumor growth. A single dose of T-DM1 >3mg/kg was sufficient to induce tumor suppression lasting >20 days after administration. 26920887 PubMed Baselga et al., 2016, Clin. Cancer Res. 3 accepted 2036 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2020-07-27 01:50:05 UTC https://civicdb.org/links/evidence_items/2036 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false PIK3CA 5290 E545K Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Does Not Support C Resistance In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). PIK3CA E545K was the only variant noted in the primary tumor (found in the sigma-rectum junction) of one patient who experienced partial response following treatment. In the larger cohort, patients with tumors harboring any PIK3CA mutation had significantly shorter progression free survival and decreased incidence of objective response than patients with wtPIK3CA tumors. See Patient 55 from Supplemental Table 1 for more information on this patient. 19223544 PubMed Sartore-Bianchi et al., 2009, Cancer Res. 2 accepted 2037 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2018-10-23 21:47:44 UTC https://civicdb.org/links/evidence_items/2037 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false PIK3CA 5290 Wildtype Colorectal Cancer 9256 Aspirin Predictive Does Not Support B Sensitivity/Response This was a retrospective study of 964 colorectal cancer patients who participated in the Nurses' Health Study and the Health Professionals Follow-up Study. Of 964 patients, 803 patients had wildtype PIK3CA (aspirin use: 337/803, no aspirin use: 466/803) and 161 had mutated PIK3CA (aspirin use: 66/161, no aspirin use: 95/161). Among patients with wild-type PIK3CA, regular use of aspirin after diagnosis was not significantly associated with increased survival. The 5-year cumulative colorectal cancer specific mortality was the same (15%) for users and nonusers of aspirin after diagnosis (P = 0.92). 23094721 PubMed Liao et al., 2012, N. Engl. J. Med. 3 accepted 2038 2590 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 Somatic 2019-01-19 23:55:28 UTC https://civicdb.org/links/evidence_items/2038 https://civicdb.org/links/variants/2590 https://civicdb.org/links/genes/37 false PIK3CA 5290 E545K Lung Non-small Cell Carcinoma 3908 PI103 Predictive Supports D Sensitivity/Response H460, a gefitinib-resistant NSCLC cell line harboring PIK3CA E545K (a PIK3CA activating mutation), was used to test the anti-tumor effects of PI103. Without treatment, H460 cells expressed high levels of phosphorylated AKT. Following treatment, p-AKT decreased which correlated with cell senescence. PI103 treatment resulted in greater cell senescence in the PIK3CA E545K cell line than in A549, a wildtype PIK3CA gefinitib-resistant NSCLC cell line. 19513541 PubMed Zou et al., 2009, Int. J. Mol. Med. 2 accepted 2040 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2019-01-20 00:49:55 UTC https://civicdb.org/links/evidence_items/2040 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false KRAS 3845 G13D Breast Cancer 1612 Pictilisib Predictive Supports D Resistance This preclinical study tested the efficacy on several breast cancer cell lines of GDC-0941 (pictilisib), a selective inhibitor of all four isoforms of class I PI3-kinases over a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. MDA-MB-231 is a basal-type breast cancer cell line which harbors KRAS G13D, and it had an ICD50 of 20uM. To evaluate in vivo efficacy, cells were injected in the mammary fat pad of SCID mice and allowed to grow. Mice injected with MDA-MB-231 and treated with pictilisib saw no reduction in tumor volume compared to untreated control. There was no effect on G1 arrest in pictilisib treated cells; however, phosphorylated AKT (S473) was substantially reduced following pictilisib. Authors note that basal breast cancer cell lines were generally more resistant to pictilisib than luminal lines (p=0.02), and concluded that this cell line was resistant to pictilisib. 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 4 accepted 2041 81 30 12 25398281 25398281 C T ENST00000256078.4 75 GRCh37 While the KRAS G13 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort. This mutation, along with the mutations affecting the neighboring G12 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, results are conflicting with retrospective analyses suggesting a better response to EGFR-Inhibition. A recent prospective phase-II study (12 patients, Schirripa et. al. 2015) could not reproduce this finding and another prospective phase II trial is currently ongoing. Somatic 2021-02-11 00:35:21 UTC https://civicdb.org/links/evidence_items/2041 https://civicdb.org/links/variants/81 https://civicdb.org/links/genes/30 false PIK3CA 5290 Rare Mutation Breast Cancer 1612 Prognostic Supports B Better Outcome Prognostic significance of PIK3CA mutations was evaluated in a retrospective study of 590 patients with surgically resected invasive breast cancer. Tumors harboring rare PIK3CA mutations (N345K: 2.4%, C420R: 1.2%, E545A: 1.2%, E545Q: 0.3%, E545G: 0.3%, Q546R: 0.7%, Q546P: 0.2%, H1047L: 2.2%) were significantly associated with lower grade, HER2 negativity, and lymph-node negative status compared with WT. 19671852 PubMed Kalinsky et al., 2009, Clin. Cancer Res. 2 accepted 2042 3222 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 Somatic 2020-10-28 00:44:30 UTC https://civicdb.org/links/evidence_items/2042 https://civicdb.org/links/variants/3222 https://civicdb.org/links/genes/37 false PTEN 5728 Loss Breast Cancer 1612 Trastuzumab Predictive Supports B Resistance In a retrospective study of 182 metastatic breast cancer patients of mixed HER2 status treated with trastuzumab-based therapy, PTEN loss (as measured by IHC) was associated with a higher risk of death measured from initiation of trastuzumab (HR = 1.64, P = 0.029) and diagnosis of first metastasis (HR = 1.85, P = 0.003). 21594665 PubMed Razis et al., 2011, Breast Cancer Res. Treat. 2 accepted 2043 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2019-01-31 21:25:55 UTC https://civicdb.org/links/evidence_items/2043 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PTEN 5728 Loss Her2-receptor Positive Breast Cancer 0060079 Pictilisib Predictive Supports D Sensitivity/Response This preclinical study tested the efficacy of GDC-0941, a selective inhibitor of class I PI3K, on several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. HCC1569 is a PTEN null, HER2 amplified breast cancer cell line. It had an IC50 of 0.46. Authors note that HER2 amplified breast cancer cell lines are generally more sensitive to GDC-0941 than basal-type cell lines (p = 0.002). 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 3 accepted 2045 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2021-04-09 22:35:23 UTC https://civicdb.org/links/evidence_items/2045 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false EGFR 1956 Mutation Lung Non-small Cell Carcinoma 3908 Erlotinib,Gefitinib Substitutes Predictive Supports B Sensitivity/Response In a retrospective study, 166 non-small cell lung cancer (NSCLC) patients that tended to have selected characteristics known to be predictive for TKI sensitivity (i.e. women, never smokers, and patients with ADC) were treated with either gefitinib or erlotinib. EGFR mutations (n=42) were associated with improved objective response to drug treatment (71.4% vs. 20.1%, p<0.0001), improved but not significant overall survival (36.9 vs. 24.8 months, p=0.09), and longer median time to progression (not reached vs. 3.7 months, p<0.0001) when compared to wild-type EGFR. Through multivariate analyses, it was shown that EGFR mutations are independent predictive favorable factors of response to drug treatment (p<0.0001) and are significant predictors of longer time to progression (HR: 0.27, 95% CI: 0.14-0.52, p=0.0001) 21258250 PubMed Ludovini et al., 2011, J Thorac Oncol 4 accepted 2053 442 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2019-08-09 23:02:13 UTC https://civicdb.org/links/evidence_items/2053 https://civicdb.org/links/variants/442 https://civicdb.org/links/genes/19 false PIK3CA 5290 E542K Her2-receptor Positive Breast Cancer 0060079 PI-103 Predictive Supports D Sensitivity/Response As part of a preclinical study, the efficacy of PI-103 (a dual inhibitor of MTOR and Class IA PI3Ks) was evaluated for several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. HCC202 is a HER2 receptor amplified breast cancer cell line harboring PIK3CA E542K, and it had an IC50 of 0.43uM. 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 1 accepted 2058 103 37 3 178936082 178936082 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K variants are the second most recurrent PIK3CA mutations in breast cancer and are highly recurrent mutations in many other cancer types. Colorectal cancer patients with the PIK3CA E545K variant, and possibly other variants in the E545 region, may indicate poor prognosis relative to patients with other PIK3CA variants or wild-type PIK3CA. The literature also suggests that E545/E542 variants may confer resistance to EGFR inhibitors (e.g., cetuximab). An FDA approved treatment regimen including a targeted PIK3CA inhibitor is available for specific subtypes of breast cancer. While PIK3CA variants are highly prevalent in many other cancer types, targeted therapies for PIK3CA variants are still in early clinical trial phases in other cancer types. Somatic 2021-04-09 22:38:57 UTC https://civicdb.org/links/evidence_items/2058 https://civicdb.org/links/variants/103 https://civicdb.org/links/genes/37 false PIK3CA 5290 E545K Her2-receptor Positive Breast Cancer 0060079 Pictilisib Predictive Supports D Sensitivity/Response This preclinical study tested the efficacy on several breast cancer cell lines of GDC-0941 (pictilisib), a selective inhibitor of all four isoforms of class I PI3-kinases at a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. MDA-MB-361 is a HER2 amplified breast cancer cell line harboring PIK3CA E545K, and it had an IC50 of 0.14uM. To asses the effect of pictilisib on cell cycle progression and apoptosis, fluorescence based cell cycle and flow cytometry were used to measure the proportion of cells in various phases and the relative presence of Annexin V, a marker of apoptosis. Untreated, 68% of cells were in G1 or sub-G1. Following treatment with 1.0uM pictilisib, the proportion of cells in G1 or sub-G1 rose to 78%, and the amount of Annexin V detected rose 3 fold. A substantial reduction in phosphorylated AKT (S473) was also noted. Authors concluded that pictilisib had a modest effect on cell cycle progression and encouraged apoptosis in this cell line, and that this cell line is sensitive to pictilisib. Authors further noted that HER2 amplified cell lines were generally more sensitive, regardless of mutation, to pictilisib than basal-like breast cancer cell lines (p=0.002). 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 4 accepted 2062 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2021-03-03 20:16:37 UTC https://civicdb.org/links/evidence_items/2062 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false ERBB2 2064 Amplification Breast Cancer 1612 Pictilisib Predictive Supports D Sensitivity/Response This preclinical study tested the efficacy of GDC-0941, a selective inhibitor of class I PI3K, on several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. Authors tested six HER2 amplified breast cancer cell lines for sensitivity to GDC-0941. Their IC50s ranged from 0.19uM to 1.29uM (5/6 cell lines had IC50s below 1umol/L). Authors further note that HER2 amplified breast cancer cell lines are generally more sensitive to GDC-0941 than basal-type cell lines (p = 0.002). 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 3 accepted 2071 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2021-04-09 22:46:07 UTC https://civicdb.org/links/evidence_items/2071 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false PTEN 5728 Loss Breast Cancer 1612 Pictilisib Predictive Does Not Support D Sensitivity/Response This preclinical study tested the efficacy of GDC-0941, a selective inhibitor of class I PI3K, on several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. The authors tested several basal and luminal cell lines harboring PTEN loss for sensitivity to GDC-0941. ZR-75-1, a luminal-type cell line, had an IC50 of 0.15uM and reduction in phosphorylated AKT was noted following administration of GDC-0941. EVSTA-T, a luminal-type cell line, had an IC50 of 0.36uM; treatment resulted in an relative increase of Sub-G and G phase cells from 49% to 78% of total cells evaluated; there was a 12fold increase in annexin V (an apoptotic marker), and a substantial reduction in phosphorylated AKT following GDC-0941 administration. Seven basal-like cell lines harbored PTEN loss and had IC50s ranging fom 0.30uM to 20.00uM (4/7 had IC50s greater than 1 uM). There was a varied reduction in phosphorylated AKT among basal-like cell lines. Authors note that PTEN status may have low predictive power for response, and suggested that other factors such as basal/luminal characteristics may be more informative for GDC-0941 response. Authors further note that luminal type cell lines are generally more sensitive to GDC-0941 than basal type cell lines (p=0.02). 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 2 accepted 2074 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2021-04-09 23:08:13 UTC https://civicdb.org/links/evidence_items/2074 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PIK3CA 5290 C420R Her2-receptor Positive Breast Cancer 0060079 Pictilisib Predictive Supports D Sensitivity/Response This preclinical study tested the efficacy on several HER2 amplified breast cancer cell lines of GDC-0941 (pictilisib), a selective inhibitor of all four isoforms of class I PI3-kinases at a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. Two HER2 amplified breast cancer cell lines harboring PIK3CA C420R were tested for sensitivity to pictilisib. EFM-192A had an IC50 of 0.32uM and JIMT-1 had an IC50 of 0.86uM. Authors note that HER2 amplified cell lines were generally more sensitive, regardless of mutation, to pictilisib than basal-like cell lines (p=0.002). 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 3 accepted 2078 931 37 3 178927980 178927980 T C ENST00000263967.3 75 GRCh37 Somatic 2021-02-12 18:38:10 UTC https://civicdb.org/links/evidence_items/2078 https://civicdb.org/links/variants/931 https://civicdb.org/links/genes/37 false PIK3CA 5290 K111N Her2-receptor Positive Breast Cancer 0060079 Pictilisib Predictive Supports D Sensitivity/Response This preclinical study tested the efficacy on several breast cancer cell lines of GDC-0941 (pictilisib), a selective inhibitor of all four isoforms of class I PI3-kinases at a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. BT-474 is a HER2 amplified breast cancer cell line harboring PIK3CA K111N, and it had an IC50 of 0.23uM. To evaluate in vivo efficacy, cells were injected in the mammary fat pad of SCID mice and allowed to grow. Mice subsequently treated with 100mg/kg pictilisib experienced a 69% tumor reduction, and those treated with 150mg/kg experienced an 82% tumor reduction, with respect to untreated control. Authors note that pictilisib was well tolerated and observed no toxicities or significant weight loss. Authors further note that HER2 amplified cell lines were generally more sensitive, regardless of mutation, to pictilisib than basal-like cell lines (p=0.002). 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 4 accepted 2085 1234 37 3 178916946 178916946 G C ENST00000263967.3 75 GRCh37 Somatic 2021-02-12 18:49:47 UTC https://civicdb.org/links/evidence_items/2085 https://civicdb.org/links/variants/1234 https://civicdb.org/links/genes/37 false PIK3CA 5290 Mutation Breast Cancer 1612 Trastuzumab Predictive Supports B Resistance In retrospective study of 175 metastatic breast cancer patients treated with trastuzumab-based therapy, the presence of a PIK3CA mutation (E542K, E545K, or H1047R) was associated with a greater risk of progression (HR = 1.86, P = 0.014, multivariate analysis ) compared to wildtype PIK3CA. 21594665 PubMed Razis et al., 2011, Breast Cancer Res. Treat. 3 accepted 2087 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2019-01-26 22:47:52 UTC https://civicdb.org/links/evidence_items/2087 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047L Breast Cancer 1612 Pictilisib Predictive Supports D Sensitivity/Response This preclinical study tested the efficacy on several breast cancer cell lines of GDC-0941 (pictilisib), a selective inhibitor of all four isoforms of class I PI3-kinases at a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1 umol/L, respectively, with a maximum tested concentration of 20 umol/L. EFM-19 is a luminal type breast cancer cell line harboring PIK3CA H1047L, and it had an IC50 of 0.09uM, suggesting sensitivity. Authors note that luminal-like cell lines were generally more sensitive, regardless of mutation, to pictilisib than basal-like (p=.02) 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 3 accepted 2089 1151 37 3 178952085 178952085 A T ENST00000263967.3 75 GRCh37 Somatic 2021-02-16 19:54:39 UTC https://civicdb.org/links/evidence_items/2089 https://civicdb.org/links/variants/1151 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Her2-receptor Positive Breast Cancer 0060079 Pictilisib Predictive Supports D Sensitivity/Response This preclinical study tested the efficacy on several breast cancer cell lines of GDC-0941 (pictilisib), a selective inhibitor of all four isoforms of class I PI3-kinases at a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. KPL4 is a HER2 amplified breast cancer cell line harboring PIK3CA H1047R, and it had an IC50 of 0.28uM. To evaluate in vivo efficacy, cells were injected in the mammary fat pad of SCID mice, and allowed to grow. Subsequently, pictilisib was administered orally daily for 14 days. Mice treated with 100mg/kg experienced a 76% tumor reduction, and those treated with 150mg/kg experienced a 90% tumor reduction, with respect to untreated control. Phosphorylated AKT (S473) was substantially reduced with pictilisib administration. Three other HER2 amplified breast cancer cell lines harbored PIK3CA H1047R: UACC-893, HCC1954, MDA-MB-453, which had IC50s of 0.41uM, 0.49uM, and 0.64uM, suggesting that PIK3CA H1047R induces sensitivity to pictilisib in HER2 amplified breast cancer. Authors note that pictilisib was well tolerated in vivo and further note that HER2 amplified cell lines were generally more sensitive, regardless of mutation, to pictilisib than basal-like cell lines (p=0.002). 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 4 accepted 2096 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2021-02-16 19:56:54 UTC https://civicdb.org/links/evidence_items/2096 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Breast Cancer 1612 Prognostic Supports B Better Outcome Prognostic significance of PIK3CA mutations was evaluated in a retrospective study of 590 patients with surgically resected invasive breast cancer. Patients whose tumors harbored PIK3CA H1047R (n=88, 14.9%) experienced significantly higher 10-year overall survival rate (76% vs 62%) and lower 10-year probability of breast cancer specific death (11% vs 23%) compared to those with wildtype PIK3CA. They also experienced a 2.8 and 2 fold reduction in probability of death due to breast cancer at 5 and 10 years. Authors found that PIK3CA H1047R was specifically associated with lymph node-negative status: 64% of H1047R patients were lymph-node negative compared to 48% of patients with PIK3CA WT and helical domain mutated tumors (P=0.007). PIK3CA H1047R was positively associated with lymph node negative status, lower nodal stage, lower overall stage, and smaller tumor size compared to WT PIK3CA 19671852 PubMed Kalinsky et al., 2009, Clin. Cancer Res. 2 accepted 2097 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2020-10-28 00:41:47 UTC https://civicdb.org/links/evidence_items/2097 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false PIK3CA 5290 Mutation Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Supports B Resistance In a retrospective study of 105 HER2-positive metastic breast cancer patients treated with trastuzumab-based therapy, the presence of a PIK3CA mutation (E542K, E545K, or H1047R) was associated with a greater risk of progression (HR = 2.50, P = 0.003, multivariate analysis) compared to wildtype PIK3CA. 21594665 PubMed Razis et al., 2011, Breast Cancer Res. Treat. 3 accepted 2098 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2019-01-26 22:31:32 UTC https://civicdb.org/links/evidence_items/2098 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Breast Cancer 1612 Prognostic Supports B Better Outcome In Japanese invasive breast cancer patients, PIK3CA mutation was associated with improved relapse-free survival (p < .05). 17202311 PubMed Maruyama et al., 2007, Clin. Cancer Res. 2 accepted 2100 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2019-08-08 20:22:30 UTC https://civicdb.org/links/evidence_items/2100 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Breast Cancer 1612 Pictilisib Predictive Supports D Sensitivity/Response This preclinical study tested the efficacy of GDC-0941, a selective inhibitor of class I PI3K, on several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. Three cell lines harbored PIK3CA H1047R. T-47D is a luminal type breast cancer cell line, and it had an IC50 of 0.22uM. Treatment with GDC-0941 resulted in a substantial reduction of phosphorylated AKT. BT-20 is a basal breast cancer cell line which had an ICD50 of 0.62uM. MFM-223 is basal cell line that had an ICD50 of 2.10uM, and experienced some reduction in pAKT. Authors note that luminal-like cell lines were generally more sensitive to GDC-0941 than basal-like (p=0.02). 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 2 accepted 2102 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2021-04-09 23:14:13 UTC https://civicdb.org/links/evidence_items/2102 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Emtansine Predictive Does Not Support D Resistance As part of a pre-clinical experiment, the efficacy of ado-trastuzumab emtansine (T-DM1) was compared to that of trastuzumab against various HER2 positive cell lines. HCC1954 and KPL-4 cell lines expressing PIK3CA H1047R were associated with similar sensitivity to T-DM1 as PIK3CA wild-type cell line SK-BR-3; reduced cell viability was observed at concentrations > 0.01 ug/mL in all three cell lines. Conversely, the cell lines harboring PIK3CA H1047R were resistant to trastuzumab in vitro at all concentrations tested (0-10 ug/mL). Further, treatment with T-DM1 on SCID mice xenografted with KPL-4 (PIK3CA H1047R cells) resulted in inhibition of tumor growth. A single dose of T-DM1 >5mg/kg was sufficient to induce tumor regression >20 days after administration. 26920887 PubMed Baselga et al., 2016, Clin. Cancer Res. 3 accepted 2103 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2020-07-27 01:55:21 UTC https://civicdb.org/links/evidence_items/2103 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false PIK3CA 5290 Mutation Colorectal Cancer 9256 Prognostic Supports B Poor Outcome This retrospective study examines outcomes of 158 primary sporadic colorectal cancer patients who had undergone surgical resection and were treated with 5-fluorouracil based chemotherapy. PIK3CA mutations were associated with reduced relapse-free survival in stage II/III patients (HR:2.587, 95% CI:1.108-6.039, P=0.0280, univariate analysis; HR:2.478, 95% CI:1.028-5.973, P=0.0433, multivariate analysis) and reduced disease-specific survival in patients of any stage (n=18 vs. n=140, P=0.0357) compared to wildtype PIK3CA. Authors noted that the tumors of 6 patients harbored both PIK3CA and KRAS mutations, but stated that the presence of PIK3CA mutations did not correlate with the presence of KRAS mutations. 17590872 PubMed Kato et al., 2007, Int. J. Cancer 3 accepted 2105 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2021-02-02 22:56:51 UTC https://civicdb.org/links/evidence_items/2105 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PIK3CA 5290 E545K Rectum Cancer 1993 Prognostic Supports B Poor Outcome This study examined outcomes of 240 rectum cancer patients treated with total mesorectal excision therapy. Tumor samples were obtained at the time of surgery and genotyped for PIK3CA exon 10 and 21 mutations (listed as exon 9 and 20 in the publication, as it was common at the time of its publication to exclude non-coding exon 1). Of the 19 patients whose tumors harbored PIK3CA mutations, nine harbored PIK3CA E545K. PIK3CA E545K was associated with poor outcome compared to other PIK3CA mutations for local and distant recurrences (HR: 11.6, P < 0.001; HR 3.7, P = 0.006). Additionally, 89% of patients whose tumors harbored PIK3CA E545K experienced a relapse. 19903786 PubMed He et al., 2009, Clin. Cancer Res. 2 accepted 2106 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2020-07-09 22:10:48 UTC https://civicdb.org/links/evidence_items/2106 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false BRAF 673 V600E Colorectal Cancer 9256 Cetuximab,Panitumumab Substitutes Predictive Supports B Resistance In metastatic colorectal cancer patients with wildtype KRAS status, those with a BRAF V600E mutation were less likely to respond to treatment with cetuximab or panitumumab than those with wildtype BRAF (0% vs. 32% , P=0.029). Regardless of KRAS status, patients with BRAF mutations had reduced progression-free and overall survival (P=0.0107 and P <0.0001, respectively). Transfection of the colorectal cancer cell line DiFi with a BRAF V600E expression vector conferred decreased sensitivity to cetuximab and panitumumab in comparison to cells transfected with empty vector. 19001320 PubMed Di Nicolantonio et al., 2008, J. Clin. Oncol. 3 accepted 2115 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2017-05-12 03:37:33 UTC https://civicdb.org/links/evidence_items/2115 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Predictive Supports B Resistance In a study of metastatic colorectal cancer patients who received 5-FU-based first-line chemotherapy, those with BRAF V600E mutations had reduced progression-free survival (4.3mo vs. 12.5mo, HR:4.9, 95%CI:2.7-9.0, P<0.0001, univariate analysis; HR:4.0, 95%CI:2.2-7.4, P<0.0001, multivariate analysis) and reduced overall survival (10.9mo vs. 40.5mo, HR:4.5, 95%CI:2.4-8.4, P<0.0001, univariate analysis; HR:4.1, 95%CI:2.1-8.0, P<0.0001, multivariate analysis) compared to those with wildtype BRAF. 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer accepted 2116 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-07-19 22:35:01 UTC https://civicdb.org/links/evidence_items/2116 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Oxaliplatin Predictive Supports B Resistance Of 100 metastatic colorectal cancer patients treated with oxaliplatin-based first-line therapy, the 6 patients with either BRAF V600E or D594K had reduced progression-free survival compared to 94 patients with wildtype BRAF (5.0mo vs. 11.7mo, HR:6.4, 95%CI:2.6-15.6, P<0.0001). 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 2117 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-07-19 23:02:19 UTC https://civicdb.org/links/evidence_items/2117 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Irinotecan Predictive Supports B Resistance The presence of BRAF V600E or D594K was associated with reduced progression-free survival in 5 patients with metastatic colorectal cancer treated with irinotecan-based first line therapy (3.5mo vs. 12.8mo, HR:4.1, 95%CI:1.5-11.3, P=0.006) when compared to 39 patients with wildtype BRAF. 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 2118 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-07-19 22:53:18 UTC https://civicdb.org/links/evidence_items/2118 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Oxaliplatin,Capecitabine,Bevacizumab Combination Predictive Supports B Resistance In a study of metastatic colorectal cancer patients treated with capecitabine, oxaliplatin, and bevacizumab, those with BRAF V600E mutations had reduced progression-free survival (5.9mo vs. 12.2mo, P=0.003) and reduced overall survival (15.0mo vs. 24.6mo, P=0.002) compared to those with wildtype BRAF. 19571295 PubMed Tol et al., 2009, N. Engl. J. Med. 3 accepted 2121 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-10-29 23:48:39 UTC https://civicdb.org/links/evidence_items/2121 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Melanoma 1909 Trametinib Predictive Supports B Sensitivity/Response In a study of 322 advanced melanoma patients with BRAF-V600E (N=281), BRAF-V600K (N=40), or both mutations (N=1), treatment with trametinib was associated with improved progression-free survival (4.8mo vs. 1.5mo; HR: 0.45, 95% CI: 0.33-0.63, P<0.001) compared to chemotherapy control group. Additionally, treatment with trametinib was associated with increased 6-month overall survival (HR: 0.54, 95% CI: 0.32-0.92, P=0.01). The authors note similar outcomes for the primary efficacy population (V600E only) and the intention-to-treat population. 22663011 PubMed Flaherty et al., 2012, N. Engl. J. Med. NCT01245062 4 accepted 2135 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-12-30 18:28:15 UTC https://civicdb.org/links/evidence_items/2135 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Thyroid Gland Papillary Carcinoma 3969 Prognostic Supports B Poor Outcome In a study of 102 papillary thyroid cancer patients with a 15 year median follow-up time, those with BRAF V600E mutations had reduced overall survival compared to those with wildtype BRAF (P=0.015, log-rank test). The presence of BRAF V600E was associated with poorer outcome as defined by persistent disease or death (Odds ratio:14.63, 95%CI:1.28-167.29, P=0.03, multivariate analysis. 18682506 PubMed Elisei et al., 2008, J. Clin. Endocrinol. Metab. 4 accepted 2137 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2019-02-09 23:46:48 UTC https://civicdb.org/links/evidence_items/2137 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false EGFR 1956 Mutation Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports B Sensitivity/Response In a phase 3 clinical trial of East Asian advanced pulmonary adenocarcinoma patients, a subset of patients with EGFR mutations (n=261) treated with gefitinib were associated with improved response (HR:0.48, 95% CI:0.36-0.64, P<0.001), compared to carboplatin plus paclitaxel treatment. The frequency of mutation in exon 19 deletion and L858R was 53.6% (140/261) and 42.5% (111/261), respectively. 19692680 PubMed Mok et al., 2009, N. Engl. J. Med. NCT00322452 5 accepted 2148 442 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2020-08-12 20:22:48 UTC https://civicdb.org/links/evidence_items/2148 https://civicdb.org/links/variants/442 https://civicdb.org/links/genes/19 false EGFR 1956 Mutation Lung Non-small Cell Carcinoma 3908 Afatinib Predictive Supports B Sensitivity/Response In a phase 2b/3 study of 585 stage IIIB-IV lung adenocarcinoma patients who had a previous round of EGFR-TKI treatment, archival material was available for 141 patients. EGFR mutational analysis revealed that 96 tumors had an EGFR mutation, of which 76 (79%) were positive for either L858R or a deletion in exon 19. These mutations were associated with improved progression-free survival (median 3.3 months vs 1.0 month ; HR:0.51, 95% CI:0.31-0.85, P<0.009) compared to placebo control. No difference was reported between the treatment groups for EGFR mutation negative subgroup. 22452896 PubMed Miller et al., 2012, Lancet Oncol. NCT00656136 4 accepted 2153 442 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2021-01-21 07:52:18 UTC https://civicdb.org/links/evidence_items/2153 https://civicdb.org/links/variants/442 https://civicdb.org/links/genes/19 false EGFR 1956 Ex19 del L858R Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports C Sensitivity/Response A phase 2 study of 120 stage IIIB-IV lung adenocarcinoma patients reported improved progression free survival in patients with EGFR mutation (defined as exon 19 deletion or exon 21 mutation) when treated (n=13) with gefitinib and pemetrexed/platinum combination therapy (HR: 0.20, 95% CI: 0.05-0.75, P=0.017) as compared to treatment (n=18) with pemtrexed/platinum alone. In the subgroup of patients without EGFR mutation (defined as all patients without the specific EGFR exon 19 deletion or L858R mutation) a difference in median PFS was not seen between the chemotherapy versus chemotherapy with gefitinib treatment groups. 24755888 PubMed Yu et al., 2014, Cancer Biol. Ther. 4 accepted 2156 1854 19 Somatic 2017-10-02 20:42:41 UTC https://civicdb.org/links/evidence_items/2156 https://civicdb.org/links/variants/1854 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Adenocarcinoma 3910 Osimertinib Predictive Supports C Sensitivity/Response In a lung adenocarcinoma patient harboring an EGFR E746_A750 mutation and an acquired EGFR T790M co-mutation, EGFR T790M was associated with sensitivity to osimertinib monotherapy. Prior to the development of the EGFR T790M mutation, the patient was treated with gefitinib and achieved a partial response, but subsequently tumor progression occurred; however, osimertinib treatment resulted a favorable tumor response with the extinguishment of the EGFR T790M mutation. In a stage IV lung adenocarcinoma patient harboring an EGFR L858R mutation and an acquired EGFR T790M co-mutation, EGFR T790M was associated with sensitivity to osimertinib monotherapy. Prior to the development of the EGFR T790M mutation, the patient was treated with erlotinib, followed by gefitinib for 12 months and achieved stable disease, but subsequently metastasis occurred; the EGFR T790M was then identified and subsequent 10 month treatment with osimertinib monotherapy resulted in a 45% disease regression. 26269204 PubMed Planchard et al., 2015, Ann. Oncol. 2 accepted 2157 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/2157 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Gefitinib,Erlotinib Substitutes Predictive Supports C Resistance In a study of 6 patients with progressive non-small cell lung cancer during gefitinib or erlotinib therapy, comparison of DNA sequences from the original diagnostic biopsy specimen and a post-treatment biopsy specimen demonstrated that 3 patients acquired a new EGFR-T790M mutation. Analysis of EGFR sequence from 155 NSCLC samples prior to treatment with an EGFR inhibitor showed no T790M mutations, suggesting that T790M is associated with progression on gefitinib or erlotinib. In vitro experiments showed that the addition of T790M drastically reduced sensitivity to gefitinib or erlotinib in cells containing the sensitizing EGFR mutation L858R. 15737014 PubMed Pao et al., 2005, PLoS Med. 4 accepted 2158 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2020-12-16 20:31:58 UTC https://civicdb.org/links/evidence_items/2158 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports C Resistance In a study of 14 patients with progressive non-small cell lung cancer during gefitinib, comparison of DNA sequences from the original diagnostic biopsy specimen and the second biopsy specimen demonstrated that 7 patients acquired a new EGFR-T790M mutation. 17020982 PubMed Kosaka et al., 2006, Clin. Cancer Res. accepted 2159 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2020-12-03 18:33:00 UTC https://civicdb.org/links/evidence_items/2159 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 true EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Lapatinib Predictive Supports D Resistance In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H1975 cells (EGFR-L858R/T790M), inhibition of cell growth was used as an assay to determine sensitivity to reversible tyrosine kinase inhibitor drugs. Cells with an EGFR L858R/T790M mutation demonstrated a reduced response to lapatinib (IC50: >4000nM vs. 534nM) compared to wildtype EGFR cells. Similarly, NIH-3T3 ectopically expression EGFR-L858R/T790M showed reduced sensistivity to lapatinib compared to EGFR wt or L585R mutant cells. These results were further confirmed in a Ba/F3 cell line model 18408761 PubMed Li et al., 2008, Oncogene 4 accepted 2160 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2017-07-27 15:36:22 UTC https://civicdb.org/links/evidence_items/2160 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Dacomitinib Predictive Supports D Sensitivity/Response In an in vitro study using NCI-H322 cells (wildtype EGFR) and NCI-H1975 cells (EGFR-L858R/T790M), inhibition of cell growth was used as an assay to determine sensitivity to irreversible tyrosine kinase inhibitor (TKI) drugs. PF00299804 inhibited the growth of Ba/F3 cell lines containing the EFGR T790M resistance mutation as well as H1975 and H3255 cell lines that contain both EGFR L858R and T790M mutations and H820 containing an EGFR exon 19 deletion (Del 747_L751, Ins S) and a T790M mutation. All three cell lines were resistant to gefitinib in vitro, but sensitive to PF00299804 (IC50 <1 μmol/L for all three cell lines). 18089823 PubMed Engelman et al., 2007, Cancer Res. 3 accepted 2161 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2017-07-27 15:38:04 UTC https://civicdb.org/links/evidence_items/2161 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Neratinib Predictive Supports D Sensitivity/Response The NSCLC cell line NCI-H1975 carrying the EGFR T790M mutation was resistant to erlotinib but showed increased sensitivity to HKI-272 (neratinib, IC50: 0.29 μmol/L). In an in vitro study Ba/F3 cells transfected with either EGFR-L858R or EGFR-L858R/T790M were used to assay cell growth. Ba/F3 cells require IL-3 in order to proliferate, but cells transfected with an activated oncogene are IL-3 independent. Cells with an EGFR L858R/T790M mutation demonstrated an improved response to neratinib (IC50: 0.185umol/L vs. >10umol/L) compared to the same cells treated with erlotinib. 16818618 PubMed Shimamura et al., 2006, Cancer Res. 2 accepted 2162 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2017-07-27 15:38:13 UTC https://civicdb.org/links/evidence_items/2162 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Afatinib Predictive Supports D Sensitivity/Response In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H1975 cells (EGFR-L858R/T790M), inhibition of cell growth was used as an assay to determine sensitivity to tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R/T790M mutation demonstrated an improved response to afatinib (IC50: 99nM vs. >4000nM) compared to the same cells treated with erlotinib. In an in vivo mouse xenograft study, the growth of cells with an EGFR-L858R/T790M mutation were more sensitive to treatment of afatinib (concentration: 15-20mg/kg) (median tumor volume = 75-150mm^3 vs. 1000mm^3), compared to reversible TKI lapatinib-treated xenografts. However, no complete responses were observed with afatinib alone. 18408761 PubMed Li et al., 2008, Oncogene 2 accepted 2163 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2017-07-27 15:37:43 UTC https://civicdb.org/links/evidence_items/2163 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Afatinib Predictive Supports D Sensitivity/Response In an in vitro study using purified EGFR protein, kinase activity was assayed and compared for wildtype EGFR, EGFR-T790M and EGFR-T790M/L858R using both reversible and irreversible TKI drugs. EFGR proteins with T790M or T790M/L858R mutations were more sensitive to afatinib treatment (IC50: 9.8nM and 24nM, respectively vs. IC50: >1000nM and >1000nM, respectively) compared to treatment with erlotinib or lapatinib treatment. In an in vitro study using NCI-H358 cells (wildtype EGFR) and NCI-H1975 cells (EGFR-L858R/T790M), inhibition of cell growth was used as an assay to determine sensitivity to tyrosine kinase inhibitor drugs. Cells with an EGFR L858R/T790M mutation demonstrated an improved response to afatinib (GI50: 42.0nM vs. >1000nM) compared to the same cells treated with erlotinib. However, IC50s were intermediate compared to a more potent pan-HER inhibitor. 21732342 PubMed Cha et al., 2012, Int. J. Cancer 2 accepted 2164 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2017-07-27 15:37:54 UTC https://civicdb.org/links/evidence_items/2164 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Lung Non-small Cell Carcinoma 3908 Canertinib Predictive Supports D Sensitivity/Response In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H1975 cells (EGFR-L858R/T790M), inhibition of cell growth was used as an assay to determine sensitivity to tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R/T790M mutation demonstrated an improved response to canertinib (IC50: 101nM vs. >4000nM) compared to the same cells treated with erlotinib. IC50 values of canertinib were comparable to afatinib. 18408761 PubMed Li et al., 2008, Oncogene 2 accepted 2165 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2017-07-27 15:36:55 UTC https://civicdb.org/links/evidence_items/2165 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false ABL1 25 BCR::ABL F359V Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports D Resistance A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The F359V mutation was moderately resistant to imatinib. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 2 accepted 2167 892 4 9 133748414 133748414 T G ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 16:35:09 UTC https://civicdb.org/links/evidence_items/2167 https://civicdb.org/links/variants/892 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359V Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. An accelerated-phase (AP) patient improved to chronic phase. M351T, E255K, and F359V variants were each present in ~25% of transcripts beginning at 6, 11, and 14 months, respectively. At 20 months, the patient returned to accelerated phase with an increase in the proportion of E255K variants to ~75% of transcripts. Another AP patient had a complete hematologic response with the M351T variant present in ~25 to ~75% of transcripts and the F359V variant present in ~25% to ~50% of transcripts between 8 and 16 months after therapy initiation but prior to resistance. At 17 months, the patient progressed to myeloid blast crisis and there was cytogenetic evidence of a double Ph-chromosome. At that time, no secondary variants could be detected. 12623848 PubMed Branford et al., 2003, Blood 2 accepted 2168 892 4 9 133748414 133748414 T G ENST00000318560.5 75 GRCh37 Somatic 2020-07-24 22:54:22 UTC https://civicdb.org/links/evidence_items/2168 https://civicdb.org/links/variants/892 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359V Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In two cell-based studies, a panel of either 18 or 16 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The F359V mutation was moderately resistant to imatinib . 15930265 PubMed O'Hare et al., 2005, Cancer Res. accepted 2169 892 4 9 133748414 133748414 T G ENST00000318560.5 75 GRCh37 Somatic 2017-05-19 16:42:00 UTC https://civicdb.org/links/evidence_items/2169 https://civicdb.org/links/variants/892 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359V Chronic Myeloid Leukemia 8552 Nilotinib Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the F359V mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to nilotinib treatment (IC50: 5.16-fold), as compared to Ba/F3 cells expressing BCR-ABL1 fusion protein (reported to be sensitizing to nilotinib). Sensitivity was determined by assessing cell proliferation. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 3 accepted 2170 892 4 9 133748414 133748414 T G ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 16:39:52 UTC https://civicdb.org/links/evidence_items/2170 https://civicdb.org/links/variants/892 https://civicdb.org/links/genes/4 false KRAS 3845 G13D Colorectal Cancer 9256 Panitumumab Predictive Supports C Resistance Three patients participating in a large retrospective study of EGFR monoclonal antibodies in metastatic, treatment refractory colorectal cancer had tumors which harbored KRAS G13D, were wildtype for NRAS, BRAF and PIK3CA, and had individual response data. All three patients were males treated with panitumumab monotherapy. Their characteristics are as follows: 51 year old who experienced progressive disease (PFS: 8 weeks; OS: 24 weeks) and had three prior lines of chemotherapy; 54 year old who experienced progressive disease (PFS: 8 weeks; OS: 17 weeks) and had two prior lines of chemotherapy; 52 year old who experienced stable disease (PFS: 12 weeks; OS: 46 weeks) and had two prior lines of chemotherapy. Per the authors criteria, the clinical benefit rate is 1/3 and the response rate is 0/3. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 2178 81 30 12 25398281 25398281 C T ENST00000256078.4 75 GRCh37 While the KRAS G13 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort. This mutation, along with the mutations affecting the neighboring G12 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, results are conflicting with retrospective analyses suggesting a better response to EGFR-Inhibition. A recent prospective phase-II study (12 patients, Schirripa et. al. 2015) could not reproduce this finding and another prospective phase II trial is currently ongoing. Somatic 2020-12-02 00:00:38 UTC https://civicdb.org/links/evidence_items/2178 https://civicdb.org/links/variants/81 https://civicdb.org/links/genes/30 false NRAS 4893 Q61L Colorectal Cancer 9256 Irinotecan,Cetuximab Combination Predictive Supports C Resistance Two patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored NRAS Q61L and were wildtype for KRAS, BRAF and PIK3CA. Both patients experienced stable disease, which the authors classified as non-response. The two patients whose tumors harbored NRAS Q61L included a 53 year old female treated with cetuximab and irinotecan as a 6th line treatment who had PFS of 12 weeks and OS of 25 weeks; and a 64 year old female treated with cetuximab and ironotecan as a 3rd line therapy who had PFS of 12 weeks and OS of 46 weeks. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 2181 95 36 1 115256529 115256529 T A ENST00000369535.4 75 GRCh37 NRAS Q61 mutations have been found in multiple myeloma, gastrointestinal stromal tumors, melanoma, and others. A melanoma patient harboring a mutation at this locus responded to treatment with the akylating agent temozolomide. However, in colorectal cancer patients, mutations at this locus have been shown to confer resistance to cetuximab. The prognostic impact of mutations at this locus is currently under study. Somatic 2020-11-10 21:54:02 UTC https://civicdb.org/links/evidence_items/2181 https://civicdb.org/links/variants/95 https://civicdb.org/links/genes/36 false KRAS 3845 G13D Colorectal Cancer 9256 Selumetinib,Dactolisib Combination Predictive Supports D Sensitivity/Response In 28 out of 40 (70%) metastatic colorectal cancer tumors harboring KRAS, NRAS, PIK3CA or BRAF mutations and implanted into mice, the therapeutic combination of the MEK inhibitor AZD6244 and the PI3K/mTor inhibitor BEZ235 resulted in disease stabilization. Mean tumor growth was lower in the tumors treated with AZD6244+ BEZ235 (+77% vs. +267%, P=1E-6) compared to AZD6244 alone and (+77% vs. +222%, P=0.0014) BEZ235 alone. 32/40 mice harbored KRAS mutations including 5 G13D mutations where disease stabilization was achieved in 2/5 mice treated with AZD6244 or combination therapy and 0/5 mice treated with BEZ235 alone. 22392911 PubMed Migliardi et al., 2012, Clin. Cancer Res. 2 accepted 2183 81 30 12 25398281 25398281 C T ENST00000256078.4 75 GRCh37 While the KRAS G13 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort. This mutation, along with the mutations affecting the neighboring G12 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, results are conflicting with retrospective analyses suggesting a better response to EGFR-Inhibition. A recent prospective phase-II study (12 patients, Schirripa et. al. 2015) could not reproduce this finding and another prospective phase II trial is currently ongoing. Somatic 2017-07-21 16:29:44 UTC https://civicdb.org/links/evidence_items/2183 https://civicdb.org/links/variants/81 https://civicdb.org/links/genes/30 false NRAS 4893 Q61R Colorectal Cancer 9256 Cetuximab Predictive Supports C Resistance Five patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored NRAS Q61R and were wildtype for KRAS, BRAF and PIK3CA. Overall, one patient experienced stable disease, and the other four experienced progressive disease.The five patients whose tumors harbored NRAS Q61R included a 65 year old male treated with cetuximab monotherapy as a 3rd line treatment who experienced progressive disease and had PFS of 6 weeks and OS of 41 weeks; a 47 year old female treated with cetuximab and ironotecan as a 5th line therapy who experienced progressive disease and had PFS of 4 weeks and OS of 10 weeks; a 60 year old female treated with cetuximab and ironotecan as a 3rd line therapy who experienced stable disease and had PFS of 24 weeks and OS of 38 weeks; a 47 year old female treated with cetuximab and ironotecan as a 3rd line therapy who experienced progressive disease and had PFS of 14 weeks and OS of 18 weeks; and a 77 year old male treated with cetuximab monotherapy as a 1st line therapy who experienced progressive disease and had PFS of 7 weeks and OS of 67 weeks. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 2 accepted 2184 96 36 1 115256529 115256529 T C ENST00000369535.4 75 GRCh37 NRAS Q61 mutations have been found in multiple myeloma, gastrointestinal stromal tumors, melanoma, and others. A melanoma patient harboring a mutation at this locus responded to treatment with the akylating agent temozolomide. However, in colorectal cancer patients, mutations at this locus have been shown to confer resistance to cetuximab. The prognostic impact of mutations at this locus is currently under study. Somatic 2020-11-10 22:03:32 UTC https://civicdb.org/links/evidence_items/2184 https://civicdb.org/links/variants/96 https://civicdb.org/links/genes/36 false BRAF 673 Mutation Colorectal Cancer 9256 Cetuximab,Chemotherapy Combination Predictive Supports B Resistance This was a retrospective study of 350 patients with metastatic, chemotherapy refractory colorectal cancer treated with cetuximab + chemotherapy who had individual response data and whose tumors were KRAS wildtype and BRAF assessable. Patients harboring BRAF mutations (total n=24, V600E n=23, D594G n=1) had a lower response rate than did patients with wildtype BRAF (n=326; 2/24 [4.3%] vs 124/326 [38%], OR: 0.15, p=0.0012). BRAF mutant patients also experienced significantly lower disease control rate, PFS, and OS (median 26 vs 54 weeks, HR: 3.03 p<0.0001) in response to cetuximab treatment. In multivariate analysis, the significant associations between BRAF mutations and poor outcome were confirmed. The authors noted that two responders had the following genotypes: V600E mutation in low copy number, and BRAF D594G, and suggested that mutation status of BRAF is more informative than those of NRAS and PIK3CA exon 20 for predicting cetuximab response (second only to KRAS). 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 2187 399 5 7 140453136 140481403 ENST00000288602.6 75 GRCh37 Somatic 2020-11-13 22:31:51 UTC https://civicdb.org/links/evidence_items/2187 https://civicdb.org/links/variants/399 https://civicdb.org/links/genes/5 false NRAS 4893 Q61K Colorectal Cancer 9256 Cetuximab,Chemotherapy Combination Predictive Supports C Resistance Four patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored NRAS Q61K and were wildtype for KRAS, BRAF and PIK3CA. One patient experienced partial response and three patients experienced progressive disease. The four patients whose tumors harbored NRAS Q61K included an 80 year old male treated with cetuximab and irinotecan as a 3rd line treatment who experienced progressive disease and had PFS of 6 weeks and OS of 43 weeks; a 51 year old male treated with cetuximab and ironotecan as a 3rd line therapy who experienced a partial response and had PFS of 24 weeks and OS of 54 weeks; a 64 year old male treated with cetuximab and ironotecan as a 5th line therapy who experienced progressive disease and had PFS of 8 weeks and OS of 33 weeks; and a 65 year old female treated with cetuximab, oxaliplatin and 5FU as a 2nd line therapy who experienced progressive disease and had PFS of 31 weeks and OS of 50 weeks. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 2189 427 36 1 115256530 115256530 G T ENST00000369535.4 75 GRCh37 Somatic 2020-11-10 22:29:20 UTC https://civicdb.org/links/evidence_items/2189 https://civicdb.org/links/variants/427 https://civicdb.org/links/genes/36 false NRAS 4893 Q61K Colorectal Cancer 9256 Selumetinib,Dactolisib Combination Predictive Supports D Sensitivity/Response In 28 out of 40 (70%) metastatic colorectal cancer tumors harboring mutations in KRAS, NRAS, BRAF, or PIK3CA and implanted into mice, the therapeutic combination of the MEK inhibitor AZD6244 and the PI3K/mTor inhibitor BEZ235 resulted in disease stabilization. Mean tumor growth was lower in the tumors treated with AZD6244+ BEZ235 (+77% vs. +267%, P=1E-6) compared to AZD6244 alone and (+77% vs. +222%, P=0.0014) BEZ235 alone. NRAS mutations were in 4/40 tumors (three Q61K, one G12D). 22392911 PubMed Migliardi et al., 2012, Clin. Cancer Res. 3 accepted 2192 427 36 1 115256530 115256530 G T ENST00000369535.4 75 GRCh37 Somatic 2017-07-21 16:30:34 UTC https://civicdb.org/links/evidence_items/2192 https://civicdb.org/links/variants/427 https://civicdb.org/links/genes/36 false KRAS 3845 G12D Colorectal Cancer 9256 Panitumumab Predictive Supports C Resistance One patient participating in a large retrospective study of EGFR monoclonal antibodies in metastatic, treatment refractory colorectal cancer had a tumor which harbored KRAS G12D, was wildtype for NRAS, BRAF and PIK3CA, and had individual response data. This patient was was a 55 year old female treated with panitumumab monotherapy as 3rd line therapy who experienced progressive disease (PFS: 8 weeks; OS: 9 weeks). 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 2193 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2020-12-01 23:49:05 UTC https://civicdb.org/links/evidence_items/2193 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false PIK3CA 5290 Q546K Colorectal Cancer 9256 Cetuximab,Irinotecan Combination Predictive Does Not Support C Resistance One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored PIK3CA Q546K (exon 10), was wildtype for KRAS, BRAF and NRAS, and had individual response data. This patient was was a 75 year old female treated with cetuximab and irinotecan as 2nd line therapy (discontinued for toxic/biochemical reasons) who experienced a partial response (PFS: 43 weeks, OS: 57 weeks). Using clinical data compiled from the larger cohort, authors concluded that PIK3CA exon 10 (listed as exon 9 in the source) mutations predict weak or no resistance to cetuximab. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 2 accepted 2198 885 37 3 178936094 178936094 C A ENST00000263967.3 75 GRCh37 Somatic 2020-11-25 22:50:55 UTC https://civicdb.org/links/evidence_items/2198 https://civicdb.org/links/variants/885 https://civicdb.org/links/genes/37 false BRAF 673 D594G Colorectal Cancer 9256 Cetuximab,Irinotecan Combination Predictive Does Not Support C Resistance One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored BRAF D594G and was wildtype for KRAS, NRAS and PIK3CA. This patient was a 63 year old female treated with cetuximab and irinotecan (3rd line) who was one of two patients harboring a BRAF mutant tumor to experience a partial response. Progression free survival was 36 weeks and overall survival was 42 weeks from time of cetuximab administration. Authors note that cetuximab response is in accordance with cell line data suggesting that D594G cannot directly activate MAPK signaling, and that D594G mutants have low levels of p-MEK and are resistant to MEK inhibition. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 2201 611 5 7 140453154 140453154 T C ENST00000288602.6 75 GRCh37 This BRAF mutation has a markedly reduced kinase activity and leads to paradoxical MEK-pathway activation via CRAF binding. Somatic 2020-11-13 22:41:34 UTC https://civicdb.org/links/evidence_items/2201 https://civicdb.org/links/variants/611 https://civicdb.org/links/genes/5 false NRAS 4893 G13R Colorectal Cancer 9256 Cetuximab,Irinotecan Combination Predictive Supports C Resistance One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored NRAS G13R, was wildtype for KRAS, BRAF and PIK3CA, and had individual response data. This patient was was a 68 year old male treated with cetuximab + irinotecan as 3rd line therapy who experienced stable disease (PFS: 18 weeks; OS: 34 weeks). Authors considered stable disease as both clinical benefit and non response. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 1 accepted 2204 896 36 1 115258745 115258745 C G ENST00000369535.4 75 GRCh37 Somatic 2020-12-02 00:10:45 UTC https://civicdb.org/links/evidence_items/2204 https://civicdb.org/links/variants/896 https://civicdb.org/links/genes/36 false KRAS 3845 A146T Colorectal Cancer 9256 Dactolisib,Selumetinib Combination Predictive Supports D Sensitivity/Response In 28 out of 40 (70%) metastatic colorectal cancer tumors implanted into mice, the therapeutic combination of the MEK inhibitor AZD6244 and the PI3K/mTor inhibitor BEZ235 resulted in disease stabilization. Mean tumor growth was lower in the tumors treated with AZD6244+ BEZ235 (+77% vs. +267%, P=1E-6) compared to AZD6244 alone and (+77% vs. +222%, P=0.0014) BEZ235 alone. 32/40 tumors harbored KRAS mutations including 2 A146T tumors (1 also harboring PIK3CA E545K) which both showed disease stabilization during doublet therapy but progression on either single agent. 22392911 PubMed Migliardi et al., 2012, Clin. Cancer Res. 3 accepted 2206 906 30 12 25378562 25378562 C T ENST00000256078.4 75 GRCh37 Somatic 2017-07-21 16:32:50 UTC https://civicdb.org/links/evidence_items/2206 https://civicdb.org/links/variants/906 https://civicdb.org/links/genes/30 false KRAS 3845 G12D Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance This was a retrospective study of 691 cetuximab treated patients with metastatic colorectal cancer. Of those, 76 patients harbored KRAS G12D, were BRAF, NRAS and PIK3CA wt, and had individual response data. Five patients had partial response, 34 had stable disease, and 37 progressed. Treatments included cetuximab + irinotecan (n=61), cetuximab + FOLFIRI (n=6), cetuximab monotherapy (n=5), cetuximab + oxaliplatin + 5FU (n=2), cetuximab + 5FU (n=1), cetuximab + oxaliplatin + bevacizumab (n=1). Median PFS was 12 weeks (3-169 weeks), median OS was 31 weeks (6-232 weeks), and median number of previous chemotherapy lines was 2 (0-5). Median age was 62 years old (32-86), and there were 43 males and 33 females. Using these data and data from the larger cohort, authors concluded that KRAS mutation was strongly associated with poor response to cetuximab and suggested that mutation status of KRAS is the most informative compared to BRAF, NRAS, and PIK3CA exon 20 for predicting cetuximab response. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 2207 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2020-12-07 01:36:02 UTC https://civicdb.org/links/evidence_items/2207 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false KRAS 3845 A146V Colorectal Cancer 9256 Dactolisib,Selumetinib Combination Predictive Supports D Sensitivity/Response In 28 out of 40 (70%) metastatic colorectal cancer tumors harboring NRAS, KRAS, BRAF or PIK3CA mutations and implanted into mice, the therapeutic combination of the MEK inhibitor AZD6244 and the PI3K/mTor inhibitor BEZ235 resulted in disease stabilization. Mean tumor growth was lower in the tumors treated with AZD6244+ BEZ235 (+77% vs. +267%, P=1E-6) compared to AZD6244 alone and (+77% vs. +222%, P=0.0014) BEZ235 alone. 32/40 tumors harbored KRAS mutations including 2 tumors with A146V mutations which achieved stable disease with combined therapy but progressive disease in either monotherapy. 22392911 PubMed Migliardi et al., 2012, Clin. Cancer Res. 3 accepted 2209 322 30 12 25378561 25378561 G A ENST00000256078.4 75 GRCh37 Somatic 2017-07-21 16:31:53 UTC https://civicdb.org/links/evidence_items/2209 https://civicdb.org/links/variants/322 https://civicdb.org/links/genes/30 false NRAS 4893 Mutation Colorectal Cancer 9256 Cetuximab,Chemotherapy Combination Predictive Supports B Resistance This was a retrospective study of 605 patients with metastatic, chemotherapy refractory colorectal cancer treated with cetuximab + chemotherapy. Patients with KRAS wildtype, NRAS assessable tumors, and individual response data (n=301) were genotyped for NRAS mutations. Patients harboring NRAS mutant tumors (n=13) had a significantly lower response rate than did patients with wildtype NRAS (n=289; 1/13 [7.7%] vs 110/289 [77.9%]; p =.013). However, there was no significant difference between patients with mutant or wildtype NRAS in disease control rate, progression free survival, or overall survival. Authors note that their small sample size of patients with NRAS mutant tumors made it difficult to assess the effect of NRAS mutation on survival thus the large confidence intervals. Authors further note that the close relationship between KRAS and NRAS, and the lack of NRAS response to another EGFR inhibitor (panitumumab) support the inclusion of NRAS genotyping prior to cetuximab treatment. Authors suggest screening for mutations in the following gene order: KRAS, BRAF, NRAS, PIK3CA exon 21 (listed as PIK3CA exon 20 in the source). 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 2 accepted 2210 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2020-12-07 02:35:36 UTC https://civicdb.org/links/evidence_items/2210 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false KRAS 3845 G12C Colorectal Cancer 9256 Selumetinib,Dactolisib Combination Predictive Supports D Sensitivity/Response In 28 out of 40 (70%) metastatic colorectal cancer tumors harboring BRAF, KRAS, NRAS or PIK3CA mutations and implanted into mice, the therapeutic combination of the MEK inhibitor AZD6244 and the PI3K/mTor inhibitor BEZ235 resulted in disease stabilization. Mean tumor growth was lower in the tumors treated with AZD6244+ BEZ235 (+77% vs. +267%, P=1E-6) compared to AZD6244 alone and (+77% vs. +222%, P=0.0014) BEZ235 alone. 32/40 tumors harbored KRAS mutations including 4 G12C mutations where disease stabilization occurred in 3/4 treated with BEZ235 or doublet therapy and 2/4 treated with AZD6244 only. 22392911 PubMed Migliardi et al., 2012, Clin. Cancer Res. 2 accepted 2212 78 30 12 25398285 25398285 C A ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2017-07-21 16:31:16 UTC https://civicdb.org/links/evidence_items/2212 https://civicdb.org/links/variants/78 https://civicdb.org/links/genes/30 false PIK3CA 5290 E545Q Colorectal Cancer 9256 Irinotecan,Cetuximab Combination Predictive Does Not Support C Resistance Two patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored PIK3CA E545Q (exon 10), were wildtype for NRAS, BRAF and PIK3CA, and had individual response data. Both were treated with cetuximab and irinotecan and experienced partial responses. One patient was a 44 year old female, on 5th line therapy, with a PFS of 67 weeks and an OS of 209 weeks. The other patient was a 46 year old male, on 2nd line therapy, with a PFS of 22 weeks and an OS of 105 weeks. Using these and data from the larger cohort, authors concluded that PIK3CA exon 10 (listed as exon 9 in source) mutations are associated with weak or no resistance to cetuximab. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 2213 881 37 3 178936091 178936091 G C ENST00000263967.3 75 GRCh37 Somatic 2020-11-25 22:27:46 UTC https://civicdb.org/links/evidence_items/2213 https://civicdb.org/links/variants/881 https://civicdb.org/links/genes/37 false PIK3CA 5290 E545K Colorectal Cancer 9256 Cetuximab Predictive Does Not Support C Resistance This was a retrospective study of 691 cetuximab treated patients with metastatic, chemotherapy refractory colorectal cancer. Of those, 16 patients harbored PIK3CA E545K (exon 10), were wt for BRAF, NRAS and PIK3CA, and had individual response data. Five patients had partial response, six had stable disease, and five progressed, resulting in a response rate of 5/16 and a clinical benefit rate of 11/16 according to author criteria. Treatments included cetuximab + irinotecan (n=13), cetuximab monotherapy (n=1), cetuximab + bevacizumab (n=1), and cetuximab + oxaliplatin + 5FU (n=1). Median PFS was 24 weeks (2-60 weeks), median OS was 43 weeks (9-107 weeks), and median number of previous chemotherapy lines was 2 (1-5). Median age was 58 years old (43-79), and there were 10 males and 6 females. Using these and data from the larger cohort, authors concluded that PIK3CA exon 10 (listed as exon 9 in source) mutations are associated with weak or no resistance to cetuximab. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 2217 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2020-11-25 22:28:20 UTC https://civicdb.org/links/evidence_items/2217 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false KRAS 3845 G12D Colorectal Cancer 9256 Dactolisib,Selumetinib Combination Predictive Supports D Sensitivity/Response In 28 out of 40 (70%) metastatic colorectal cancer tumors harboring KRAS, NRAS, BRAF or PIK3CA mutations and implanted into mice, the therapeutic combination of the MEK inhibitor AZD6244 and the PI3K/mTor inhibitor BEZ235 resulted in disease stabilization. Mean tumor growth was lower in the tumors treated with AZD6244+ BEZ235 (+77% vs. +267%, P=1E-6) compared to AZD6244 alone and (+77% vs. +222%, P=0.0014) BEZ235 alone. 32/40 tumors studied had KRAS mutations with 9 G12D (2 with PIK3CA H1047R) and 13 other G12 mutations. 22392911 PubMed Migliardi et al., 2012, Clin. Cancer Res. 3 accepted 2218 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2017-07-20 22:35:26 UTC https://civicdb.org/links/evidence_items/2218 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false KRAS 3845 G12V Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance This was a retrospective study of 691 cetuximab treated patients with metastatic colorectal cancer. Of those, 39 patients harbored KRAS G12V, were BRAF, NRAS and PIK3CA wt, and had individual response data. Three patients had partial response, 16 had stable disease, and 20 progressed. Treatments included cetuximab + irinotecan (n=30), cetuximab + FOLFIRI (n=2), cetuximab monotherapy (n=2), cetuximab + oxaliplatin + 5FU (n=2), cetuximab + 5FU (n=1), cetuximab + irinotecan + oxaliplatin + 5FU + bevacizumab (n=1), and cetuximab+irinotecan+oxaliplatin+5FU (n=1). Median PFS was 12 weeks (1-37 weeks), median OS was 32 weeks (4-77 weeks), and median number of previous chemotherapy lines was 2 (0-5). Median age was 63 years old (34-76), and there were 21 males and 18 females. Authors concluded that KRAS mutation was strongly associated with poor response to cetuximab and suggested that mutation status of KRAS is the most informative compared to BRAF, NRAS, and PIK3CA exon 20 for predicting cetuximab response. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 2219 425 30 12 25398284 25398284 C A ENST00000256078.4 75 GRCh37 KRAS mutations are the most common mutations in pancreatic cancer occurring in > 90% of cases. Of these the G12D activating mutation is the most prevalent and results in a loss of GTPase activity which in turn leads to a constitutively active form of KRAS. This is enough to cause pre-cancerous pancreatic intraepithelial lesions Somatic 2020-11-25 01:08:18 UTC https://civicdb.org/links/evidence_items/2219 https://civicdb.org/links/variants/425 https://civicdb.org/links/genes/30 false ATM 472 T2666A Chronic Lymphocytic Leukemia 1040 Doxorubicin Predictive Supports D Resistance Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. Cells were treated with doxorubicin to induce double-strand (DSB) and p21 induction was monitored by qPCR. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the T2666A variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 91% of cells by FISH. Western blot showed null ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. 23585524 PubMed Navrkalova et al., 2013, Haematologica 3 accepted 2221 901 69 11 108204681 108204681 A G ENST00000278616.4 75 GRCh37 Somatic 2020-05-11 03:02:16 UTC https://civicdb.org/links/evidence_items/2221 https://civicdb.org/links/variants/901 https://civicdb.org/links/genes/69 false ATM 472 Mutation Chronic Lymphocytic Leukemia 1040 Doxorubicin Predictive Supports D Resistance Primary cells from chronic lymphocytic leukemia patients were treated with doxorubicin to induce double-strand (DSB). In this setting, cells harboring rare ATM variants (n=8) had significantly higher viability, measured by mitochondrial dehydrogenase activity, compared to wildtype cells (n=8, p < 0.001) suggesting resistance. A qPCR functional assay showed that samples with rare ATM variants (n= 20) had significantly less p21 expression after treatment with doxorubicin compared to treated wildtype controls (n=31, p < 0.001). Furthermore, there was significantly decreased expression of BBC3, BAX, and GADD45 genes which are downstream of ATM in the DNA damage response. In the above studies, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for p21 induction to confirm wildtype p53. 23585524 PubMed Navrkalova et al., 2013, Haematologica 4 accepted 2222 178 69 11 108093559 108239826 ENST00000278616.4 75 GRCh37 Somatic 2020-05-11 04:21:20 UTC https://civicdb.org/links/evidence_items/2222 https://civicdb.org/links/variants/178 https://civicdb.org/links/genes/69 false ATM 472 R3008C Chronic Lymphocytic Leukemia 1040 Doxorubicin Predictive Supports D Resistance Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the R3008C variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. In a patient sample with the R3008C variant of ATM in trans with a wild-type allele, confirmed by sanger sequencing, western blot showed stable ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. The authors propose that this variant has a dominant-negative effect. 23585524 PubMed Navrkalova et al., 2013, Haematologica 3 accepted 2223 903 69 11 108236086 108236086 C T ENST00000278616.4 75 GRCh37 Somatic 2020-05-11 03:08:43 UTC https://civicdb.org/links/evidence_items/2223 https://civicdb.org/links/variants/903 https://civicdb.org/links/genes/69 false ATM 472 c.902-1G>T Chronic Lymphocytic Leukemia 1040 Doxorubicin Predictive Supports D Resistance Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the c.902-1G>T variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. In a patient sample with the c.902-1G>T variant of ATM, confirmed by sanger sequencing, western blot showed null ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. The authors note that this patient had uniparental disomy of 11q. 23585524 PubMed Navrkalova et al., 2013, Haematologica 3 accepted 2224 3049 69 Unknown 2020-05-11 04:42:20 UTC https://civicdb.org/links/evidence_items/2224 https://civicdb.org/links/variants/3049 https://civicdb.org/links/genes/69 false KRAS 3845 A146P Colorectal Cancer 9256 Irinotecan,Cetuximab Combination Predictive Supports C Resistance In a retrospective study of 68 irinotecan-refractory metastatic colorectal cancer patients, one patient's tumor harbored a KRAS codon 146 mutation but was wildtype for BRAF, and KRAS codons 12, 13, and 61. This patient did not respond to irinotecan and cetuximab combination therapy and experienced progression free survival (PFS) lasting less than 10 months and overall survival (OS) lasting less than 30 months. Median PFS for patients with BRAF, KRAS G12/G13 wildtype tumors harboring mutations in either KRAS codon 146 (n=1) or KRAS codon 61 (n=7) was lower than patients whose tumors were additionally wildtype for KRAS A146 and Q61 (PFS: 3.8 vs 5.3mo, p= 0.023), though there wasn't a significant difference in overall survival (OS: 9.7 vs 14.8 mo, p=0.320). 19603018 PubMed Loupakis et al., 2009, Br. J. Cancer 3 accepted 2225 905 30 12 25378562 25378562 C G ENST00000256078.4 75 GRCh37 Somatic 2021-02-01 23:24:27 UTC https://civicdb.org/links/evidence_items/2225 https://civicdb.org/links/variants/905 https://civicdb.org/links/genes/30 false KRAS 3845 G12/G13 Colorectal Cancer 9256 Prognostic Does Not Support B Poor Outcome In a retrospective study of 427 chemotherapy-refractory metastatic colorectal patients treated with either panitumumab monotherapy or best supportive care (BSC), KRAS codon 12 or 13 mutations were observed in 43% of the tumor samples. The effect of BSC on PFS was the same in the KRAS mutant group as in the KRAS wildtype group (7.3 vs 7.3 weeks), suggesting that the presence of KRAS mutations does not support worse outcome compared to wildtype KRAS. 18316791 PubMed Amado et al., 2008, J. Clin. Oncol. NCT00113763,NCT00113776 3 accepted 2231 77 30 12 25398280 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2020-09-03 22:12:35 UTC https://civicdb.org/links/evidence_items/2231 https://civicdb.org/links/variants/77 https://civicdb.org/links/genes/30 false KRAS 3845 G12V Colorectal Cancer 9256 Panitumumab Predictive Supports C Resistance In a retrospective study of 427 metastatic colorectal patients, KRAS mutations were observed in 43% of the tumor samples. Patients with mutations in codon 12 or 13 of KRAS were associated with reduced response to panitumumab compared to wildtype KRAS (HR:0.99, 95% CI:0.73-1.36 vs. HR:0.45, 95% CI:0.34-0.59; P<0.0001). Additionally, patients with KRAS mutations showed no significant improvement between treatment with panitumumab and best supportive care alone (PFS: 7.4 wk vs 7.3 wk). 18316791 PubMed Amado et al., 2008, J. Clin. Oncol. NCT00113763,NCT00113776 accepted 2232 425 30 12 25398284 25398284 C A ENST00000256078.4 75 GRCh37 KRAS mutations are the most common mutations in pancreatic cancer occurring in > 90% of cases. Of these the G12D activating mutation is the most prevalent and results in a loss of GTPase activity which in turn leads to a constitutively active form of KRAS. This is enough to cause pre-cancerous pancreatic intraepithelial lesions Somatic 2017-03-31 02:21:03 UTC https://civicdb.org/links/evidence_items/2232 https://civicdb.org/links/variants/425 https://civicdb.org/links/genes/30 false KRAS 3845 G12D Colorectal Cancer 9256 Panitumumab Predictive Supports C Resistance In a retrospective study of 427 metastatic colorectal patients, KRAS mutations were observed in 43% of the tumor samples. Patients with mutations in codon 12 or 13 of KRAS were associated with reduced response to panitumumab compared to wildtype KRAS (HR:0.99, 95% CI:0.73-1.36 vs. HR:0.45, 95% CI:0.34-0.59; P<0.0001). Additionally, patients with KRAS mutations showed no significant improvement between treatment with panitumumab and best supportive care alone (PFS: 7.4 wk vs 7.3 wk). 18316791 PubMed Amado et al., 2008, J. Clin. Oncol. NCT00113763,NCT00113776 accepted 2236 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2017-03-31 02:21:39 UTC https://civicdb.org/links/evidence_items/2236 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false KRAS 3845 G12D Lung Cancer 1324 Gefitinib Predictive Supports B Resistance In recurrent lung cancer patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib, patients with KRAS mutations had a lower frequency of partial response (PR) and stable disease (SD) and a higher rate of progressive disease (PD) (PR:0, SD:1, PD:15 vs. PR:24, SD:8, PD:14; P=0.0274) compared to wildtype KRAS patients. Patients with KRAS mutations also had a shorter overall survival compared to wildtype KRAS patients (HR:2.542, 95% CI:1.048-6.168, P=0.0390). 17409929 PubMed Endoh et al., 2006, J Thorac Oncol 2 accepted 2240 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2017-04-11 19:52:02 UTC https://civicdb.org/links/evidence_items/2240 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports B Resistance In advanced-stage (IIIB or IV) non-small cell lung cancer patients treated with erlotinib and placebo, patients whose tumors harbored KRAS mutations (n=8) had a lower 12-week progression-free survival rate (0% vs. 37%, P=0.0390) compared to wildtype KRAS patients (n=35). Authors concluded that KRAS mutation was associated with poor response to erlotinib monotherapy. 22025157 PubMed Ramalingam et al., 2011, J. Clin. Oncol. NCT00760929 2 accepted 2242 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2020-12-29 22:41:31 UTC https://civicdb.org/links/evidence_items/2242 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 G12D Multiple Myeloma 9538 Melphalan Predictive Supports B Resistance In a study of patients receiving melphalan-based therapy, those with KRAS codon 12 mutations were less likely to have a positive response than those with wildtype KRAS (26.9% vs. 58.3%, P=0.015). 19284554 PubMed Greco et al., 2009, J. Exp. Clin. Cancer Res. 2 accepted 2247 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2019-08-12 21:55:17 UTC https://civicdb.org/links/evidence_items/2247 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false KRAS 3845 G12D Multiple Myeloma 9538 Melphalan Predictive Supports D Resistance In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. 11050000 PubMed Rowley et al., 2000, Blood 2 accepted 2250 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2017-07-21 11:23:10 UTC https://civicdb.org/links/evidence_items/2250 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false KRAS 3845 G12D Multiple Myeloma 9538 Melphalan Predictive Supports D Resistance In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. 12483530 PubMed Rowley et al., 2002, Oncogene accepted 2251 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2017-03-31 02:28:05 UTC https://civicdb.org/links/evidence_items/2251 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false KRAS 3845 G12D Multiple Myeloma 9538 Melphalan Predictive Supports D Resistance In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. 16497971 PubMed Hoang et al., 2006, Blood 2 accepted 2252 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2017-07-21 11:24:48 UTC https://civicdb.org/links/evidence_items/2252 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false KRAS 3845 G12C Colorectal Cancer 9256 Panitumumab Predictive Supports C Resistance In a retrospective study of 427 metastatic colorectal patients, KRAS mutations were observed in 43% of the tumor samples. Patients with mutations in codon 12 or 13 of KRAS were associated with reduced response to panitumumab compared to wildtype KRAS (HR:0.99, 95% CI:0.73-1.36 vs. HR:0.45, 95% CI:0.34-0.59; P<0.0001). Additionally, patients with KRAS mutations showed no significant improvement between treatment with panitumumab and best supportive care alone (PFS: 7.4 wk vs 7.3 wk). 18316791 PubMed Amado et al., 2008, J. Clin. Oncol. NCT00113763,NCT00113776 accepted 2253 78 30 12 25398285 25398285 C A ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2017-03-31 02:22:36 UTC https://civicdb.org/links/evidence_items/2253 https://civicdb.org/links/variants/78 https://civicdb.org/links/genes/30 false KRAS 3845 G12C Lung Cancer 1324 Gefitinib Predictive Supports B Resistance In recurrent lung cancer patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib, patients with KRAS mutations had a lower frequency of partial response (PR) and stable disease (SD) and a higher rate of progressive disease (PD) (PR:0, SD:1, PD:15 vs. PR:24, SD:8, PD:14; P=0.0274) compared to wildtype KRAS patients. Patients with KRAS mutations also had a shorter overall survival compared to wildtype KRAS patients (HR:2.542, 95% CI:1.048-6.168, P=0.0390). 17409929 PubMed Endoh et al., 2006, J Thorac Oncol 2 accepted 2257 78 30 12 25398285 25398285 C A ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2017-04-11 19:49:13 UTC https://civicdb.org/links/evidence_items/2257 https://civicdb.org/links/variants/78 https://civicdb.org/links/genes/30 false KRAS 3845 G12C Multiple Myeloma 9538 Melphalan Predictive Supports B Resistance In a study of patients receiving melphalan-based therapy, those with KRAS codon 12 mutations were less likely to have a positive response than those with wildtype KRAS (26.9% vs. 58.3%, P=0.015). 19284554 PubMed Greco et al., 2009, J. Exp. Clin. Cancer Res. accepted 2258 78 30 12 25398285 25398285 C A ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2017-03-31 02:50:20 UTC https://civicdb.org/links/evidence_items/2258 https://civicdb.org/links/variants/78 https://civicdb.org/links/genes/30 false KRAS 3845 G12C Multiple Myeloma 9538 Melphalan Predictive Supports D Resistance In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. 11050000 PubMed Rowley et al., 2000, Blood 2 accepted 2261 78 30 12 25398285 25398285 C A ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2017-07-21 11:23:23 UTC https://civicdb.org/links/evidence_items/2261 https://civicdb.org/links/variants/78 https://civicdb.org/links/genes/30 false KRAS 3845 G12C Multiple Myeloma 9538 Melphalan Predictive Supports D Resistance In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. 12483530 PubMed Rowley et al., 2002, Oncogene accepted 2262 78 30 12 25398285 25398285 C A ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2017-03-31 02:27:25 UTC https://civicdb.org/links/evidence_items/2262 https://civicdb.org/links/variants/78 https://civicdb.org/links/genes/30 false KRAS 3845 G12C Multiple Myeloma 9538 Melphalan Predictive Supports D Resistance In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. 16497971 PubMed Hoang et al., 2006, Blood 2 accepted 2263 78 30 12 25398285 25398285 C A ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2017-07-21 11:24:59 UTC https://civicdb.org/links/evidence_items/2263 https://civicdb.org/links/variants/78 https://civicdb.org/links/genes/30 false KRAS 3845 G12R Colorectal Cancer 9256 Panitumumab Predictive Supports C Resistance In a retrospective study of 427 metastatic colorectal patients, KRAS mutations were observed in 43% of the tumor samples. Patients with mutations in codon 12 or 13 of KRAS were associated with reduced response to panitumumab compared to wildtype KRAS (HR:0.99, 95% CI:0.73-1.36 vs. HR:0.45, 95% CI:0.34-0.59; P<0.0001). Additionally, patients with KRAS mutations showed no significant improvement between treatment with panitumumab and best supportive care alone (PFS: 7.4 wk vs 7.3 wk). 18316791 PubMed Amado et al., 2008, J. Clin. Oncol. NCT00113763,NCT00113776 accepted 2264 530 30 12 25398285 25398285 C G ENST00000256078.4 75 GRCh37 Somatic 2017-03-31 02:23:28 UTC https://civicdb.org/links/evidence_items/2264 https://civicdb.org/links/variants/530 https://civicdb.org/links/genes/30 false KRAS 3845 G12V Lung Cancer 1324 Gefitinib Predictive Supports C Resistance In recurrent lung cancer patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib, patients with KRAS mutations had a lower frequency of partial response (PR) and stable disease (SD) and a higher rate of progressive disease (PD) (PR:0, SD:1, PD:15 vs. PR:24, SD:8, PD:14; P=0.0274) compared to wildtype KRAS patients. Patients with KRAS mutations also had a shorter overall survival compared to wildtype KRAS patients (HR:2.542, 95% CI:1.048-6.168, P=0.0390). 17409929 PubMed Endoh et al., 2006, J Thorac Oncol 2 accepted 2268 425 30 12 25398284 25398284 C A ENST00000256078.4 75 GRCh37 KRAS mutations are the most common mutations in pancreatic cancer occurring in > 90% of cases. Of these the G12D activating mutation is the most prevalent and results in a loss of GTPase activity which in turn leads to a constitutively active form of KRAS. This is enough to cause pre-cancerous pancreatic intraepithelial lesions Somatic 2017-05-11 15:29:49 UTC https://civicdb.org/links/evidence_items/2268 https://civicdb.org/links/variants/425 https://civicdb.org/links/genes/30 false KRAS 3845 G12S Colorectal Cancer 9256 Panitumumab Predictive Supports C Resistance In a retrospective study of 427 metastatic colorectal patients, KRAS mutations were observed in 43% of the tumor samples. Patients with mutations in codon 12 or 13 of KRAS were associated with reduced response to panitumumab compared to wildtype KRAS (HR:0.99, 95% CI:0.73-1.36 vs. HR:0.45, 95% CI:0.34-0.59; P<0.0001). Additionally, patients with KRAS mutations showed no significant improvement between treatment with panitumumab and best supportive care alone (PFS: 7.4 wk vs 7.3 wk). 18316791 PubMed Amado et al., 2008, J. Clin. Oncol. NCT00113763,NCT00113776 accepted 2269 913 30 12 25398285 25398285 C T ENST00000256078.4 75 GRCh37 Somatic 2017-03-31 01:51:15 UTC https://civicdb.org/links/evidence_items/2269 https://civicdb.org/links/variants/913 https://civicdb.org/links/genes/30 false KRAS 3845 G12S Lung Cancer 1324 Gefitinib Predictive Supports B Resistance In recurrent lung cancer patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib, patients with KRAS mutations had a lower frequency of partial response (PR) and stable disease (SD) and a higher rate of progressive disease (PD) (PR:0, SD:1, PD:15 vs. PR:24, SD:8, PD:14; P=0.0274) compared to wildtype KRAS patients. Patients with KRAS mutations also had a shorter overall survival compared to wildtype KRAS patients (HR:2.542, 95% CI:1.048-6.168, P=0.0390). 17409929 PubMed Endoh et al., 2006, J Thorac Oncol 2 accepted 2273 913 30 12 25398285 25398285 C T ENST00000256078.4 75 GRCh37 Somatic 2017-04-11 18:55:55 UTC https://civicdb.org/links/evidence_items/2273 https://civicdb.org/links/variants/913 https://civicdb.org/links/genes/30 false KRAS 3845 G12S Multiple Myeloma 9538 Melphalan Predictive Supports B Resistance In a study of patients receiving melphalan-based therapy, those with KRAS codon 12 mutations were less likely to have a positive response than those with wildtype KRAS (26.9% vs. 58.3%, P=0.015). 19284554 PubMed Greco et al., 2009, J. Exp. Clin. Cancer Res. accepted 2274 913 30 12 25398285 25398285 C T ENST00000256078.4 75 GRCh37 Somatic 2017-03-31 01:57:41 UTC https://civicdb.org/links/evidence_items/2274 https://civicdb.org/links/variants/913 https://civicdb.org/links/genes/30 false KRAS 3845 G12S Multiple Myeloma 9538 Melphalan Predictive Supports D Resistance In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. 11050000 PubMed Rowley et al., 2000, Blood 2 accepted 2277 913 30 12 25398285 25398285 C T ENST00000256078.4 75 GRCh37 Somatic 2017-07-21 11:23:36 UTC https://civicdb.org/links/evidence_items/2277 https://civicdb.org/links/variants/913 https://civicdb.org/links/genes/30 false KRAS 3845 G12S Multiple Myeloma 9538 Melphalan Predictive Supports D Resistance In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. 12483530 PubMed Rowley et al., 2002, Oncogene 2 accepted 2278 913 30 12 25398285 25398285 C T ENST00000256078.4 75 GRCh37 Somatic 2017-07-21 11:24:02 UTC https://civicdb.org/links/evidence_items/2278 https://civicdb.org/links/variants/913 https://civicdb.org/links/genes/30 false KRAS 3845 G12S Multiple Myeloma 9538 Melphalan Predictive Supports D Resistance In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. 16497971 PubMed Hoang et al., 2006, Blood 2 accepted 2279 913 30 12 25398285 25398285 C T ENST00000256078.4 75 GRCh37 Somatic 2017-07-21 11:24:28 UTC https://civicdb.org/links/evidence_items/2279 https://civicdb.org/links/variants/913 https://civicdb.org/links/genes/30 false TP53 7157 R273L Ovarian Cancer 2394 Cisplatin,Carboplatin Substitutes Predictive Supports C Resistance Ovarian cancer patients with TP53 missense mutations were refractory to platinum-based chemotherapy (66% vs. 34% in wildtype, P=0.008) and had a shorter time to disease progression (n=54, P=0.037). A study of ovarian carcinoma patients (n=178) reported a reduced overall survival (HR:1.59, 95% CI:1.09-2.33, P=0.014) for patients with mutations in TP53. 11595686 PubMed Reles et al., 2001, Clin. Cancer Res. accepted 2286 918 45 17 7577120 7577120 C A ENST00000269305.4 75 GRCh37 Somatic 2017-05-08 13:10:57 UTC https://civicdb.org/links/evidence_items/2286 https://civicdb.org/links/variants/918 https://civicdb.org/links/genes/45 false TP53 7157 R273C Stomach Carcinoma 5517 Mitomycin,Etoposide,Cisplatin Combination Predictive Does Not Support C Sensitivity/Response A female patient taking part in a 25 patient gastric cancer trial was diagnosed at age 46, and received preoperative high dose chemotherapy (HDCT). Japanese Society for Gastric Cancer Response Score was 0. Resection was performed on patients with greater than 50% size reduction of the lesion. This patient did not undergo resection, and had on overall survival of 7.4 months. 14514923 PubMed Bataille et al., 2003, MP, Mol. Pathol. 3 accepted 2292 121 45 17 7577121 7577121 G A ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R273 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been suggested that the R273 mutants have been correlated with worse overall survival in breast cancer patients when compared to wild-type. Somatic 2018-12-18 22:59:28 UTC https://civicdb.org/links/evidence_items/2292 https://civicdb.org/links/variants/121 https://civicdb.org/links/genes/45 false TP53 7157 Y220C Stomach Carcinoma 5517 Cisplatin,Mitomycin,Etoposide Combination Predictive Supports C Sensitivity/Response A male patient taking part in a 25 patient gastric cancer trial was diagnosed at age 50, harbored a TP53 mutation and received preoperative high dose chemotherapy (HDCT). Japanese Society for Gastric Cancer Response Score was 2. Resection was performed on patients with >50% size reduction of the lesion. Consistent with response to preoperative chemotherapy, this patient did undergo resection, and had an overall survival of 12.6 months. 14514923 PubMed Bataille et al., 2003, MP, Mol. Pathol. 3 accepted 2306 922 45 17 7578190 7578190 T C ENST00000269305.4 75 GRCh37 Somatic 2019-08-18 02:16:32 UTC https://civicdb.org/links/evidence_items/2306 https://civicdb.org/links/variants/922 https://civicdb.org/links/genes/45 false TP53 7157 R175H Stomach Carcinoma 5517 EAP Protocol Predictive Supports C Sensitivity/Response In a study of 25 patients with advanced gastric cancer, mutations in TP53 were identified in 32% of primary tumors. TP53 mutations were associated with an improved response to preoperative treatment of a modified EAP protocol (combination of doxorubicin, etoposide and cisplatin). Patients with mutations in TP53 had an increased median survival compared to patients with wildtype TP53 (18.5mo vs. 10.2mo, P=0.044). 14514923 PubMed Bataille et al., 2003, MP, Mol. Pathol. accepted 2310 116 45 17 7578406 7578406 C T ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R175H variant seems not only to result in loss of tumor-suppression, but also acts as a gain-of-function mutation that promotes tumorigenesis in mouse models. Cell lines harboring this mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been shown that the R175H mutation is correlated with worse overall survival than wild-type TP53, but is not as detrimental as the R248W variant. This variant is rare in population databases (ACMG code: PM2; 0.000003980 total exome AF gnomAD v2.1.1). Somatic 2017-05-15 07:25:26 UTC https://civicdb.org/links/evidence_items/2310 https://civicdb.org/links/variants/116 https://civicdb.org/links/genes/45 false IDH1 3417 R132C Brain Glioma 0060108 Temozolomide Predictive Supports B Sensitivity/Response In a study of 189 low-grade gliomas, IDH (IDH1 or IDH2) mutations were found in 132 patients (70%). IDH mutations were associated with improved rate of response to temozolomide as compared to patients with wildtype IDH (61% vs. 17% , P=0.01). 20975057 PubMed Houillier et al., 2010, Neurology 2 accepted 2327 59 26 2 209113113 209113113 G A ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes and acute myeloid leukemia (AML), IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2017-07-25 19:50:31 UTC https://civicdb.org/links/evidence_items/2327 https://civicdb.org/links/variants/59 https://civicdb.org/links/genes/26 false IDH1 3417 R132C High Grade Glioma 3070 AGI-5198 Predictive Supports D Sensitivity/Response In an experimental in vitro study, glioma cells expressing IDH1 R132C were associated with sensitivity to AGI-5198 (IC50: 0.16M vs. IC50 > 100.00M), as compared to cells expressing wild-type IDH1. Sensitivity was determined by assessing cell growth. 23558169 PubMed Rohle et al., 2013, Science 2 accepted 2329 59 26 2 209113113 209113113 G A ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes and acute myeloid leukemia (AML), IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2017-07-10 21:43:33 UTC https://civicdb.org/links/evidence_items/2329 https://civicdb.org/links/variants/59 https://civicdb.org/links/genes/26 false IDH1 3417 R132 High Grade Glioma 3070 Bevacizumab Predictive Supports B Sensitivity/Response In a clinical study of 63 recurrent glioma patients, patients treated with bevacizumab monotherapy (n=11) and harboring IDH1 codon 132 mutation were associated with improved progression free survival (3.23 months vs. 1.37 months, P=0.05), as compared to patients with wild-type IDH1. 22199315 PubMed Lv et al., 2011, Anticancer Res. 2 accepted 2330 58 26 2 209113111 209113113 ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes, IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2020-02-07 00:15:33 UTC https://civicdb.org/links/evidence_items/2330 https://civicdb.org/links/variants/58 https://civicdb.org/links/genes/26 false IDH1 3417 R132C Acute Myeloid Leukemia 9119 Ivosidenib Predictive Supports B Sensitivity/Response In a clinical study of 17 relapsed or refractory AML patients harboring IDH1 mutations, these patients were associated with response to AG-120 monotherapy; 4/7 patients who achieved a response experienced complete remission. 25583779 PubMed 2015, Cancer Discov 2 accepted 2331 59 26 2 209113113 209113113 G A ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes and acute myeloid leukemia (AML), IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2017-07-25 19:50:13 UTC https://civicdb.org/links/evidence_items/2331 https://civicdb.org/links/variants/59 https://civicdb.org/links/genes/26 false IDH1 3417 R132C Acute Myeloid Leukemia 9119 BPTES Predictive Supports D Sensitivity/Response In an experimental study of acute myeloid leukemia (AML) cell lines expressing IDH1 R132C, IDH1 R132G, or IDH1 R132H mutations were associated with increased sensitivity to small molecule glutaminase inhibitor, bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) as compared to AML cell lines expressing wild-type IDH1. Sensitivity was determined by assessing cell growth. 24333121 PubMed Emadi et al., 2014, Exp. Hematol. 3 accepted 2332 59 26 2 209113113 209113113 G A ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes and acute myeloid leukemia (AML), IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2017-07-25 19:50:52 UTC https://civicdb.org/links/evidence_items/2332 https://civicdb.org/links/variants/59 https://civicdb.org/links/genes/26 false PIK3CA 5290 C420R Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Emtansine Predictive Does Not Support D Resistance As part of a pre-clinical experiment, the efficacy of ado-trastuzumab emtansine (T-DM1) was compared to that of trastuzumab against various HER2 positive cell lines. EFM-192A cell line expressing PIK3CA C420R was associated with similar sensitivity to T-DM1 as PIK3CA wild-type cell line SK-BR-3; substantially reduced cell viability was observed at concentrations > 0.01 ug/mL in both cell lines. Conversely, when treated with trastuzumab, the cell line harboring PIK3CA C420R experienced a smaller reduction in cell viability. 26920887 PubMed Baselga et al., 2016, Clin. Cancer Res. 3 accepted 2346 931 37 3 178927980 178927980 T C ENST00000263967.3 75 GRCh37 Somatic 2020-07-27 02:02:07 UTC https://civicdb.org/links/evidence_items/2346 https://civicdb.org/links/variants/931 https://civicdb.org/links/genes/37 false PIK3CA 5290 Mutation Lung Non-small Cell Carcinoma 3908 Gefitinib,Erlotinib Substitutes Predictive Supports B Resistance In a retrospective study, 166 non-small cell lung cancer (NSCLC) patients that tended to have selected characteristics known to be predictive for TKI sensitivity (i.e. women, never smokers, and patients with ADC) were treated with either gefitinib or erlotinib. PIK3CA mutations (n=6) were associated with no difference in objective response to drug treatment (16.6% vs. 35.2%, p=0.61), shorter overall survival (9.9 vs. 30.2 months, p<0.001), and shorter median time to progression (2.3 vs. 6.0 months, p=0.01) when compared to wild-type PIK3CA. Through multivariate analyses, it was shown that PIK3CA mutations are significant predictors of worse overall survival (HR: 5.81, 95% CI: 2.43-13.91, p=0.0001) and shorter time to progression (HR: 2.71 95% CI: 1.23-4.79, p=0.03). 21258250 PubMed Ludovini et al., 2011, J Thorac Oncol 3 accepted 2355 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2019-08-09 23:00:19 UTC https://civicdb.org/links/evidence_items/2355 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false KRAS 3845 Exon 2 Mutation Colorectal Cancer 9256 Prognostic Does Not Support B Poor Outcome This retrospective study examines outcomes of 158 primary sporadic colorectal cancer patients who had undergone surgical resection and were treated with 5-fluorouracil based chemotherapy. KRAS exon 2 mutations (listed as KRAS exon 1 as it was common at the time of source publication to exclude non-coding exon 1) were not associated with differences in disease specific survival compared to wt KRAS (n = 50 mutant, n = 108 wt; p =0.6077) or in relapse free survival. Authors noted that the tumors of 6 patients harbored both PIK3CA and KRAS mutations, but stated that the presence of PIK3CA mutations did not correlate with the presence of KRAS mutations. 17590872 PubMed Kato et al., 2007, Int. J. Cancer 3 accepted 2361 75 30 12 25398208 25398329 ENST00000256078.4 75 GRCh37 Exon 2 mutations have been associated with reduced response rates or resistance to EGFR inhibitors in non-small cell lung and colorectal cancer. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. Somatic 2021-02-02 23:34:25 UTC https://civicdb.org/links/evidence_items/2361 https://civicdb.org/links/variants/75 https://civicdb.org/links/genes/30 false BRAF 673 V600E Colorectal Cancer 9256 Prognostic Does Not Support C Poor Outcome This study examined outcomes of 240 rectum cancer patients treated with total mesorectal excision therapy. Tumor samples were obtained at the time of surgery and genotyped for BRAF exon 15 mutations. BRAF V600E was identified in 5 cases. The authors reported that no differences were found in overall survival between patients with and without BRAF mutations (P > 0.1). 19903786 PubMed He et al., 2009, Clin. Cancer Res. 2 accepted 2362 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-07-09 22:08:52 UTC https://civicdb.org/links/evidence_items/2362 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Gefitinib,Erlotinib Substitutes Predictive Supports B Resistance In a retrospective study, 166 non-small cell lung cancer (NSCLC) patients that tended to have selected characteristics known to be predictive for TKI sensitivity (i.e. women, never smokers, and patients with ADC) were treated with either gefitinib or erlotinib. KRAS mutations (n=11) were associated with lack of objective response to drug treatment (0.0% vs. 35.7%, p=0.03), no significant difference in overall survival (19.3 vs. 28.6 months, p=0.47), and shorter median time to progression (2.7 vs. 5.6 months, p=0.003) when compared to wild-type KRAS. Through multivariate analyses, it was shown that KRAS mutations were significant predictors of shorter time to progression (HR: 2.43, 95% CI: 1.23-4.79, p=0.01). 21258250 PubMed Ludovini et al., 2011, J Thorac Oncol 3 accepted 2385 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2019-08-09 23:07:57 UTC https://civicdb.org/links/evidence_items/2385 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KIT 3815 T417_D419delinsY Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports C Sensitivity/Response This patient was part of a larger cohort of 397 patients with incurable (i.e. metastatic or unresectable) CD117-positive Gastrointestinal stromal tumors (GISTs) enrolled in the North American phase III study SWOG S0033/CALGB 150105 who were treated with either 400mg or 800mg of imatinib per day. This patient's GIST had a KIT exon 8 deletion/insertion TYD417-419Y. This patient represents the first reported sporadic GIST with a KIT exon 8 mutation as germline DNA from surrounding normal tissue was was KIT wildtype. The patient had an unconfirmed partial response to 400mg daily imatinib (TTP 8.1 months) and a censored OS of 59.3 months. 18955451 PubMed Heinrich et al., 2008, J. Clin. Oncol. 2 accepted 2417 2620 29 Somatic 2019-02-08 17:40:25 UTC https://civicdb.org/links/evidence_items/2417 https://civicdb.org/links/variants/2620 https://civicdb.org/links/genes/29 false KIT 3815 F506_F508DUP Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Does Not Support C Sensitivity/Response This patient was part of a larger cohort of 397 patients with incurable (i.e. metastatic or unresectable) CD117-positive Gastrointestinal stromal tumors (GISTs) enrolled in the North American phase III study SWOG S0033/CALGB 150105. Patients in the study were treated with either 400mg or 800mg of imatinib per day. This patient's GIST harbored a tandem reduplication of KIT codons 506 to 508 (FAF) after F508 (F506_F508dup). The patient's response to imatinib was not assessed but the TTP was 10.6 months. 18955451 PubMed Heinrich et al., 2008, J. Clin. Oncol. 1 accepted 2441 2621 29 4 55592192 55592200 TTTGCATTT ENST00000288135.5 75 Somatic 2019-02-08 17:45:58 UTC https://civicdb.org/links/evidence_items/2441 https://civicdb.org/links/variants/2621 https://civicdb.org/links/genes/29 false KIT 3815 N822H Cancer 162 Imatinib Predictive Does Not Support D Resistance In an in vitro study of imatinib sensitivity, KIT N822H was cloned into a plasmid by site-directed mutagenesis of KIT WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. Cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of KIT activation. Cells expressing KIT N822H were as sensitive to imatinib as ligand activated wildtype KIT (IC50: 100-200 nmol/L). 14645423 PubMed Heinrich et al., 2003, J. Clin. Oncol. 2 accepted 2445 987 29 4 55599338 55599338 A C GRCh37 Somatic 2019-02-23 01:37:32 UTC https://civicdb.org/links/evidence_items/2445 https://civicdb.org/links/variants/987 https://civicdb.org/links/genes/29 false KIT 3815 N822K Cancer 162 Imatinib Predictive Does Not Support D Sensitivity/Response In an in vitro study of imatinib sensitivity, KIT N822K was cloned into a plasmid by site-directed mutagenesis of KIT WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. Cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of KIT activation. Cells expressing KIT N822K were as sensitive to imatinib as ligand activated wildtype KIT (IC50: 100-200 nmol/L). 14645423 PubMed Heinrich et al., 2003, J. Clin. Oncol. 2 accepted 2448 1263 29 4 55599340 55599340 T A ENST00000288135.5 75 GRCh37 Somatic 2019-02-23 01:39:00 UTC https://civicdb.org/links/evidence_items/2448 https://civicdb.org/links/variants/1263 https://civicdb.org/links/genes/29 false KIT 3815 D816V Cancer 162 Imatinib Predictive Supports D Resistance In an in vitro study of imatinib sensitivity, KIT D816V was cloned into a plasmid by site-directed mutagenesis of KIT WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. Cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of KIT activation. Cells expressing KIT D816V were resistant to imatinib up to 10 umol/L. 14645423 PubMed Heinrich et al., 2003, J. Clin. Oncol. 2 accepted 2451 65 29 4 55599321 55599321 A T ENST00000288135.5 75 GRCh37 KIT D816V is a mutation observed in acute myeloid leukemia (AML). This variant has been linked to poorer prognosis and worse outcome in AML patients. Somatic 2019-02-23 01:41:00 UTC https://civicdb.org/links/evidence_items/2451 https://civicdb.org/links/variants/65 https://civicdb.org/links/genes/29 false PDGFRA 5156 V561D Cancer 162 Imatinib Predictive Does Not Support D Resistance In an in vitro study of imatinib sensitivity, PDGFRA V561D was cloned into a plasmid by site-directed mutagenesis of PDGFRA WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. The cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of PDGFRA activation. Cells expressing PDGFRA V561D were as sensitive to imatinib as ligand activated wildtype PDGFRA (IC50: 100-200 nmol/L). 14645423 PubMed Heinrich et al., 2003, J. Clin. Oncol. 2 accepted 2454 941 38 4 55141036 55141036 T A ENST00000257290.5 75 GRCh37 Somatic 2019-02-23 01:49:12 UTC https://civicdb.org/links/evidence_items/2454 https://civicdb.org/links/variants/941 https://civicdb.org/links/genes/38 false PDGFRA 5156 D842_H845DELDIMH Cancer 162 Imatinib Predictive Does Not Support D Resistance In an in vitro study of imatinib sensitivity, PDGFRA D842_H845del was cloned into a plasmid by site-directed mutagenesis of PDGFRA WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. Cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of PDGFRA activation. Cells expressing PDGFRA D842_H845del were as sensitive to imatinib as ligand activated wildtype PDGFRA (IC50: 100-200 nmol/L). 14645423 PubMed Heinrich et al., 2003, J. Clin. Oncol. 2 accepted 2460 943 38 GRCh37 Somatic 2019-02-23 02:20:27 UTC https://civicdb.org/links/evidence_items/2460 https://civicdb.org/links/variants/943 https://civicdb.org/links/genes/38 false PDGFRA 5156 D842V Cancer 162 Imatinib Predictive Supports D Resistance In an in vitro study of imatinib sensitivity, PDGFRA D842V was cloned into a plasmid by site-directed mutagenesis of PDGFRA WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. The cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of PDGFRA activation. Cells expressing PDGFRA D842V required 10-20 fold higher concentrations of imatinib as ligand activated wildtype PDGFRA (IC50: 1-2 umol/L). 14645423 PubMed Heinrich et al., 2003, J. Clin. Oncol. 2 accepted 2463 99 38 4 55152093 55152093 A T ENST00000257290.5 75 GRCh37 PDGFRA D842 mutations are characterized broadly as imatinib resistance mutations. This is most well characterized in gastrointestinal stromal tumors, but other cell lines containing these mutations have been shown to be resistant as well. Exogenous expression of the A842V mutation resulted in constitutive tyrosine phosphorylation of PDGFRA in the absence of ligand in 293T cells and cytokine-independent proliferation of the IL-3-dependent Ba/F3 cell line, both evidence that this is an activating mutation. In imatinib resistant cell lines, a number of other therapeutics have demonstrated efficacy. These include; crenolanib, sirolimus, and midostaurin (PKC412). Somatic 2019-02-23 02:24:09 UTC https://civicdb.org/links/evidence_items/2463 https://civicdb.org/links/variants/99 https://civicdb.org/links/genes/38 false KIT 3815 K484_G487DEL Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports C Sensitivity/Response This patient was from a larger cohort of 397 patients with incurable (i.e. metastatic or unresectable) CD117-positive Gastrointestinal stromal tumors (GISTs) enrolled in the North American phase III study SWOG S0033/CALGB 150105. Patients in the study were treated with either 400mg or 800mg of imatinib per day. This patient's GIST harbored a homozygous deletion of KIT codons 484 to 487 (KHNG; K484_G487del). The patient's response to imatinib was not assessed, and the TTP was 46.9 months. 18955451 PubMed Heinrich et al., 2008, J. Clin. Oncol. 1 accepted 2465 2622 29 Somatic 2019-02-08 17:50:50 UTC https://civicdb.org/links/evidence_items/2465 https://civicdb.org/links/variants/2622 https://civicdb.org/links/genes/29 false KIT 3815 Exon 9 Mutation Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports B Sensitivity/Response This prospective study of 127 patients with metastatic gastrointestinal stromal tumors (GISTs) examined the relationship between KIT genotype and treatment outcome for patients enrolled in a randomized phase II trial of imatinib (CSTI571B 2222). 23 patients harbored KIT exon 9 mutated GISTs: 22 harbored A502_503Ydup and 1 harbored F506_F508dup. Of patients harboring KIT exon 9 mutated GISTs, 11 (47.8%) had a partial response, 6 had stable disease, 4 had progressive disease and 2 were nonassessable. Patients with KIT exon 9 mutant GISTs were significantly more likely to have a partial response than those with WT KIT (P = .013), though significantly less likely than those with KIT exon 11 mutated GISTs (P = .0006). Patients harboring KIT exon 9 mutant GISTs experienced longer event free survival (median: 200 days) than those with WT KIT GISTs (82 days). Furthermore, there was a signficant difference in overall survival between patients with KIT exon 9 mutant and double WT kinase GISTs (P = .0067). There was no significant difference in the rate of treatment failure for patients with exon 9 mutation compared with those with no KIT or PDGFRA mutation (P = .14). 14645423 PubMed Heinrich et al., 2003, J. Clin. Oncol. 3 accepted 2466 509 29 4 55592023 55592216 ENST00000288135.5 75 GRCh37 In patients with gastrointestinal stromal tumors (GIST), imatinib has improved outcomes for patients with KIT mutations. However, acquired resistance to imatinib is common. Patients harboring exon 9 KIT mutations may benefit from higher imatinib doses (800mg/daily). Similarly, imatinib-refractory tumors showed sensitivity to sunitinib treatment. Improved responses to either treatment were not observed in patients with exon 11 mutations. Somatic 2019-02-23 00:21:12 UTC https://civicdb.org/links/evidence_items/2466 https://civicdb.org/links/variants/509 https://civicdb.org/links/genes/29 false KIT 3815 V560G Cancer 162 Imatinib Predictive Does Not Support D Resistance In an in vitro study of imatinib sensitivity, KIT V560G was cloned into a plasmid by site-directed mutagenesis of KIT WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. The cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for the presence of phosphorylated tyrosine, a measure of KIT activation. Cells expressing KIT V560G were as sensitive to imatinib as ligand activated wildtype KIT (IC50: 100-200 nmol/L). 14645423 PubMed Heinrich et al., 2003, J. Clin. Oncol. 2 accepted 2469 972 29 4 55593613 55593613 T G ENST00000288135.5 75 GRCh37 Somatic 2019-02-23 01:20:26 UTC https://civicdb.org/links/evidence_items/2469 https://civicdb.org/links/variants/972 https://civicdb.org/links/genes/29 false KIT 3815 Exon 11 Mutation Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports B Sensitivity/Response This prospective study of 397 patients with incurable (i.e. metastatic or unresectable) CD117-positive Gastrointestinal stromal tumors (GISTs) examined the relationship between KIT genotype and treatment outcome for patients enrolled in the North American phase III study SWOG S0033/CALGB 150105 who were treated with either 400mg or 800mg of imatinib per day. The study found that patients whose tumors harbored mutations in KIT exon 11 had signficantly superior responses to imatinib, regardless of dose, than those whose tumors harbored wildtype KIT or KIT exon 9 mutations. This is evidenced by the findings that imatinib-treated patients whose tumors contained KIT exon 11 mutations had longer overall survival compared to those with exon 9 mutations (60.0mo vs.38.4mo, P=0.011) or wildtype KIT (60mo vs. 49.0mo, P=0.049). Patients with exon 11 mutations had improved progression-free survival in comparison to those with exon 9 mutations (24.7mo vs. 16.7mo, P=0.0013) or wildtype KIT (24.7mo vs. 12.8mo, P=0.005). 18955451 PubMed Heinrich et al., 2008, J. Clin. Oncol. 4 accepted 2471 66 29 4 55593582 55593708 ENST00000288135.5 75 GRCh37 c-KIT mutations in exon 11 lie within the juxtamembrane domain, and are very recurrent in gastrointestinal stromal tumors, often bearing a poorer prognosis than other KIT mutations. Cells harboring exon 11 mutations have shown sensitivity to the tyrosine kinase inhibitor imatinib, offering a better prognosis to patients treated with the drug in the first year. Small cohorts of melanoma patients harboring exon 11 KIT mutations have shown response to imatinib and sunitinib. Somatic 2019-02-08 17:24:31 UTC https://civicdb.org/links/evidence_items/2471 https://civicdb.org/links/variants/66 https://civicdb.org/links/genes/29 false KIT 3815 K642E Cancer 162 Imatinib Predictive Does Not Support D Resistance In an in vitro study of imatinib sensitivity, KIT K642E was cloned into a plasmid by site-directed mutagenesis of KIT WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. Cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Then, protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of KIT activation. Cells expressing KIT K642E were as sensitive to imatinib as ligand activated wildtype KIT (IC50: 100-200 nmol/L). 14645423 PubMed Heinrich et al., 2003, J. Clin. Oncol. 2 accepted 2472 978 29 4 55594221 55594221 A G ENST00000288135.5 75 GRCh37 Somatic 2019-02-23 01:34:11 UTC https://civicdb.org/links/evidence_items/2472 https://civicdb.org/links/variants/978 https://civicdb.org/links/genes/29 false PDGFRA 5156 V561D Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports C Sensitivity/Response This case study examines one patient from a larger cohort of 397 patients with incurable (i.e. metastatic or unresectable) CD117-positive Gastrointestinal stromal tumors (GISTs) enrolled in the North American phase III study SWOG S0033/CALGB 150105. Patients in this cohort were treated with either 400mg or 800mg of imatinib per day. This patient's GIST harbored PDGFRA exon 12 V561D. The patient was treated with 800mg of imatinib per day, and had not progressed or died as of 31 months of follow up (vs median TTP of 12.8 months for WT). 18955451 PubMed Heinrich et al., 2008, J. Clin. Oncol. 1 accepted 2474 941 38 4 55141036 55141036 T A ENST00000257290.5 75 GRCh37 Somatic 2019-02-08 18:32:29 UTC https://civicdb.org/links/evidence_items/2474 https://civicdb.org/links/variants/941 https://civicdb.org/links/genes/38 false KIT 3815 Exon 13 Mutation Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports C Sensitivity/Response This prospective study of 127 patients with metastatic gastrointestinal stromal tumors (GISTs) examined the relationship between kinase (KIT and PDGFRA) genotype and treatment outcome for patients enrolled in a randomized phase II trial of imatinib (CSTI571B 2222). Two patients' GISTs harbored KIT exon 13 mutations, and both experienced partial responses to imatinib. The authors conclude that this uncommon variant is sensitive to imatinib. 14645423 PubMed Heinrich et al., 2003, J. Clin. Oncol. 2 accepted 2475 2643 29 4 55594177 55594287 ENST00000288135.5 75 GRCh37 Somatic 2019-02-26 18:17:04 UTC https://civicdb.org/links/evidence_items/2475 https://civicdb.org/links/variants/2643 https://civicdb.org/links/genes/29 false KIT 3815 Exon 9 Mutation Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports B Reduced Sensitivity This prospective study of 397 patients with incurable (i.e. metastatic or unresectable) CD117-positive Gastrointestinal stromal tumors (GISTs) examined the relationship between KIT genotype and treatment outcome for patients enrolled in the North American phase III study SWOG S0033/CALGB 150105 who were treated with either 400mg or 800mg of imatinib per day. Of 33 patients with KIT exon-9 mutant GISTs, 31 harbored KIT A502_Y503 internal tandom duplication, one harbored K484_G487del (KHNG). Of the KIT exon 9 mutant patients, 14 were treated with 400mg daily and 19 were treated with 800mg daily. Patients with KIT exon-9 mutant GISTs had a significantly higher response rate when treated with 800mg compared with 400mg (CR/PR 17% vs 67% for 400mg and 800mg, respectively; OR, 9.05; p = .02). However, the authors report that there was not a significant difference in time to progression or overall survival between the two dose groups for patients harboring KIT exon-9 mutant GISTs. 18955451 PubMed Heinrich et al., 2008, J. Clin. Oncol. 2 accepted 2477 509 29 4 55592023 55592216 ENST00000288135.5 75 GRCh37 In patients with gastrointestinal stromal tumors (GIST), imatinib has improved outcomes for patients with KIT mutations. However, acquired resistance to imatinib is common. Patients harboring exon 9 KIT mutations may benefit from higher imatinib doses (800mg/daily). Similarly, imatinib-refractory tumors showed sensitivity to sunitinib treatment. Improved responses to either treatment were not observed in patients with exon 11 mutations. Somatic 2019-02-08 18:37:20 UTC https://civicdb.org/links/evidence_items/2477 https://civicdb.org/links/variants/509 https://civicdb.org/links/genes/29 false PDGFRA 5156 D842V Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports C Resistance This prospective study of 127 patients with metastatic gastrointestinal stromal tumors (GISTs) examined the relationship between kinase (KIT and PDGFRA) genotype and treatment outcome for patients enrolled in a randomized phase II trial of imatinib (CSTI571B 2222). Three patients' GISTs harbored PDGFRA D842V. Two of these patients experienced progressive disease and one was unassessable. The authors conclude that this finding is consistent with the work of others suggesting that PDGFRA D842V is an imatinib resistant variant in GIST. 14645423 PubMed Heinrich et al., 2003, J. Clin. Oncol. 2 accepted 2478 99 38 4 55152093 55152093 A T ENST00000257290.5 75 GRCh37 PDGFRA D842 mutations are characterized broadly as imatinib resistance mutations. This is most well characterized in gastrointestinal stromal tumors, but other cell lines containing these mutations have been shown to be resistant as well. Exogenous expression of the A842V mutation resulted in constitutive tyrosine phosphorylation of PDGFRA in the absence of ligand in 293T cells and cytokine-independent proliferation of the IL-3-dependent Ba/F3 cell line, both evidence that this is an activating mutation. In imatinib resistant cell lines, a number of other therapeutics have demonstrated efficacy. These include; crenolanib, sirolimus, and midostaurin (PKC412). Somatic 2019-02-26 18:23:49 UTC https://civicdb.org/links/evidence_items/2478 https://civicdb.org/links/variants/99 https://civicdb.org/links/genes/38 false KIT 3815 EXPRESSION Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports B Sensitivity/Response In a prospective phase III study (SWOG S0033/CALGB 150105) of 407 patients with gastrointestinal stromal tumors (GISTs), 397 patients were observed to be CD117-positive (i.e. KIT-positive) and 10 patients were CD117-negative. Patients were treated with either 400mg or 800mg of imatinib per day. When compared to CD117-positive, GISTs, CD117-negative GISTs did not show significant difference in median time to progression (18.3 months vs. 20.5 months; P = 0.46), however, CD-117-negative GISTs showed reduced overall survival relative to CD-117-positive GISTs (25.8 months vs. 57.1 months; P= 0.01). 18955451 PubMed Heinrich et al., 2008, J. Clin. Oncol. 2 accepted 2480 429 29 4 55524085 55606881 ENST00000288135.5 75 GRCh37 Somatic 2019-02-08 19:06:15 UTC https://civicdb.org/links/evidence_items/2480 https://civicdb.org/links/variants/429 https://civicdb.org/links/genes/29 false KIT 3815 W557_K558del Cancer 162 Imatinib Predictive Does Not Support D Resistance In an in vitro study of imatinib sensitivity, KIT W557_K558del was cloned into a plasmid by site-directed mutagenesis of KIT WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. Cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of KIT activation. Cells expressing KIT W557_K558del were as sensitive to imatinib as ligand activated wildtype KIT (IC50: 100-200 nmol/L). 14645423 PubMed Heinrich et al., 2003, J. Clin. Oncol. 2 accepted 2481 961 29 4 55593603 55593608 TGGAAG ENST00000288135.5 75 GRCh37 Somatic 2019-02-23 02:25:21 UTC https://civicdb.org/links/evidence_items/2481 https://civicdb.org/links/variants/961 https://civicdb.org/links/genes/29 false KIT 3815 Y503_F504insAY Cancer 162 Imatinib Predictive Does Not Support D Resistance In an in vitro study of imatinib sensitivity, KIT Y503_F504insAY was cloned into a plasmid by site-directed mutagenesis of KIT WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. Cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Then, protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of KIT activation. Cells expressing KIT Y503_F504insAY were as sensitive to imatinib as ligand activated wildtype KIT (IC50: 100-200 nmol/L). 14645423 PubMed Heinrich et al., 2003, J. Clin. Oncol. 2 accepted 2484 946 29 4 55592185 55592186 GCCTAT ENST00000288135.5 75 GRCh37 Somatic 2019-02-23 01:32:04 UTC https://civicdb.org/links/evidence_items/2484 https://civicdb.org/links/variants/946 https://civicdb.org/links/genes/29 false PDGFRA 5156 Exon 18 Mutation Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Does Not Support C Sensitivity/Response These four patients were part of a larger cohort of 397 patients with incurable (i.e. metastatic or unresectable) CD117-positive Gastrointestinal stromal tumors (GISTs) enrolled in the North American phase III study SWOG S0033/CALGB 150105 who were treated with either 400mg or 800mg of imatinib per day. All four patients' GISTs harbored PDGFRA exon 18 mutatations (one I843_S847delinsM, three D842_H845del). The overall survival was more than 12 months for all four of these patients (mean 40.8 months), which is comparable to patients with WT PDGFRA (49.0months). 18955451 PubMed Heinrich et al., 2008, J. Clin. Oncol. 1 accepted 2486 2623 38 Somatic 2019-02-08 18:22:12 UTC https://civicdb.org/links/evidence_items/2486 https://civicdb.org/links/variants/2623 https://civicdb.org/links/genes/38 false PDGFRA 5156 Mutation Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports C Sensitivity/Response This prospective study of 127 patients with metastatic gastrointestinal stromal tumors (GISTs) examined the relationship between kinase (KIT and PDGFRA) genotype and treatment outcome for patients enrolled in a randomized phase II trial of imatinib (CSTI571B 2222). Six GISTs harbored PDGFRA mutations, three of which were deemed imatinib-sensitive by the authors: 1 DIMH842-845 deletion, one I843 deletion, and one V561D point mutation. Two of these patients' GISTs experienced partial responses to imatinib and one experienced progressive disease. Overall, the partial response rate of patients with an imatinib sensitive mutation of KIT or PDGFRA was 75.7% (87 of 115 patients), whereas the partial response rate in patients with no kinase mutation or a previously described imatinib resistant mutation was 0% (0 of 12 patients). The authors concluded that PDGFRA gain-of-function mutations may account for imatinib sensivity in some WT KIT GISTs. 14645423 PubMed Heinrich et al., 2003, J. Clin. Oncol. 3 accepted 2487 3274 38 Somatic 2021-02-25 19:03:13 UTC https://civicdb.org/links/evidence_items/2487 https://civicdb.org/links/variants/3274 https://civicdb.org/links/genes/38 false BRAF 673 V600E Thyroid Gland Papillary Carcinoma 3969 Prognostic Supports B Poor Outcome In a meta-analysis of 8 studies, papillary thyroid cancer patients with BRAF V600E mutation had a higher frequency of recurrence and persistent disease compared to those with wildtype BRAF (28.5% vs. 12.8% , Risk ratio:2.14, 95%CI:1.67-2.74, P<0.00001). 21882184 PubMed Kim et al., 2012, Cancer 3 accepted 2503 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-10-24 15:48:39 UTC https://civicdb.org/links/evidence_items/2503 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600K Melanoma 1909 Dabrafenib Predictive Supports B Sensitivity/Response Patients were treated with a specific RAF inhibitor (dabrafenib), which improved overall survival of patients with BRAF mutations (P<0.003), compared to non-treated patients with BRAF mutations. Patients having BRAF mutations were associated with reduced overall survival (11.1 mo vs. 46.1 mo for wild-type, P=0.006). BRAF mutations were more frequent in tumors with superficially spreading histological sub-type (43% vs. 19% , P<0.001) compared to BRAF wild-type tumors. 21343559 PubMed Long et al., 2011, J. Clin. Oncol. accepted 2505 563 5 7 140453136 140453137 AC TT ENST00000288602.6 75 GRCh37 Somatic 2018-07-06 14:17:59 UTC https://civicdb.org/links/evidence_items/2505 https://civicdb.org/links/variants/563 https://civicdb.org/links/genes/5 false BRAF 673 V600K Melanoma 1909 Trametinib Predictive Supports B Sensitivity/Response In a study of 322 advanced melanoma patients with BRAF-V600E (N=281), BRAF-V600K (N=40), or both mutations (N=1), treatment with trametinib was associated with improved progression-free survival (4.8mo vs. 1.5mo; HR: 0.45, 95% CI: 0.33-0.63, P<0.001) compared to chemotherapy control group. Additionally, treatment with trametinib was associated with increased 6-month overall survival (HR: 0.54, 95% CI: 0.32-0.92, P=0.01). The authors note similar outcomes for the primary efficacy population (V600E only) and the intention-to-treat population, however, sub-group analysis for patients with V600K did not show significant improvement in PFS (HR: 0.50, 95% CI:0.18-1.35). 22663011 PubMed Flaherty et al., 2012, N. Engl. J. Med. NCT01245062 2 accepted 2506 563 5 7 140453136 140453137 AC TT ENST00000288602.6 75 GRCh37 Somatic 2021-02-02 01:49:03 UTC https://civicdb.org/links/evidence_items/2506 https://civicdb.org/links/variants/563 https://civicdb.org/links/genes/5 false EGFR 1956 G719A Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports C Sensitivity/Response In a study of 297 non-small cell lung cancer patients, 15% of the analyzed tumors had EGFR mutations including deletions in exon 19 (n=22), L858R (n=16) and G719A (n=2). Patients with EGFR mutations treated with gefitinib were associated with improved response rates (42.1% vs. 6.6%, P=0.04) compared to wildtype EGFR patients. 20038723 PubMed Douillard et al., 2010, J. Clin. Oncol. NCT00076388 accepted 2508 999 19 7 55241708 55241708 G C ENST00000275493.2 75 GRCh37 Somatic 2017-05-18 15:21:37 UTC https://civicdb.org/links/evidence_items/2508 https://civicdb.org/links/variants/999 https://civicdb.org/links/genes/19 false EGFR 1956 Wildtype Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports B Resistance In a phase 3 clinical trial of East Asian pulmonary adenocarcinoma patients, a subset of patients with EGFR mutations (n=261) treated with gefitinib were associated with improved response compared to carboplatin plus paclitaxel treatment, but in patients shown to be negative for EGFR mutation (n=176), patients given gefitinib fared worse than those given carboplatin and paclitaxel: Hazard ratio 2.85 (85% CI 2.05-3.98) p<0.001 19692680 PubMed Mok et al., 2009, N. Engl. J. Med. NCT00322452 4 accepted 2512 2174 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2020-08-12 20:25:13 UTC https://civicdb.org/links/evidence_items/2512 https://civicdb.org/links/variants/2174 https://civicdb.org/links/genes/19 false EGFR 1956 E746_A750del Bronchiolo-alveolar Adenocarcinoma 4926 Erlotinib Predictive Supports C Sensitivity/Response EGFR exons 18-24 were analyzed in 7 patients who had shown a partial response to erlotinib in a phase II trial for bronchioloalveolar carcinoma (BAC, or in situ pulmonary adenocarcinoma). One patient (Patient E2) had the E746_A750del mutation. The patient was a male never smoker, and demonstrated response for 8.5 months. Overall survival was 21+ months as the patient was alive at study end. 15329413 PubMed Pao et al., 2004, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 2513 1002 19 7 55242465 55242479 GGAATTAAGAGAAGC ENST00000275493.2 75 GRCh37 Somatic 2020-04-19 20:12:11 UTC https://civicdb.org/links/evidence_items/2513 https://civicdb.org/links/variants/1002 https://civicdb.org/links/genes/19 false EGFR 1956 Exon 19 Deletion Lung Adenocarcinoma 3910 Gefitinib Predictive Supports B Sensitivity/Response In a phase 3 clinical trial of Korean, never-smoker, lung adenocarcinoma patients, a subset of patients with EGFR mutations (n=42) treated with gefitinib were associated with improved overall response rate compared to gemcitabine plus cisplatin treatment (84.6%, 22/26, vs. 37.5%, 6/16, P=0.002). By contrast, in EGFR mutation negative cases, the response rate was much lower (25.9%, 7/27). The frequency of mutation in exon 19 deletion and L858R was 64.3% (27/42) and 36.4% (16/42), respectively. Exon 19 and L858R mutations were mutually exclusive in this cohort. 22370314 PubMed Han et al., 2012, J. Clin. Oncol. 3 accepted 2519 133 19 7 55242415 55242513 ENST00000275493.2 75 GRCh37 Deletions within exon 19 of EGFR are most common in lung cancer. These deletions, in non-small cell lung cancer, have been shown to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib, afatinib, and erlotinib. There is also data to suggest that this event is a good prognostic marker in lung adenocarcinoma. Examples of exon 19 deletions include: p.746_A750delELREA, p.747_753delinsS, p.747_752delLREATS, and p.747_751delLREAT. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/2519 https://civicdb.org/links/variants/133 https://civicdb.org/links/genes/19 false EGFR 1956 Mutation Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports B Sensitivity/Response Mutational profiling was performed on EGFR exons 18-24 from a group of 10 retrospectively chosen patients who had shown partial response or clinical imporvement in response to gefitinib, and in 8 patients who had not shown gefitinib response. 7 of 10 sensitive patients had mutations in EGFR, while none of the 8 gefitinib refractory patients showed EGFR mutation in these exons (p=0.004) 15329413 PubMed Pao et al., 2004, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 2559 442 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2017-09-08 20:08:57 UTC https://civicdb.org/links/evidence_items/2559 https://civicdb.org/links/variants/442 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports B Sensitivity/Response In a phase 3 clinical trial of non-small cell lung cancer (NSCLC) patients, a subset of patients with EGFR mutations (n=44) treated with gefitinib were associated with improved progression free survival (HR: 0.16, 95% CI: 0.05-0.49, P=0.001), and a higher objective response rate (ORR: 42.1% vs 21.1%, p=0.04) compared to patients treated with docetaxel. Of the 44 patients, 22 had an exon 19 deletion, 16 had an L858R mutation, one patient had an exon 20 T790M mutation, two had an exon G719A mutation and four had other mutations. 20038723 PubMed Douillard et al., 2010, J. Clin. Oncol. NCT00076388 4 accepted 2621 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2017-10-21 23:33:22 UTC https://civicdb.org/links/evidence_items/2621 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Adenocarcinoma 3910 Gefitinib Predictive Supports C Sensitivity/Response Mutational profiling was performed on EGFR exons 18-24 from a group of 10 retrospectively chosen patients who had shown partial response or clinical improvement in response to gefitinib. Of 7 tumors with EGFR mutations, 1 was L858R. The patient was a female former smoker who had lung adenocarcinoma histology, and demonstrated response for 5 months, with overall survival 8 months. 15329413 PubMed Pao et al., 2004, Proc. Natl. Acad. Sci. U.S.A. 1 accepted 2624 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/2624 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 E746_A750del Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports D Sensitivity/Response In an in vitro study using PC9 cells (EGFR exon 19 deletion), inhibition of cell viability was used as an assay to determine sensitivity to EGFR tyrosine kinase inhibitors. PC9 cells demonstrated an increased sensitivity to gefitinib (IC50: 23.0 nmol/L vs 200.0 nmol/L) compared to NCI-H2073 cells (EGFR wild type). 24893891 PubMed Cross et al., 2014, Cancer Discov 2 accepted 2625 1002 19 7 55242465 55242479 GGAATTAAGAGAAGC ENST00000275493.2 75 GRCh37 Somatic 2021-02-03 23:17:23 UTC https://civicdb.org/links/evidence_items/2625 https://civicdb.org/links/variants/1002 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Lapatinib Predictive Supports D Sensitivity/Response In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to reversible tyrosine kinase inhibitor drugs. Cells with an EGFR L858R mutation demonstrated an improved response to lapatinib (IC50: 63nM vs. 534nM) compared to wildtype EGFR cells. 18408761 PubMed Li et al., 2008, Oncogene 3 accepted 2626 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2020-08-10 20:20:17 UTC https://civicdb.org/links/evidence_items/2626 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Dacomitinib Predictive Supports D Sensitivity/Response In an in vitro study using NCI-H322 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to irreversible tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R mutation demonstrated an improved response to Dacomitinib (IC50: 0.007umol/L vs. >10umol/L) compared to wildtype EGFR cells or compared to reversible TKI drug gefitinib (IC50: 0.075umol/L vs. wild-type >10umol/L). 18089823 PubMed Engelman et al., 2007, Cancer Res. 3 accepted 2627 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2019-09-05 19:42:20 UTC https://civicdb.org/links/evidence_items/2627 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Neratinib Predictive Supports D Sensitivity/Response In an in vitro study using NCI-H3255 cells (EGFR L858R), inhibition of cell growth was used as an assay to determine sensitivity to tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R mutation demonstrated sensitivity to neratinib (IC50: 0.0049 μmol/L) compared to EGFRwt A549 cells (IC50 > 1 μmol/L). 16818618 PubMed Shimamura et al., 2006, Cancer Res. 3 accepted 2628 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2020-11-23 21:07:21 UTC https://civicdb.org/links/evidence_items/2628 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Afatinib Predictive Supports D Sensitivity/Response In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to irreversible tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R mutation demonstrated an improved response to afatinib (IC50: 0.7nM vs. 60nM) compared to wildtype EGFR cells. 18408761 PubMed Li et al., 2008, Oncogene 2 accepted 2629 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2018-04-18 20:58:35 UTC https://civicdb.org/links/evidence_items/2629 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Canertinib Predictive Supports D Sensitivity/Response In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to irreversible tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R mutation demonstrated an improved response to canertinib (IC50: 1nM vs. 198nM) compared to wildtype EGFR cells. 18408761 PubMed Li et al., 2008, Oncogene 3 accepted 2631 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2020-08-10 20:15:10 UTC https://civicdb.org/links/evidence_items/2631 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports C Sensitivity/Response In a phase II trial for bronchioloalveolar carcinoma (BAC, or in situ pulmonary adenocarcinoma), EGFR exons 18-24 were analyzed in 7 patients who had shown a partial response to erlotinib. Two patients had the del L858R mutation. One patient was a male former smoker who demonstrated response for 3 months with overall survival of 3.5 months, and the other patient was a female never smoker who had response for 6 months and overall survival of 17+ months as the patient was alive at study end. 15329413 PubMed Pao et al., 2004, Proc. Natl. Acad. Sci. U.S.A. 2 accepted 2632 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2017-09-08 20:54:33 UTC https://civicdb.org/links/evidence_items/2632 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Adenocarcinoma 3910 Gefitinib Predictive Supports B Sensitivity/Response In a phase 3 clinical trial of Korean, never-smoker, lung adenocarcinoma patients, a subset of patients with EGFR mutations (n=42) treated with gefitinib were associated with improved overall response rate compared to gemcitabine plus cisplatin treatment (84.6%, 22/26, vs. 37.5%, 6/16, P=0.002). By contrast, in EGFR mutation negative cases, the response rate was much lower (25.9%, 7/27). The frequency of mutation in exon 19 deletion and L858R was 64.3% (27/42) and 36.4% (16/42), respectively. Exon 19 and L858R mutations were mutually exclusive in this cohort. 22370314 PubMed Han et al., 2012, J. Clin. Oncol. 3 accepted 2634 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/2634 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false ABL1 25 BCR::ABL M244V Chronic Myeloid Leukemia 8552 Imatinib Predictive Does Not Support C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A late-chronic phase patient had only a partial hematologic response which improved to a major cytogenetic response after dose escalation 18 months after therapy initiation. At months 7 and 8, the M244V was present in 100% of transcripts. No further testing for secondary variants was performed. At 18 months, 25% of cells were Ph-positive, but this did not meet the authors' threshold for loss of MCR which is >65% Ph-positive cells or an increase of 30%. 12623848 PubMed Branford et al., 2003, Blood 3 accepted 2636 1021 4 9 133738330 133738330 A G ENST00000318560.5 75 GRCh37 Somatic 2020-07-24 21:49:49 UTC https://civicdb.org/links/evidence_items/2636 https://civicdb.org/links/variants/1021 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M244V Cancer 162 Imatinib Predictive Supports D Sensitivity/Response A panel of 16 mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and evaluated for antiproliferative activity and substrate or auto-phosphorylation assays. The authors considered the M244V mutation sensitive to imatinib (IC50: 2000 vs. 260 nmol/L, 8x fold change, in a proliferative assay compared to Ba/F3 cells with unmutated BCR-ABL fusions). 15930265 PubMed O'Hare et al., 2005, Cancer Res. 3 accepted 2638 1021 4 9 133738330 133738330 A G ENST00000318560.5 75 GRCh37 Somatic 2020-08-29 00:30:30 UTC https://civicdb.org/links/evidence_items/2638 https://civicdb.org/links/variants/1021 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M244V Cancer 162 Dasatinib,Nilotinib Substitutes Predictive Does Not Support D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the M244V mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to dasatinib and nilotinib treatment (IC50: 93.1 nM and 891.4 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 87.6 nM and 642.3 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 2640 1021 4 9 133738330 133738330 A G ENST00000318560.5 75 GRCh37 Somatic 2021-02-17 23:55:47 UTC https://civicdb.org/links/evidence_items/2640 https://civicdb.org/links/variants/1021 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L248V Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports D Resistance A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The L248V mutation was moderately resistant to imatinib. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 2 accepted 2641 1022 4 9 133738342 133738342 C G ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 16:34:19 UTC https://civicdb.org/links/evidence_items/2641 https://civicdb.org/links/variants/1022 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L248V Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A late-chronic phase (CP) patient had a complete hematologic response but acquired resistance after 7 months of therapy and discontinued imatinib 3 months later. At month 11, the L248V, G250E, S417Y, E459K variants were present in approximately 25, 25, 25, and 50% of transcripts, respectively. The patient died in myeloid blast crisis at month 14 after a bone marrow transplant. 12623848 PubMed Branford et al., 2003, Blood 2 accepted 2642 1022 4 9 133738342 133738342 C G ENST00000318560.5 75 GRCh37 Somatic 2020-07-11 00:26:57 UTC https://civicdb.org/links/evidence_items/2642 https://civicdb.org/links/variants/1022 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L248V Chronic Myeloid Leukemia 8552 Imatinib Mesylate,Dasatinib,Nilotinib Substitutes Predictive Supports D Resistance In an in vitro study, a Ba/F3-p210BCR-ABL1 cell line was ENU-mutated and exposed to graded concentrations of imatinib, nilotinib or dasatinib to identify resistance mutations. The L248V mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to 2 μM imatinib (3 clones recovered, ~2% of viable clones in this treatment), 50nM nilotinib (1 clone, ~2%), and 5nM dasatinib (3 clones, ~9%). In a review of 20 publications, this mutation was described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 2644 1022 4 9 133738342 133738342 C G ENST00000318560.5 75 GRCh37 Somatic 2018-10-08 22:26:42 UTC https://civicdb.org/links/evidence_items/2644 https://civicdb.org/links/variants/1022 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G250E Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports D Resistance A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The G250E mutation was resistant to imatinib. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 3 accepted 2645 1023 4 9 133738349 133738349 G A ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 16:34:57 UTC https://civicdb.org/links/evidence_items/2645 https://civicdb.org/links/variants/1023 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G250E Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A late-chronic phase (CP) patient had a complete hematologic response (CHR) but acquired resistance 7 months after therapy initiation. At month 11, the L248V, G250E, S417Y, E459K variants were present in approximately 25, 25, 25, and 50% of transcripts, respectively. The patient died in accelerated phase at month 14. An accelerated-phase patient had a CHR but progressed to partial hematologic response concurrent with the appearance of the G250E variant in ~25% of transcripts and the M351T variant in ~50% of transcripts. The patient died at 12 months. 12623848 PubMed Branford et al., 2003, Blood 2 accepted 2646 1023 4 9 133738349 133738349 G A ENST00000318560.5 75 GRCh37 Somatic 2020-07-11 00:30:40 UTC https://civicdb.org/links/evidence_items/2646 https://civicdb.org/links/variants/1023 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G250E Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In two cell-based studies, a panel of either 18 or 16 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The G250E mutation was resistant to imatinib . 15930265 PubMed O'Hare et al., 2005, Cancer Res. accepted 2647 1023 4 9 133738349 133738349 G A ENST00000318560.5 75 GRCh37 Somatic 2017-05-19 16:45:48 UTC https://civicdb.org/links/evidence_items/2647 https://civicdb.org/links/variants/1023 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G250E Chronic Myeloid Leukemia 8552 Nilotinib Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the G250E mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to nilotinib treatment (IC50: 4.56-fold), as compared to Ba/F3 cells expressing BCR-ABL1 fusion protein (reported to be sensitizing to nilotinib). Sensitivity was determined by assessing cell proliferation. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 2 accepted 2648 1023 4 9 133738349 133738349 G A ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 16:40:02 UTC https://civicdb.org/links/evidence_items/2648 https://civicdb.org/links/variants/1023 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G250E Cancer 162 Nilotinib Predictive Does Not Support D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the G250E mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to nilotinib treatment (IC50: 866 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 642.3 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 2649 1023 4 9 133738349 133738349 G A ENST00000318560.5 75 GRCh37 Somatic 2021-02-17 23:56:47 UTC https://civicdb.org/links/evidence_items/2649 https://civicdb.org/links/variants/1023 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Q252H Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports D Sensitivity/Response A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The Q252H mutation was sensitive to imatinib. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 3 accepted 2650 1024 4 9 133738356 133738356 G C ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 16:34:44 UTC https://civicdb.org/links/evidence_items/2650 https://civicdb.org/links/variants/1024 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Q252H Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A chronic-phase (CP) patient achieved a complete hematologic response (CHR). The Q252H variant was detected but was absent when the patient progressed to myeloid blast crisis (MBC) with a double Philadelphia chromosome and died. A second CP patient had a partial hematologic response (PHR) with the Q252H and M351T variants. They progressed to MBC and the double Ph-chromosome was later detected without any secondary variants prior to death. The third CP patient had a PHR but became resistant. The Q252H variant was later detected and the patient died in MBC. An accelerated-phase (AP) patient had a CHR but progressed to MBC with the appearance of the Q252H variant. The patient died in MBC after a bone marrow transplant. 12623848 PubMed Branford et al., 2003, Blood 3 accepted 2651 1024 4 9 133738356 133738356 G C ENST00000318560.5 75 GRCh37 Somatic 2020-07-24 22:34:31 UTC https://civicdb.org/links/evidence_items/2651 https://civicdb.org/links/variants/1024 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Q252H Cancer 162 Nilotinib,Dasatinib Substitutes Predictive Does Not Support D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the Q252H mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to dasatinib and nilotinib treatment (IC50: 62.3 nM and 895.5 nM) as compared to wild-type expressing Ba/F3 cells (IC50: 87.6 nM and 642.3 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 2653 1024 4 9 133738356 133738356 G C ENST00000318560.5 75 GRCh37 Somatic 2021-02-17 23:53:47 UTC https://civicdb.org/links/evidence_items/2653 https://civicdb.org/links/variants/1024 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253H Chronic Myeloid Leukemia 8552 Nilotinib,Imatinib Mesylate Substitutes Predictive Supports D Resistance In an in vitro study, a Ba/F3-p210BCR-ABL1 cell line was ENU-mutated and exposed to graded concentrations of imatinib, nilotinib or dasatinib to identify resistance mutations. The Y253H mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to 50nM nilotinib (14 clones recovered, ~30% of viable clones in this treatment), 500nM nilotinib (50 clones, ~63%), and 16 nM imatinib (16 clones; ~48%). Resistant clones were also found at 2, 4, and 8 μM imatinib. In a review of 20 publications, this mutation was described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 3 accepted 2654 1025 4 9 133738357 133738357 T C ENST00000318560.5 75 GRCh37 Somatic 2018-10-08 22:22:48 UTC https://civicdb.org/links/evidence_items/2654 https://civicdb.org/links/variants/1025 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253F Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports D Resistance A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The Y253F mutation was moderately resistant to imatinib. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 2 accepted 2655 1026 4 9 133738358 133738358 A T ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 16:34:30 UTC https://civicdb.org/links/evidence_items/2655 https://civicdb.org/links/variants/1026 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255V Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. An AP patient had a complete hematologic response. After 9 months of therapy, the patient progressed returning to chronic phase. Concurrently, the Y253F and E255V variants were found in ~50% and ~50% of BCR-ABL1 transcripts, respectively. Imatinib was withdrawn at 10 months and the patient died 14 months after treatment initiation. 12623848 PubMed Branford et al., 2003, Blood 3 accepted 2656 1173 4 9 133738364 133738364 A T ENST00000318560.5 75 GRCh37 Somatic 2020-07-10 23:47:29 UTC https://civicdb.org/links/evidence_items/2656 https://civicdb.org/links/variants/1173 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253F Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In two cell-based studies, a panel of either 18 or 16 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The Y253F mutation was moderately resistant to imatinib . 15930265 PubMed O'Hare et al., 2005, Cancer Res. accepted 2657 1026 4 9 133738358 133738358 A T ENST00000318560.5 75 GRCh37 Somatic 2017-05-19 16:49:28 UTC https://civicdb.org/links/evidence_items/2657 https://civicdb.org/links/variants/1026 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253F Cancer 162 Bafetinib,Dasatinib,Nilotinib Substitutes Predictive Does Not Support D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the Y253F mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to nilotinib, dasatinib, and bafetinib (INNO-406) treatment (IC50: 975.3 nM, 16.8 nM, and 490.8 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 642.3 nM, 87.6 nM, and 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 2658 1026 4 9 133738358 133738358 A T ENST00000318560.5 75 GRCh37 Somatic 2021-02-17 23:52:17 UTC https://civicdb.org/links/evidence_items/2658 https://civicdb.org/links/variants/1026 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports D Resistance A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The E255K mutation was resistant to imatinib. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 3 accepted 2659 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2017-07-25 16:32:03 UTC https://civicdb.org/links/evidence_items/2659 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A late-chronic phase patient had a complete hematologic response but progressed to partial hematologic response just before the detection of E255K variants. The patient died from disease progression. Three accelerated phase (AP) patients had complete hematologic responses but became resistant concurrently or just prior to detection of the E255K variant. They died from disease progression. A fourth AP patient had the M351T variant and required dose escalation. After the addition of chemotherapy, E255K and F359V variants arose. The patient returned to AP at which point E255K variants were the most prevalent. 12623848 PubMed Branford et al., 2003, Blood 4 accepted 2660 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2020-07-10 23:41:26 UTC https://civicdb.org/links/evidence_items/2660 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports D Resistance A panel of 16 mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and evaluated for anti-proliferative activity and substrate or auto-phosphorylation assays. The E255K mutation was resistant to imatinib (20-fold IC50 increase for the proliferation assay). 15930265 PubMed O'Hare et al., 2005, Cancer Res. 3 accepted 2661 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2017-07-25 16:32:15 UTC https://civicdb.org/links/evidence_items/2661 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Nilotinib Predictive Supports D Resistance In an in vitro study, Ba/F3 cell line stably expressing the E255K mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to nilotinib treatment (IC50: 6.69-fold), as compared to Ba/F3 cells expressing BCR-ABL1 fusion protein (reported to be sensitizing to nilotinib). Sensitivity was determined by assessing cell proliferation. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 2 accepted 2662 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2017-07-25 16:31:43 UTC https://civicdb.org/links/evidence_items/2662 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL D276G Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports D Resistance A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The D276G mutation was moderately resistant to imatinib. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 2 accepted 2663 1027 4 9 133747520 133747520 A G ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 16:34:07 UTC https://civicdb.org/links/evidence_items/2663 https://civicdb.org/links/variants/1027 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E355G Chronic Myeloid Leukemia 8552 Imatinib Predictive Does Not Support C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A CP patient had complete cytogenetic response until progressing to accelerated phase with concurrent detection of the E355G variant. After dose escalation, this patient achieved a major cytogenetic response with continued presence of E355G. Another CP patient had a major cytogenetic response to imatinib which was maintained after the detection of the E355G variant. 12623848 PubMed Branford et al., 2003, Blood 3 accepted 2664 1487 4 9 133748403 133748403 A G ENST00000318560.5 75 GRCh37 Somatic 2020-07-11 00:19:06 UTC https://civicdb.org/links/evidence_items/2664 https://civicdb.org/links/variants/1487 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL D276G Chronic Myeloid Leukemia 8552 Nilotinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line stably expressing the D276G mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with sensitivity to nilotinib treatment (IC50: 2.00-fold), as compared to Ba/F3 cells expressing BCR-ABL1 fusion protein (reported to be sensitizing to nilotinib). Sensitivity was determined by assessing cell proliferation. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 2 accepted 2666 1027 4 9 133747520 133747520 A G ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 16:39:42 UTC https://civicdb.org/links/evidence_items/2666 https://civicdb.org/links/variants/1027 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports D Resistance A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The T315I mutation was resistant to imatinib. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 4 accepted 2667 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2017-07-25 16:33:52 UTC https://civicdb.org/links/evidence_items/2667 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A late-chronic phase (CP) patient had major cytogenetic response until 11 months after therapy initiation when they acquired resistance. The T315I variant was present in ~25%, ~75%, and ~100% of transcripts at month 9, 11, and 16 months, respectively. An accelerated-phase patient had a complete cytogenetic response but progressed to leukemic blast crisis 9 months after therapy initiation when the T315I variant was present in 100% of transcripts. The patient died at 9.5 months. 12623848 PubMed Branford et al., 2003, Blood 3 accepted 2668 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2020-07-11 00:42:37 UTC https://civicdb.org/links/evidence_items/2668 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports D Resistance A panel of 16 mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and evaluated for anti-proliferative activity and substrate or auto-phosphorylation assays. The T315I mutation was resistant to imatinib (>25-fold IC50 increase for the proliferation assay). 15930265 PubMed O'Hare et al., 2005, Cancer Res. 4 accepted 2669 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2020-08-29 00:06:08 UTC https://civicdb.org/links/evidence_items/2669 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Nilotinib Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the T315I mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to nilotinib treatment (IC50: 39.41-fold), as compared to Ba/F3 cells expressing BCR-ABL1 fusion protein (reported to be sensitizing to nilotinib). Sensitivity was determined by assessing cell proliferation. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 4 accepted 2670 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2017-07-25 16:39:30 UTC https://civicdb.org/links/evidence_items/2670 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Cancer 162 Nilotinib,Bafetinib,Dasatinib,Imatinib Substitutes Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the T315I mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to nilotinib, imatinib, dasatinib, and bafetinib (INNO-406) treatment (IC50: > 2000.0 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 642.3 nM, 1712 nM, 87.6 nM and 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 2671 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2021-02-17 23:47:18 UTC https://civicdb.org/links/evidence_items/2671 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports D Resistance A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The F317L mutation was moderately resistant to imatinib. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 2 accepted 2674 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2017-07-25 16:32:59 UTC https://civicdb.org/links/evidence_items/2674 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A chronic phase (CP) patient had complete hematologic response. The F317L variant was present in ~100% of transcripts at 4 months and the patient progressed to myeloid blast crisis 3 months later. Imatinib was discontinued 9 months after initiation, and the patient went into remission after chemotherapy at month 19. 12623848 PubMed Branford et al., 2003, Blood 2 accepted 2675 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2020-07-11 00:38:27 UTC https://civicdb.org/links/evidence_items/2675 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In two cell-based studies, a panel of either 18 or 16 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The F317L mutation was moderately resistant to imatinib . 15930265 PubMed O'Hare et al., 2005, Cancer Res. accepted 2676 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2017-05-19 16:53:37 UTC https://civicdb.org/links/evidence_items/2676 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Cancer 162 Nilotinib,Bafetinib Substitutes Predictive Does Not Support D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the F317L mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to nilotinib and bafetinib treatment (IC50: 929.8 nM and 293.5 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 642.3 nM and 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 2677 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2021-02-17 23:45:13 UTC https://civicdb.org/links/evidence_items/2677 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL S417Y Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A late-chronic phase (CP) patient had a complete hematologic response but acquired resistance 7 months after therapy initiation. At month 11, the L248V, G250E, S417Y, E459K variants were present in approximately 25, 25, 25, and 50% of transcripts, respectively. The patient died in accelerated phase at month 14. 12623848 PubMed Branford et al., 2003, Blood 2 accepted 2679 1613 4 9 133750419 133750419 C A ENST00000318560.5 75 GRCh37 Somatic 2020-07-11 00:24:38 UTC https://civicdb.org/links/evidence_items/2679 https://civicdb.org/links/variants/1613 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In two cell-based studies, a panel of either 18 or 16 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The F317L mutation was moderately resistant to imatinib . 15930265 PubMed O'Hare et al., 2005, Cancer Res. accepted 2680 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2018-06-19 19:31:05 UTC https://civicdb.org/links/evidence_items/2680 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABCB1 5243 Overexpression Chronic Myeloid Leukemia 8552 Dasatinib,Bafetinib Substitutes Predictive Supports D Resistance The BCR-ABL1 expressing imatinib-resistant cell line K562/D1-9 overexpresses P-glycoprotein (ABCB1), a known drug membrane transporter. Bafetinib (INNO-406) and dasatinib showed drastically higher IC50 values (970.3 nM and 91nM) in K562/D1-9 than the non-resistant K562 cell line (24.7 nM and 1.5nM), suggesting resistance in the presence of ABCB1 overexpression. The authors state that Bafetinib resistance is likely attributable to it being substrates of P-glycoprotein while nilotinib, which is unlikely to be a P-glycoprotein substrate, had a smaller change in IC50 between the two cell lines. Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 2681 2915 4244 Somatic 2021-02-17 23:35:51 UTC https://civicdb.org/links/evidence_items/2681 https://civicdb.org/links/variants/2915 https://civicdb.org/links/genes/4244 false ABL1 25 BCR::ABL M351T Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports D Sensitivity/Response A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The M351T mutation was sensitive to imatinib. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 3 accepted 2682 1029 4 9 133748391 133748391 T C ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 16:33:39 UTC https://civicdb.org/links/evidence_items/2682 https://civicdb.org/links/variants/1029 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M351T Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. Three CP patients, with the M351T variants detected prior to resistance, had hematologic responses prior to progression. One patient became resistant after the appearance of the M351T variant but responded to dose escalation. The last patient, who also had the Q252H variant, progressed to myeloid blast crisis (MBC) after which there was cytogenetic evidence of a double Ph-chromosome and no detectable secondary variants. Three accelerated-phase (AP) patients returned to CP and had M351T variants. One of these patients also had E255K and F359V variants and progressed to AP. The remaining two, one of whom also had H396R variant, progressed to MBC and died. Two additional AP patients also had M351T variants but initially had CHRs. One who also had the G250E variant died from disease progression. The other also had the F359V variant progressed to MBC with cytogenetic evidence of the double Ph-chromosome and no detectable secondary variants at progression. 12623848 PubMed Branford et al., 2003, Blood 4 accepted 2683 1029 4 9 133748391 133748391 T C ENST00000318560.5 75 GRCh37 Somatic 2020-07-24 22:16:57 UTC https://civicdb.org/links/evidence_items/2683 https://civicdb.org/links/variants/1029 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M351T Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Sensitivity/Response In two cell-based studies, a panel of either 18 or 16 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The M351T mutation was sensitive to imatinib . 15930265 PubMed O'Hare et al., 2005, Cancer Res. accepted 2684 1029 4 9 133748391 133748391 T C ENST00000318560.5 75 GRCh37 Somatic 2017-05-22 02:13:48 UTC https://civicdb.org/links/evidence_items/2684 https://civicdb.org/links/variants/1029 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M351T Chronic Myeloid Leukemia 8552 Nilotinib Predictive Supports D Sensitivity/Response In an in vitro study, Ba/F3 cell line stably expressing the M351T mutation in the ABL1 portion of the BCR-ABL1 gene fusion was associated with sensitivity to nilotinib treatment (IC50: 0.44-fold), comparable to Ba/F3 cells expressing BCR-ABL1 fusion protein (reported to be sensitizing to nilotinib). Sensitivity was determined by assessing cell proliferation. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 3 accepted 2685 1029 4 9 133748391 133748391 T C ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 16:39:17 UTC https://civicdb.org/links/evidence_items/2685 https://civicdb.org/links/variants/1029 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M351T Cancer 162 Dasatinib,Nilotinib,Bafetinib Substitutes Predictive Does Not Support D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the M351T mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to nilotinib, dasatinib, and bafetinib treatment (IC50: 580.4 nM, 88 nM, 582.9 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 642.3 nM, 87.6 nM, 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 2686 1029 4 9 133748391 133748391 T C ENST00000318560.5 75 GRCh37 Somatic 2021-02-17 23:44:33 UTC https://civicdb.org/links/evidence_items/2686 https://civicdb.org/links/variants/1029 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL H396R Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports D Resistance A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The H396R mutation was resistant to imatinib. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 2 accepted 2687 1030 4 9 133750356 133750356 A G ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 16:33:25 UTC https://civicdb.org/links/evidence_items/2687 https://civicdb.org/links/variants/1030 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL H396R Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. An accelerated-phase patient had a return to chronic phase but progressed to myeloid blast crisis after 5 months of therapy. At that time, the M351T and H396R variants were detected in ~50% and ~25% of transcripts, respectively. At 10 months, the patient died. 12623848 PubMed Branford et al., 2003, Blood 2 accepted 2688 1030 4 9 133750356 133750356 A G ENST00000318560.5 75 GRCh37 Somatic 2020-07-24 22:58:11 UTC https://civicdb.org/links/evidence_items/2688 https://civicdb.org/links/variants/1030 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL H396R Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In two cell-based studies, a panel of either 18 or 16 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The H396R mutation was resistant to imatinib . 15930265 PubMed O'Hare et al., 2005, Cancer Res. accepted 2689 1030 4 9 133750356 133750356 A G ENST00000318560.5 75 GRCh37 Somatic 2017-05-22 02:15:19 UTC https://civicdb.org/links/evidence_items/2689 https://civicdb.org/links/variants/1030 https://civicdb.org/links/genes/4 false TP53 7157 Overexpression Ovarian Cancer 2394 Prognostic Supports B Poor Outcome p53 overexpression (>10% positive stained nuclei) was found in 110 cases from a 178 patient cohort with invasive ovarian carcinoma who had undergone surgery. Overexpression of p53 was correlated with poor differentiation (p<0.001) and high S-phase fraction (p<0.001). 11595686 PubMed Reles et al., 2001, Clin. Cancer Res. 3 accepted 2697 1306 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 N/A 2020-10-28 06:59:00 UTC https://civicdb.org/links/evidence_items/2697 https://civicdb.org/links/variants/1306 https://civicdb.org/links/genes/45 false TP53 7157 Y234C Ovarian Cancer 2394 Cisplatin,Carboplatin Substitutes Predictive Supports C Resistance Ovarian cancer patients with TP53 missense mutations were refractory to platinum-based chemotherapy (66% vs. 34% in wildtype, P=0.008) and had a shorter time to disease progression (n=54, P=0.037). A study of ovarian carcinoma patients (n=178) reported a reduced overall survival (HR:1.59, 95% CI:1.09-2.33, P=0.014) for patients with mutations in TP53. 11595686 PubMed Reles et al., 2001, Clin. Cancer Res. accepted 2745 1068 45 17 7577580 7577580 T C ENST00000269305.4 75 GRCh37 Somatic 2017-05-08 13:06:09 UTC https://civicdb.org/links/evidence_items/2745 https://civicdb.org/links/variants/1068 https://civicdb.org/links/genes/45 false TP53 7157 ALTERATION Ovarian Cancer 2394 Carboplatin,Cisplatin Substitutes Predictive Supports B Resistance In a group of patients with invasive ovarian carcinoma who had undergone surgery, a subset of 74 patients treated with platinum based chemotherapy were assessed for p53 alteration (p53 mutation or p53 overexpression by immunostaining >10% positive). Significant decreased time to progression (p=0.037) was seen in the subset of patients with p53 alteration (n=54) in comparison to the group with normatl p53 (n=20) 11595686 PubMed Reles et al., 2001, Clin. Cancer Res. 4 accepted 2771 1307 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 P53 ALTERATION is a bucket type variant used in studies which is constructed by combining all cases of p53 mutation together with p53 overexpression. This includes cases which have p53 mutation or overexpression alone or as well as cases where both occur in combination. Somatic 2017-09-08 22:17:18 UTC https://civicdb.org/links/evidence_items/2771 https://civicdb.org/links/variants/1307 https://civicdb.org/links/genes/45 false TP53 7157 DNA Binding Domain Mutation Breast Cancer 1612 Tamoxifen Predictive Supports B Resistance In a study 202 breast cancer patients undergoing first line tamoxifen treatment, 65 patients had mutations in TP53. Among the p53 wild type population a 66% response rate was reported, where response was considered as complete response, partial response or stable disease. In a patient subgroup with mutations in p53 amino acids that directly interact with DNA, 2 of 11 (18%) of patients responded to tamoxifen. 10786679 PubMed Berns et al., 2000, Cancer Res. 3 accepted 2783 242 45 17 7577149 7578443 ENST00000269305.4 75 GRCh37 Somatic 2017-08-15 21:22:21 UTC https://civicdb.org/links/evidence_items/2783 https://civicdb.org/links/variants/242 https://civicdb.org/links/genes/45 false TP53 7157 Mutation Breast Cancer 1612 Tamoxifen Predictive Supports C Resistance In a study 202 breast cancer patients undergoing tamoxifen treatment, a higher frequency of wildtype TP53 patients responded to treatment compared to those with mutations in TP53 (66% wild-type vs. 31%, odds ratio (OR):0.22, 95CI:0.12-0.42, P<0.0001, univariate analysis; OR:0.29, 95% CI:0.12-0.42, P=0.0014, multivariate analysis). The median survival after start of therapy was shorter in patients with mutations in TP53 than for patients with wild-type TP53 (20mo vs. 29mo, HR:1.99,95% CI:1.43-2.75, P<0.001). Breast cancer patients with TP53 mutations also had a decrease in progression-free survival (HR:2.61, 95% CI:1.90-3.6, P<0.001). 10786679 PubMed Berns et al., 2000, Cancer Res. 1 accepted 2784 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2017-05-18 17:24:13 UTC https://civicdb.org/links/evidence_items/2784 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false TP53 7157 Overexpression Stomach Cancer 10534 Mitomycin,Cisplatin,Etoposide Combination Predictive Supports B Sensitivity/Response In a Phase II trial of 25 patients with metastaic gastric cancer, patients received preoperative high dose chemotherapy (HDCT) consisting of etoposide, cisplatin and mitomycin. Patients with greater than 50% regression in response to HDCT received surgery. TP53 overexpression was assayed by immunohistochemistry. 14 patients showed p53 overexpression, and 12 of these qualified for resection. Overall survival in patients with p53 overexpression was 17.3 months in contrast to patients with negative p53 immunohistochemistry, where it was 7.2 months (p=0.0003). 14514923 PubMed Bataille et al., 2003, MP, Mol. Pathol. 4 accepted 2799 1306 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 N/A 2020-10-28 06:59:29 UTC https://civicdb.org/links/evidence_items/2799 https://civicdb.org/links/variants/1306 https://civicdb.org/links/genes/45 false TP53 7157 R282L Stomach Carcinoma 5517 EAP Protocol Predictive Supports C Sensitivity/Response In a study of 25 patients with advanced gastric cancer, mutations in TP53 were identified in 32% of primary tumors. TP53 mutations were associated with an improved response to preoperative treatment of a modified EAP protocol (combination of doxorubicin, etoposide and cisplatin). Patients with mutations in TP53 had an increased median survival compared to patients with wildtype TP53 (18.5mo vs. 10.2mo, P=0.044). 14514923 PubMed Bataille et al., 2003, MP, Mol. Pathol. accepted 2818 1108 45 17 7577093 7577093 C A ENST00000269305.4 75 GRCh37 Somatic 2017-05-15 07:28:14 UTC https://civicdb.org/links/evidence_items/2818 https://civicdb.org/links/variants/1108 https://civicdb.org/links/genes/45 false TP53 7157 R213P Stomach Carcinoma 5517 EAP Protocol Predictive Supports C Sensitivity/Response In a study of 25 patients with advanced gastric cancer, mutations in TP53 were identified in 32% of primary tumors. TP53 mutations were associated with an improved response to preoperative treatment of a modified EAP protocol (combination of doxorubicin, etoposide and cisplatin). Patients with mutations in TP53 had an increased median survival compared to patients with wildtype TP53 (18.5mo vs. 10.2mo, P=0.044). 14514923 PubMed Bataille et al., 2003, MP, Mol. Pathol. accepted 2819 1109 45 17 7578211 7578211 C G ENST00000269305.4 75 GRCh37 Somatic 2017-05-15 07:16:14 UTC https://civicdb.org/links/evidence_items/2819 https://civicdb.org/links/variants/1109 https://civicdb.org/links/genes/45 false TP53 7157 Mutation Stomach Carcinoma 5517 Etoposide,Doxorubicin,Cisplatin Combination Predictive Supports C Sensitivity/Response In a study of 25 patients with advanced gastric cancer, mutations in TP53 were identified in 32% of primary tumors. TP53 mutations were associated with an improved response to preoperative treatment of a modified EAP protocol (combination of doxorubicin, etoposide and cisplatin). Patients with mutations in TP53 had an increased median survival compared to patients with wildtype TP53 (18.5mo vs. 10.2mo, P=0.044). 14514923 PubMed Bataille et al., 2003, MP, Mol. Pathol. 1 accepted 2820 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2019-08-19 03:00:46 UTC https://civicdb.org/links/evidence_items/2820 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false ABL1 25 BCR::ABL F486S Chronic Myeloid Leukemia 8552 Nilotinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line stably expressing the F486S mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with sensitivity to nilotinib treatment (IC50: 1.85-fold), comparable to Ba/F3 cells expressing BCR-ABL fusion protein. Sensitivity was determined by assessing cell proliferation. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 3 accepted 2829 1152 4 9 133755488 133755488 T C ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 16:38:59 UTC https://civicdb.org/links/evidence_items/2829 https://civicdb.org/links/variants/1152 https://civicdb.org/links/genes/4 false ATM 472 c.7089+1del Chronic Lymphocytic Leukemia 1040 Doxorubicin Predictive Supports D Resistance Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the c.7089+1del variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the c.7089+1del variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 98% of cells by FISH. Western blot showed stable ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. 23585524 PubMed Navrkalova et al., 2013, Haematologica 3 accepted 2830 3050 69 Somatic 2020-05-11 04:51:47 UTC https://civicdb.org/links/evidence_items/2830 https://civicdb.org/links/variants/3050 https://civicdb.org/links/genes/69 false ATM 472 c.7515+1_2del Chronic Lymphocytic Leukemia 1040 Doxorubicin Predictive Supports D Resistance Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the c.7515+1_2del variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the c.7515+1_2del variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 95% of cells by FISH. Western blot showed null ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. 23585524 PubMed Navrkalova et al., 2013, Haematologica 3 accepted 2831 3051 69 Somatic 2020-05-11 04:59:35 UTC https://civicdb.org/links/evidence_items/2831 https://civicdb.org/links/variants/3051 https://civicdb.org/links/genes/69 false ATM 472 K293* Chronic Lymphocytic Leukemia 1040 Doxorubicin Predictive Supports D Resistance Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the K293* variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the K293* variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 92% of cells by FISH. Western blot showed null ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. 23585524 PubMed Navrkalova et al., 2013, Haematologica 3 accepted 2832 1155 69 11 108115729 108115729 A T ENST00000278616.4 75 GRCh37 Somatic 2020-05-11 03:14:25 UTC https://civicdb.org/links/evidence_items/2832 https://civicdb.org/links/variants/1155 https://civicdb.org/links/genes/69 false ATM 472 F1025L Chronic Lymphocytic Leukemia 1040 Doxorubicin Predictive Supports D Resistance Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the F1025L variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the F1025L variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 93% of cells by FISH. Western blot showed stable ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. 23585524 PubMed Navrkalova et al., 2013, Haematologica 3 accepted 2835 1158 69 11 108142131 108142131 T G ENST00000278616.4 75 GRCh37 Somatic 2020-05-11 03:16:14 UTC https://civicdb.org/links/evidence_items/2835 https://civicdb.org/links/variants/1158 https://civicdb.org/links/genes/69 false ATM 472 D1930V Chronic Lymphocytic Leukemia 1040 Doxorubicin Predictive Supports D Resistance Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the D1930V variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the D1930V variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 88% of cells by FISH. Western blot showed null ATM expression. Treatment with doxorubicin resulted in p21 expression greater than 300% that of untreated wild-type controls. This was considered by the authors to be similar to treated wild-type controls with a median expression level 815% that of untreated controls suggesting this variant does not support resistance. 23585524 PubMed Navrkalova et al., 2013, Haematologica 2 accepted 2837 1160 69 11 108180913 108180913 A T ENST00000278616.4 75 GRCh37 Somatic 2020-05-11 05:17:57 UTC https://civicdb.org/links/evidence_items/2837 https://civicdb.org/links/variants/1160 https://civicdb.org/links/genes/69 false ATM 472 E2187* Chronic Lymphocytic Leukemia 1040 Doxorubicin Predictive Supports D Resistance Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the E2187* variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the E2187* variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 96% of cells by FISH. Western blot showed null ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. 23585524 PubMed Navrkalova et al., 2013, Haematologica 3 accepted 2839 1162 69 11 108192134 108192134 G T ENST00000278616.4 75 GRCh37 Somatic 2020-05-11 03:17:36 UTC https://civicdb.org/links/evidence_items/2839 https://civicdb.org/links/variants/1162 https://civicdb.org/links/genes/69 false ATM 472 L2427P Chronic Lymphocytic Leukemia 1040 Doxorubicin Predictive Supports D Resistance Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the L2427P variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the L2427P variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 94% of cells by FISH. Western blot showed stable ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. 23585524 PubMed Navrkalova et al., 2013, Haematologica 3 accepted 2840 1163 69 11 108199938 108199938 T C ENST00000278616.4 75 GRCh37 Unknown 2020-05-11 03:22:43 UTC https://civicdb.org/links/evidence_items/2840 https://civicdb.org/links/variants/1163 https://civicdb.org/links/genes/69 false ATM 472 F2732V Chronic Lymphocytic Leukemia 1040 Doxorubicin Predictive Supports D Resistance Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the F2732V variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the F2732V variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 98% of cells by FISH. Western blot showed stable ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. 23585524 PubMed Navrkalova et al., 2013, Haematologica 3 accepted 2841 1164 69 11 108206614 108206614 T G ENST00000278616.4 75 GRCh37 Somatic 2020-05-11 03:24:36 UTC https://civicdb.org/links/evidence_items/2841 https://civicdb.org/links/variants/1164 https://civicdb.org/links/genes/69 false ATM 472 K468FS Chronic Lymphocytic Leukemia 1040 Doxorubicin Predictive Does Not Support D Resistance Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the K468FS variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the K468FS variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 91% of cells by FISH. Western blot showed null ATM expression. Treatment with doxorubicin resulted in p21 expression greater than 300% that of untreated wild-type controls. This was considered by the authors to be similar to treated wild-type controls with a median expression level 815% that of untreated controls suggesting this variant does not support resistance. 23585524 PubMed Navrkalova et al., 2013, Haematologica 2 accepted 2843 1166 69 11 108121594 108121595 AA ENST00000278616.4 75 GRCh37 Somatic 2020-05-11 05:30:55 UTC https://civicdb.org/links/evidence_items/2843 https://civicdb.org/links/variants/1166 https://civicdb.org/links/genes/69 false ATM 472 D1682H Chronic Lymphocytic Leukemia 1040 Doxorubicin Predictive Supports D Resistance Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the D1682H variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the D1682H variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 93% of cells by FISH. Western blot showed stable ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. 23585524 PubMed Navrkalova et al., 2013, Haematologica 3 accepted 2845 1168 69 11 108170479 108170479 G C ENST00000278616.4 75 GRCh37 Somatic 2020-05-11 03:29:23 UTC https://civicdb.org/links/evidence_items/2845 https://civicdb.org/links/variants/1168 https://civicdb.org/links/genes/69 false ATM 472 A2062V Chronic Lymphocytic Leukemia 1040 Doxorubicin Predictive Supports D Resistance Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the A2062V variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the A2062V variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 87% of cells by FISH. Western blot showed stable ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. 23585524 PubMed Navrkalova et al., 2013, Haematologica 3 accepted 2846 1169 69 11 108186827 108186827 C T ENST00000278616.4 75 GRCh37 Somatic 2020-05-11 03:30:45 UTC https://civicdb.org/links/evidence_items/2846 https://civicdb.org/links/variants/1169 https://civicdb.org/links/genes/69 false ATM 472 C2488Y Chronic Lymphocytic Leukemia 1040 Doxorubicin Predictive Supports D Resistance Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the C2488Y variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the C2488Y variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 90% of cells by FISH. Western blot showed stable ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. 23585524 PubMed Navrkalova et al., 2013, Haematologica 3 accepted 2849 1172 69 11 108201096 108201096 G A ENST00000278616.4 75 GRCh37 Rare Germline 2020-05-11 03:43:13 UTC https://civicdb.org/links/evidence_items/2849 https://civicdb.org/links/variants/1172 https://civicdb.org/links/genes/69 false ABL1 25 BCR::ABL E255V Chronic Myeloid Leukemia 8552 Nilotinib Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the E255V mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to nilotinib treatment (IC50: 10.31-fold), as compared to Ba/F3 cells expressing BCR-ABL1 fusion protein. Sensitivity was determined by assessing cell proliferation. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 3 accepted 2850 1173 4 9 133738364 133738364 A T ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 16:35:50 UTC https://civicdb.org/links/evidence_items/2850 https://civicdb.org/links/variants/1173 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255V Chronic Myeloid Leukemia 8552 Nilotinib,Imatinib Mesylate Substitutes Predictive Supports D Resistance In an in vitro study, a Ba/F3-p210BCR-ABL1 cell line was ENU-mutated and exposed to graded concentrations of imatinib, nilotinib or dasatinib to identify resistance mutations. The E255V mutation in the ABL1 portion of the BCR-ABL1 fusion protein was identified and associated with resistance to imatinib (1 clone, 0.43% of viable clones in this treatment, recovered in 4 μM but none at 2, 8, or 16 μM) and nilotinib (1 clone, 1.25%, recovered at 500nM but none at 50, 2000 or 5000nM). In a review of 20 publications, this mutation was described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 2851 1173 4 9 133738364 133738364 A T ENST00000318560.5 75 GRCh37 Somatic 2018-10-08 22:10:49 UTC https://civicdb.org/links/evidence_items/2851 https://civicdb.org/links/variants/1173 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E292V Chronic Myeloid Leukemia 8552 Nilotinib Predictive Supports D Resistance In an in vitro study, a Ba/F3-p210BCR-ABL1 cell line was ENU-mutated and exposed to graded concentrations of imatinib, nilotinib or dasatinib. The E292V mutation in the ABL1 portion of the BCR-ABL1 fusion protein was identified and associated with resistance to nilotinib treatment (1 clone recovered at 50nM). In a review of 20 publications, this mutation was not previously described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 2853 1183 4 9 133747568 133747568 A T ENST00000318560.5 75 GRCh37 Somatic 2018-10-08 22:12:58 UTC https://civicdb.org/links/evidence_items/2853 https://civicdb.org/links/variants/1183 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359C Chronic Myeloid Leukemia 8552 Nilotinib,Imatinib Mesylate Substitutes Predictive Supports D Resistance In an in vitro study, a Ba/F3-p210BCR-ABL1 cell line was ENU-mutated and exposed to graded concentrations of imatinib, nilotinib or dasatinib to identify resistance mutations. The F359C mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to 50nM nilotinib (6 clones recovered, ~13% of viable clones in this treatment) and 2 μM imatinib (6 clones, ~4%). In a review of 20 publications, this mutation was described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 2854 1184 4 9 133748415 133748415 T G ENST00000318560.5 75 GRCh37 Somatic 2018-10-08 22:18:19 UTC https://civicdb.org/links/evidence_items/2854 https://civicdb.org/links/variants/1184 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L384M Chronic Myeloid Leukemia 8552 Nilotinib,Imatinib Mesylate Substitutes Predictive Supports D Resistance In an in vitro study, a Ba/F3-p210BCR-ABL1 cell line was ENU-mutated and exposed to graded concentrations of imatinib, nilotinib or dasatinib to identify resistance mutations. The L384M mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance in 50nM nilotinib (1 clone recovered, ~2% of viable clones in this treatment) and 2 μM imatinib (1 clone, ~0.7%). L384M was one of 3 novel mutations that were not identified in imatinib resistant patients from a review of 20 publications. 16772610 PubMed Bradeen et al., 2006, Blood 1 accepted 2861 1230 4 9 133750319 133750319 C A ENST00000318560.5 75 GRCh37 Somatic 2018-10-08 22:00:28 UTC https://civicdb.org/links/evidence_items/2861 https://civicdb.org/links/variants/1230 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL V299L Chronic Myeloid Leukemia 8552 Nilotinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line stably expressing the V299L mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with sensitivity to nilotinib treatment (IC50: 1.34-fold), comparable to Ba/F3 cells expressing BCR-ABL1 fusion protein. Sensitivity was determined by assessing cell proliferation. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 3 accepted 2862 1231 4 9 133747588 133747588 G C ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 16:36:17 UTC https://civicdb.org/links/evidence_items/2862 https://civicdb.org/links/variants/1231 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L387F Chronic Myeloid Leukemia 8552 Nilotinib Predictive Supports D Resistance In an in vitro study, a Ba/F3-p210BCR-ABL1 cell line was ENU-mutated and exposed to graded concentrations of imatinib, nilotinib or dasatinib. The L387F mutation in the ABL1 portion of the BCR-ABL1 fusion protein was identified and associated with resistance to nilotinib treatment (1 clone recovered at 50nM). 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 2863 1232 4 9 133750330 133750330 G C ENST00000318560.5 75 GRCh37 Somatic 2018-10-08 22:01:53 UTC https://civicdb.org/links/evidence_items/2863 https://civicdb.org/links/variants/1232 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G398R Chronic Myeloid Leukemia 8552 Nilotinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line stably expressing the G398R mutation in the ABL1 portion of the BCR-ABL1 gene fusion was associated with sensitivity to nilotinib treatment (IC50: 0.49-fold), comparable to Ba/F3 cells expressing BCR-ABL1 fusion protein (reported to be sensitizing to nilotinib). Sensitivity was determined by assessing cell proliferation. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 3 accepted 2864 1233 4 9 133750361 133750361 G C ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 16:36:03 UTC https://civicdb.org/links/evidence_items/2864 https://civicdb.org/links/variants/1233 https://civicdb.org/links/genes/4 false PIK3CA 5290 K111N Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Emtansine Predictive Does Not Support D Resistance As part of a pre-clinical experiment, the efficacy of ado-trastuzumab emtansine (T-DM1) was evaluated against various HER2 positive cell lines. BT-474 cell line expressing PIK3CA K111N was associated with similar sensitivity to T-DM1 as PIK3CA wild-type cell line SK-BR-3; reduced cell viability was observed at concentrations > 0.01 ug/mL in both cell lines. Conversely, when treated with trastuzumab, the cell line harboring PIK3CA K111N experienced a smaller reduction in cell viability. Further, treatment with T-DM1 on SCID mice xenografted with PIK3CA K111N cells resulted in inhibition of tumor growth. A single dose of T-DM1 >5mg/kg was sufficient to induce tumor regression >20 days after administration. 26920887 PubMed Baselga et al., 2016, Clin. Cancer Res. 3 accepted 2866 1234 37 3 178916946 178916946 G C ENST00000263967.3 75 GRCh37 Somatic 2020-08-14 20:32:04 UTC https://civicdb.org/links/evidence_items/2866 https://civicdb.org/links/variants/1234 https://civicdb.org/links/genes/37 false PIK3CA 5290 I391M Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Emtansine Predictive Does Not Support D Resistance As part of a pre-clinical experiment, the efficacy of ado-trastuzumab emtansine (T-DM1) was evaluated against various HER2 positive cell lines. ZR-75-30 cell line expressing PIK3CA I391M was associated with similar sensitivity to T-DM1 as PIK3CA wild-type cell line SK-BR-3; reduced cell viability was observed at concentrations > 0.01 ug/mL in both cell lines. When treated with trastuzumab, the cell line harboring PIK3CA I391M experienced similar reduction in cell viability. 26920887 PubMed Baselga et al., 2016, Clin. Cancer Res. 3 accepted 2867 1235 37 3 178927410 178927410 A G ENST00000263967.3 75 GRCh37 Somatic 2020-08-14 20:48:09 UTC https://civicdb.org/links/evidence_items/2867 https://civicdb.org/links/variants/1235 https://civicdb.org/links/genes/37 false BRCA2 675 Mutation Ovarian Cancer 2394 Rucaparib Predictive Supports B Sensitivity/Response A phase 2 trial on patients with relapsed, platinum-sensitive high grade ovarian, fallopian tube or primary peritoneal carcinoma (ARIEL2 Part1, NCT01891344) was held to assess PARP inhibitor rucaparib on 3 genetically defined subsets of patients. Out of 40 BRCA (BRCA1 or BRCA2) mutant patients, 5 had somatic BRCA2 mutation, 4 of which were homozygous mutations and one had unknown zygosity. Confirmed objective response was seen in 80% (4/5) of the somatic BRCA2 mutant subgroup. Authors note that response rate was similar regardless of whether the BRCA mutation was somatic or germline, in BRCA 1 or BRCA 2. In a BRCA wild-type subgroup, with low levels of loss of heterozygosity (LOH), confirmed objective response was observed in 10% (7/70) of the patients. Patients with BRCA mutant tumors experienced significantly longer median progression free survival than patients with BRCA wildtype, LOH low tumors (12.8 vs 5.2 mo, HR: 0.27, P<0.0001). 27908594 PubMed Swisher et al., 2017, Lancet Oncol. NCT01891344 2 accepted 2868 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Somatic 2020-08-27 23:26:46 UTC https://civicdb.org/links/evidence_items/2868 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false BRCA1 672 Q1467* Ovarian Cancer 2394 Rucaparib Predictive Supports C Sensitivity/Response In a phase 2 study of 206 recurrent, platinum-sensitive, high-grade ovarian cancer patients, patients with germline or somatic BRCA1 or BRCA2 mutation (n=40) were associated with improved progression free survival (HR 0.27, 95% CI: 0.16-0.44, p<0.0001) as compared to BRCA1/2 wild-type, loss of heterozygosity low patients (n=71) treated with rucaparib monotherapy; further, BRCA1/2 mutation patients achieved a longer median duration of response (9.2 months, 95% CI: 6.4-12.9, p=0.013 vs. 5.6 months, 95% CI: 4.6-8.5). 27908594 PubMed Swisher et al., 2017, Lancet Oncol. NCT01891344 accepted 2878 1246 6 17 41228590 41228590 G A ENST00000357654.3 75 GRCh37 Somatic 2020-12-18 19:05:47 UTC https://civicdb.org/links/evidence_items/2878 https://civicdb.org/links/variants/1246 https://civicdb.org/links/genes/6 false BRCA2 675 M1R Ovarian Cancer 2394 Rucaparib Predictive Supports C Sensitivity/Response In a phase 2 study of 206 recurrent, platinum-sensitive, high-grade ovarian cancer patients, patients with germline or somatic BRCA1 or BRCA2 mutation (n=40) were associated with improved progression free survival (HR 0.27, 95% CI: 0.16-0.44, p<0.0001) as compared to BRCA1/2 wild-type, loss of heterozygosity low patients (n=71) treated with rucaparib monotherapy; further, BRCA1/2 mutation patients achieved a longer median duration of response (9.2 months, 95% CI: 6.4-12.9, p=0.013 vs. 5.6 months, 95% CI: 4.6-8.5). 27908594 PubMed Swisher et al., 2017, Lancet Oncol. NCT01891344 accepted 2879 1247 7 13 32890599 32890599 T G ENST00000544455.1 GRCh37 Somatic 2020-12-18 19:06:12 UTC https://civicdb.org/links/evidence_items/2879 https://civicdb.org/links/variants/1247 https://civicdb.org/links/genes/7 false BRCA2 675 M1I Ovarian Cancer 2394 Rucaparib Predictive Supports C Sensitivity/Response In a phase 2 study of 206 recurrent, platinum-sensitive, high-grade ovarian cancer patients, patients with germline or somatic BRCA1 or BRCA2 mutation (n=40) were associated with improved progression free survival (HR 0.27, 95% CI: 0.16-0.44, p<0.0001) as compared to BRCA1/2 wild-type, loss of heterozygosity low patients (n=71) treated with rucaparib monotherapy; further, BRCA1/2 mutation patients achieved a longer median duration of response (9.2 months, 95% CI: 6.4-12.9, p=0.013 vs. 5.6 months, 95% CI: 4.6-8.5). 27908594 PubMed Swisher et al., 2017, Lancet Oncol. NCT01891344 accepted 2880 1248 7 13 32890600 32890600 G T ENST00000544455.1 75 GRCh37 Somatic 2020-12-18 19:06:35 UTC https://civicdb.org/links/evidence_items/2880 https://civicdb.org/links/variants/1248 https://civicdb.org/links/genes/7 false BRCA2 675 V159M Ovarian Cancer 2394 Rucaparib Predictive Supports C Sensitivity/Response In a phase 2 study of 206 recurrent, platinum-sensitive, high-grade ovarian cancer patients, patients with germline or somatic BRCA1 or BRCA2 mutation (n=40) were associated with improved progression free survival (HR 0.27, 95% CI: 0.16-0.44, p<0.0001) as compared to BRCA1/2 wild-type, loss of heterozygosity low patients (n=71) treated with rucaparib monotherapy; further, BRCA1/2 mutation patients achieved a longer median duration of response (9.2 months, 95% CI: 6.4-12.9, p=0.013 vs. 5.6 months, 95% CI: 4.6-8.5). 27908594 PubMed Swisher et al., 2017, Lancet Oncol. NCT01891344 accepted 2881 1249 7 13 32900287 32900287 G A ENST00000544455.1 75 GRCh37 Somatic 2020-12-18 19:06:56 UTC https://civicdb.org/links/evidence_items/2881 https://civicdb.org/links/variants/1249 https://civicdb.org/links/genes/7 false BRCA2 675 V211L Ovarian Cancer 2394 Rucaparib Predictive Supports C Sensitivity/Response In a phase 2 study of 206 recurrent, platinum-sensitive, high-grade ovarian cancer patients, patients with germline or somatic BRCA1 or BRCA2 mutation (n=40) were associated with improved progression free survival (HR 0.27, 95% CI: 0.16-0.44, p<0.0001) as compared to BRCA1/2 wild-type, loss of heterozygosity low patients (n=71) treated with rucaparib monotherapy; further, BRCA1/2 mutation patients achieved a longer median duration of response (9.2 months, 95% CI: 6.4-12.9, p=0.013 vs. 5.6 months, 95% CI: 4.6-8.5). 27908594 PubMed Swisher et al., 2017, Lancet Oncol. NCT01891344 accepted 2882 1250 7 13 32900751 32900751 G C GRCh37 Somatic 2020-12-18 19:07:09 UTC https://civicdb.org/links/evidence_items/2882 https://civicdb.org/links/variants/1250 https://civicdb.org/links/genes/7 false BRCA2 675 V211I Ovarian Cancer 2394 Rucaparib Predictive Supports C Sensitivity/Response In a phase 2 study of 206 recurrent, platinum-sensitive, high-grade ovarian cancer patients, patients with germline or somatic BRCA1 or BRCA2 mutation (n=40) were associated with improved progression free survival (HR 0.27, 95% CI: 0.16-0.44, p<0.0001) as compared to BRCA1/2 wild-type, loss of heterozygosity low patients (n=71) treated with rucaparib monotherapy; further, BRCA1/2 mutation patients achieved a longer median duration of response (9.2 months, 95% CI: 6.4-12.9, p=0.013 vs. 5.6 months, 95% CI: 4.6-8.5). 27908594 PubMed Swisher et al., 2017, Lancet Oncol. NCT01891344 accepted 2883 1251 7 13 32900751 32900751 G A GRCh37 Somatic 2020-12-18 19:07:21 UTC https://civicdb.org/links/evidence_items/2883 https://civicdb.org/links/variants/1251 https://civicdb.org/links/genes/7 false BRCA2 675 R2336P Ovarian Cancer 2394 Rucaparib Predictive Supports C Sensitivity/Response In a phase 2 study of 206 recurrent, platinum-sensitive, high-grade ovarian cancer patients, patients with germline or somatic BRCA1 or BRCA2 mutation (n=40) were associated with improved progression free survival (HR 0.27, 95% CI: 0.16-0.44, p<0.0001) as compared to BRCA1/2 wild-type, loss of heterozygosity low patients (n=71) treated with rucaparib monotherapy; further, BRCA1/2 mutation patients achieved a longer median duration of response (9.2 months, 95% CI: 6.4-12.9, p=0.013 vs. 5.6 months, 95% CI: 4.6-8.5). 27908594 PubMed Swisher et al., 2017, Lancet Oncol. NCT01891344 accepted 2884 1252 7 13 32921033 32921033 G C ENST00000544455.1 75 GRCh37 Somatic 2020-12-18 19:07:42 UTC https://civicdb.org/links/evidence_items/2884 https://civicdb.org/links/variants/1252 https://civicdb.org/links/genes/7 false KIT 3815 D820Y Melanoma 1909 Imatinib Predictive Supports C Resistance FFPE tumor specimens from 295 melanoma patients were screened for KIT amplification and mutation. Of these, 51 patients had variants in KIT and 28 of these were treated with imatinib mesylate at 400 mg orally, twice daily with 25 patients eligible for response evaluation. None of the patients had mutations in BRAF, NRAS, or GNAQ. Two patients achieved a durable complete response, two achieved a durable partial response, and 5 achieved stable disease >12 weeks with a median survival of 46.3 weeks. One patient harboring a somatic D820Y mutation at roughly 50% variant allele frequency (1:1 with wild type) displayed Imatinib mesylate–resistance and disease progression, which is consistent with resistant mechanisms described in Gastro-Intestinal Stromal Tumors. 21642685 PubMed Carvajal et al., 2011, JAMA NCT00470470 3 accepted 2886 986 29 4 55599332 55599332 G T ENST00000288135.5 75 GRCh37 Somatic 2017-05-11 15:03:21 UTC https://civicdb.org/links/evidence_items/2886 https://civicdb.org/links/variants/986 https://civicdb.org/links/genes/29 false KIT 3815 D820Y Melanoma 1909 Sunitinib Predictive Supports D Sensitivity/Response 28 acral or mucosal melanomas were examined for KIT expression and mutations (exons 11, 13, 17, and 18). Two of 19 melanomas examined harbored KIT mutations, with one subject harboring a D820Y mutation. Western blotting showed KIT phosphorylation (Y219) in this case and the SM3 cell line harboring the D820Y mutation. The SM3 cell line showed significant growth inhibition with sunitinib exposures of 1uM and 10uM while imatinib showed no activity. The authors comment that this indicates a potential role for sunitinib in growth inhibition of acral melanomas. 19035443 PubMed Ashida et al., 2009, Int. J. Cancer 2 accepted 2888 986 29 4 55599332 55599332 G T ENST00000288135.5 75 GRCh37 Somatic 2020-12-16 19:40:12 UTC https://civicdb.org/links/evidence_items/2888 https://civicdb.org/links/variants/986 https://civicdb.org/links/genes/29 false KIT 3815 K642E Mucosal Melanoma 0050929 Imatinib Predictive Supports C Sensitivity/Response A 69 y.o. woman presented with metastatic mucosal melanoma of the anus. KIT was amplified in the tumor and harbored the K642E mutation. Post surgery with extensive margins, she was given a dose of anti-CTLA-4 antibody and adjuvant radiation therapy for 2.5 weeks. Two weeks post radiation she developed nodules in the same region and testing indicated they were malignant melanoma with high KIT expression. She enrolled in a clinical trial with a dose of 400mg imatinib per day (Nov 2006). Less than 4 weeks later, all nodules had disappeared. Upon a lowered dosage to 200mg of imatinib, the nodules returned and subsequently the dosage was increased to 600mg/day. The patient remained melanoma-free on 600mg imatinib until a follow up in Jan 2008. The authors do not provide further details on patient outcome. 18510589 PubMed Lutzky et al., 2008, Pigment Cell Melanoma Res 2 accepted 2889 978 29 4 55594221 55594221 A G ENST00000288135.5 75 GRCh37 Somatic 2019-11-22 11:31:41 UTC https://civicdb.org/links/evidence_items/2889 https://civicdb.org/links/variants/978 https://civicdb.org/links/genes/29 false GNAS 2778 c.393T>C Bladder Urothelial Carcinoma 4006 Prognostic Supports B Better Outcome This study demostrated that the progression-free survival, metastasis-free survival, and cancer-specific survival was significantly increased in patients with T393 homozygosity i.e. TT genotypes (56%, 84%, 82%) compared with CC genotypes (35%, 53%, 58%). In multivariate Cox proportional hazard analysis, the T393C polymorphism was an independent prognostic factor for clinical outcome. Homozygous CC patients were at highest risk for progression [odds ratio (OR), 1.94; P = 0.020], metastasis (OR, 3.49; P = 0.005), and tumor-related death (OR, 2.49; P = 0.031) compared with TT genotypes. 15824158 PubMed Frey et al., 2005, Cancer Epidemiol. Biomarkers Prev. 4 accepted 2892 877 2319 20 57428713 57428713 T C ENST00000371100.4 75 GRCh37 Common Germline 2017-05-11 15:47:25 UTC https://civicdb.org/links/evidence_items/2892 https://civicdb.org/links/variants/877 https://civicdb.org/links/genes/2319 false GNAS 2778 c.393T>C Colorectal Cancer 9256 Prognostic Supports B Better Outcome In a retrospective study of 151 patients with sporadic colorectal cancer, 5-year survival rate was significantly higher in patients with International Union Against Cancer (UICC) stages I to II (mean follow-up, 43 months) and the GNAS1 T393C polymorphism-associated TT genotypes (87.8%) compared with TC (71.0%) and CC genotypes (50.0%; P = 0.009). No genotype effect could be observed for UICC stages III to IV. In multivariate Cox proportional analysis the T393C polymorphism was an independent prognostic factor for survival. Compatible with a gene-dose effect, homozygous CC patients were at highest risk for death (hazard ratio, 12.1; P = 0.006) compared with TT genotypes and heterozygous patients had an intermediate risk. 16033819 PubMed Frey et al., 2005, Clin. Cancer Res. 4 accepted 2893 877 2319 20 57428713 57428713 T C ENST00000371100.4 75 GRCh37 Common Germline 2017-05-11 15:43:07 UTC https://civicdb.org/links/evidence_items/2893 https://civicdb.org/links/variants/877 https://civicdb.org/links/genes/2319 false GNAS 2778 c.393T>C Esophageal Cancer 5041 Cisplatin,Fluorouracil Combination Predictive Supports B Resistance Overall, 63% of the patients in the T-allele group (TT + CT), i.e with the T393C genotype, were minor responders with more than 10% residual vital tumor cells in resection specimens, whereas T(-) genotypes (CC) showed a major histopathological response with less than 10% residual vital tumor cells in 80%. 19274060 PubMed Alakus et al., 2009, Pharmacogenomics J. 4 accepted 2895 877 2319 20 57428713 57428713 T C ENST00000371100.4 75 GRCh37 Common Germline 2017-04-03 19:30:13 UTC https://civicdb.org/links/evidence_items/2895 https://civicdb.org/links/variants/877 https://civicdb.org/links/genes/2319 false GNAS 2778 c.393T>C Clear Cell Renal Cell Carcinoma 4467 Prognostic Supports B Better Outcome In this study, Kaplan-Meier curves for tumor progression, development of metastasis, and tumor-related death showed a significant association of the T393C polymorphism with outcome (5-year cancer-specific survival rates: TT, 91%; TC, 81%; CC, 69%; P = 0.015). Multivariate Cox proportional analysis of a 10-year follow-up confirmed the T393C polymorphism as an independent prognostic factor in clear cell renal cell carcinoma. Homozygous CC patients were at highest risk for progression (hazard ratio, 2.48; P = 0.009) or tumor-related death (hazard ratio, 3.15; P = 0.018) compared with T-allele carriers. 16467086 PubMed Frey et al., 2006, Clin. Cancer Res. 4 accepted 2896 877 2319 20 57428713 57428713 T C ENST00000371100.4 75 GRCh37 Common Germline 2017-04-03 19:29:57 UTC https://civicdb.org/links/evidence_items/2896 https://civicdb.org/links/variants/877 https://civicdb.org/links/genes/2319 false GNAS 2778 c.393T>C Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Better Outcome In a retrospective study of 144 patients with B-cell chronic lymphocytic leukemia, the median progression-free survival was significantly different between GNAS T393C genotypes (TT 130 months; TC 100 months; CC 31 months; P = 0.0066) and an independent prognostic factor for progression-free survival by multivariable analysis [hazard ratio (HR) CC versus TT 2.7; P = 0.010]. CC genotypes were at highest risk for death compared with T-alleles (median overall survival 197 vs 310 months, respectively) in both univariate (HR, 4.8; P < 0.0001) and multivariable analysis (HR, 5.6; P = 0.002). 17020971 PubMed Frey et al., 2006, Clin. Cancer Res. 4 accepted 2897 877 2319 20 57428713 57428713 T C ENST00000371100.4 75 GRCh37 Common Germline 2017-05-11 15:26:26 UTC https://civicdb.org/links/evidence_items/2897 https://civicdb.org/links/variants/877 https://civicdb.org/links/genes/2319 false GNAS 2778 c.393T>C Melanoma 1909 Prognostic Supports B Better Outcome This study showed that GNAS1 T393C SNP represents a genetic host factor for predicting tumor progression in patients with malignant melanoma. Carriers of the C-allele showed a significantly more severe tumor progression as estimated from the time period to develop metastasis (HR 2.2, 95% CI 1.1-3.2, p = 0.017). Proportions of 5-year metastasis-free intervals were 87.1% for TT genotypes and 66.0% for C-allele carriers. Moreover, multivariable Cox regression analysis including tumor stage and melanoma subtype proved the T393C polymorphism to be an independent factor for metastasis (p = 0.012). 21156401 PubMed Frey et al., 2010, Eur. J. Med. Res. 4 accepted 2898 877 2319 20 57428713 57428713 T C ENST00000371100.4 75 GRCh37 Common Germline 2017-04-03 19:29:07 UTC https://civicdb.org/links/evidence_items/2898 https://civicdb.org/links/variants/877 https://civicdb.org/links/genes/2319 false MGMT 4255 Underexpression Glioblastoma 3068 Temozolomide Predictive Supports B Sensitivity/Response In this study, patients with low MGMT expression, compared with patients with high MGMT expression, had a significantly higher response rate (55% v 7%, respectively; P = .004) and improved PFS (median, 5.5 v 1.9 months, respectively; P = .009) and OS (median, 16 v 5 months, respectively; P = .003). Among patients with MGMT data available for analysis, radiotherapy was started and completed in 91% of patients with low MGMT expression. In contrast, among patients with high MGMT expression, only 64% started radiotherapy, and 43% completed it. These results suggest that neoadjuvant chemotherapy may be feasible for inoperable glioblastoma patients expressing low levels of MGMT without compromising subsequent treatment with radiotherapy, whereas patients with high MGMT expression are less likely to respond and more likely to experience progression before or during radiotherapy. 17442989 PubMed Chinot et al., 2007, J. Clin. Oncol. 3 accepted 2899 1255 34 10 131265448 131566271 ENST00000306010.7 75 GRCh37 N/A 2017-04-03 19:27:38 UTC https://civicdb.org/links/evidence_items/2899 https://civicdb.org/links/variants/1255 https://civicdb.org/links/genes/34 false MGMT 4255 Underexpression High Grade Glioma 3070 Temozolomide Predictive Supports B Sensitivity/Response This study showed that low MGMT mRNA expression was strongly predictive for prolonged time to progression, treatment response, and length of survival in univariate and multivariate models (p<0.0001). The degree of MGMT mRNA expression was highly correlated with the MGMT promoter methylation status (p<0.0001); however, discordant findings were seen in 12 glioblastoma patients. Patients with methylated tumors with high MGMT mRNA expression (N = 6) did significantly worse than those with low transcriptional activity (p<0.01). Conversely, unmethylated tumors with low MGMT mRNA expression (N = 6) did better than their counterparts. 21365007 PubMed Kreth et al., 2011, PLoS ONE 3 accepted 2901 1255 34 10 131265448 131566271 ENST00000306010.7 75 GRCh37 N/A 2017-04-03 19:26:53 UTC https://civicdb.org/links/evidence_items/2901 https://civicdb.org/links/variants/1255 https://civicdb.org/links/genes/34 false MGMT 4255 Underexpression Oligodendroglioma 3181 Temozolomide Predictive Supports B Sensitivity/Response In this study, loss of chromosome 1p and low MGMT protein expression were associated with objective response (P < .003 and P < .04, respectively). However, only 54% of the study group had evaluation of 1p/19q status, and MGMT protein expression was studied in only 33%. Therefore, the association between 1p deletion and low MGMT protein expression was statistically significant when evaluated further and verified in the extended group of 31 patients with low-grade oligodendrogliomas. 16541434 PubMed Levin et al., 2006, Cancer 2 accepted 2902 1255 34 10 131265448 131566271 ENST00000306010.7 75 GRCh37 N/A 2020-11-20 16:02:30 UTC https://civicdb.org/links/evidence_items/2902 https://civicdb.org/links/variants/1255 https://civicdb.org/links/genes/34 false MGMT 4255 Underexpression Glioblastoma 3068 Temozolomide Predictive Supports B Sensitivity/Response In 41 glioblastomas treated with temozolomide (TMZ) therapy (MGMT-immunopositive: n = 22, negative: n = 19), both progression free survival and overall survival were significantly better in MGMT-immunonegative glioblastomas. (PFS: P = 0.0015, OS: P = 0.0384). 21331613 PubMed Watanabe et al., 2011, Brain Tumor Pathol 3 accepted 2903 1255 34 10 131265448 131566271 ENST00000306010.7 75 GRCh37 N/A 2017-04-03 19:27:13 UTC https://civicdb.org/links/evidence_items/2903 https://civicdb.org/links/variants/1255 https://civicdb.org/links/genes/34 false MGMT 4255 Underexpression Neuroendocrine Tumor 169 Temozolomide Predictive Supports B Sensitivity/Response Among those patients who received temozolomide-based therapy in this study, the median progression-free survival for patients whose tumors showed intact MGMT expression was 9.3 months compared with 19.2 months for patients with MGMT-deficient tumors (P = 0.11). The median overall survival for patients whose tumors showed intact MGMT expression was 19.1 months; the median overall survival for patients with MGMT deficient tumors was not reached. 19118063 PubMed Kulke et al., 2009, Clin. Cancer Res. 2 accepted 2904 1255 34 10 131265448 131566271 ENST00000306010.7 75 GRCh37 N/A 2017-04-03 19:23:39 UTC https://civicdb.org/links/evidence_items/2904 https://civicdb.org/links/variants/1255 https://civicdb.org/links/genes/34 false RRM1 6240 Underexpression Lung Non-small Cell Carcinoma 3908 Gemcitabine,Cisplatin Combination Predictive Supports B Sensitivity/Response In the personalized therapy group of this study, patients received chemotherapy based on RRM-1 IHC expression levels, whereas the standard therapy group received non-customized chemotherapy. There were statistically significant improvements between the personalized therapy group versus the standard therapy group in disease control rate (82.9% vs 55.3%, P=0.004), and progression-free survival (median: 5.5 months vs 3.0 months, P=0.005). Besides, the overall survival had a tendency to become more prolonged (median: 16.0 months vs 12.4 months, P=0.286). 24595080 PubMed Nie et al., 2013, Cancer Biomark 4 accepted 2905 1257 5051 11 4116039 4160106 ENST00000300738.5 75 GRCh37 N/A 2017-04-03 19:22:32 UTC https://civicdb.org/links/evidence_items/2905 https://civicdb.org/links/variants/1257 https://civicdb.org/links/genes/5051 false EGFR 1956 S768I Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Does Not Support C Sensitivity/Response S768I mutations in exon 20 of the EGFR gene are rare and are typically seen in conjunction with sensitizing EGFR mutations. Because of this mutation's rarity and the variability of responses of treated cases, its exact prognostic and predictive role is not fully understood. In our experience, S768I mutations in isolation do not necessarily confer sensitivity to erlotinib, but in conjunction with sensitizing EGFR mutations, S768I mutations do not restrict efficacy. 27211795 PubMed Leventakos et al., 2016, J Thorac Oncol 2 accepted 2906 562 19 7 55249005 55249005 G T ENST00000275493.2 75 GRCh37 Somatic 2017-05-23 13:43:12 UTC https://civicdb.org/links/evidence_items/2906 https://civicdb.org/links/variants/562 https://civicdb.org/links/genes/19 false NRAS 4893 Q61K Lung Non-small Cell Carcinoma 3908 Trametinib,Selumetinib Substitutes Predictive Supports D Sensitivity/Response Of the 4,562 patients with lung cancers, 30 showed NRAS mutations, which corresponded to 9 different amino acid substitutions. Cell lines were developed for 6 of these mutations (one harboring Q61L, two Q61R, and three Q61K mutations) and 5/6 were sensitive to MEK inhibitors selumetinib and trametinib. One Q61K line was not sensitive to these inhibitors. 23515407 PubMed Ohashi et al., 2013, Clin. Cancer Res. 2 accepted 2907 427 36 1 115256530 115256530 G T ENST00000369535.4 75 GRCh37 Somatic 2017-05-30 19:32:15 UTC https://civicdb.org/links/evidence_items/2907 https://civicdb.org/links/variants/427 https://civicdb.org/links/genes/36 false RET 5979 C609Y Thyroid Gland Medullary Carcinoma 3973 Predisposing Supports B Pathogenic Study of a family with three generations of history indicating co-segregation of RET C609Y and multiple endocrine neoplasia type 2A, many of whom exhibited medullary thyroid cancers specifically. 22 individuals in this family were carriers of C609Y. Of these, 9 exhibited medullary thyroid cancers. While the variant is strongly suspected of being pathogenic for these tumors, this variant appears to result in later onset of cancer than some other variants and the authors recommend delaying prophylactic thyroidectomy until 10-15 years of age. In addition to this large family, the authors also provide an extensive review of prior reports of C609 variants, identifying a total of 111 patients from 19 publications, representing 21 affected kindreds and 15 sporadic cases. 89 of these cases had C609Y specifically. The authors also summarize prior functional work that suggests that C609Y has transforming activity that is significant but not as strong as some other variants. Based on all of this analysis, the authors conclude that C609Y causes medullary thyroid cancers but a milder form than some other variants. Based on this paper, the following ACMG evidence codes seem potentially valid: 'PS1', 'PS3', 'PM5', 'PP1', 'PP4', and 'PP5'. 19472011 PubMed Calva et al., 2009, Ann. Surg. Oncol. 4 accepted 2913 1260 42 10 43609070 43609070 G A ENST00000355710.3 75 GRCh37 There is some functional evidence that this variant leads to reduced RET activity (PMID: 9230192) and increased cell proliferation and resistance to apoptosis (PMID: 16715139). It has been widely reported in both familial and sporadic cases of multiple endocrine neoplasia type 2 with medullary thyroid cancers. Despite extensive WGS and Exome coverage for a combined total of ~150k alleles in the GNOMAD browser, this variant has never been observed. Rare Germline 2017-04-05 04:03:03 UTC https://civicdb.org/links/evidence_items/2913 https://civicdb.org/links/variants/1260 https://civicdb.org/links/genes/42 false FGFR1 2260 Expression Sarcoma 1115 FGF/VEGF Receptor Tyrosine Kinase Inhibitor, PD173074,FGFR Inhibitor AZD4547,Infigratinib Substitutes Predictive Supports D Sensitivity/Response Targeting of FGFR1 by RNA interference and small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is dictated by FGFR1 expression levels, and identified the MAPK-ERK1/2 axis as critical FGFR1 effector pathway. 27535980 PubMed Chudasama et al., 2017, Clin. Cancer Res. 3 accepted 2915 268 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 high expression has been reported in 11.8% (178 patients) of oral squamous cell carcinoma patients, and was enriched in early stages (Freier et. al., 2007). Another study reports FGFR1 expression in 35% of primary HNSSC (353 patients) (Göke et. al., 2015). In both studies, FGFR1 gene amplification and expression do not correlate well with about 35% of samples with FGFR1 amplification overexpressing FGFR1 (Göke et. al., 2015). FGFR1 expression also correlated with sensitivity to FGFR1 inhibitors in preclinical models of lung cancer (Wynes et. al., 2014), HNSSC (Göke et. al., 2015) and urothelial carcinoma (Lamont et. al., 2011). Somatic 2017-11-19 17:38:34 UTC https://civicdb.org/links/evidence_items/2915 https://civicdb.org/links/variants/268 https://civicdb.org/links/genes/1885 false KIT 3815 N822K Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports C Resistance 147 patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib (CSTI571-B2222). Specimens from 43 pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. N822K was observed as a secondary KIT mutation in two patients with secondary imatinib resistance and one patient with primary resistance, and also as a primary mutation in a patient with primary resistance. The mutation was shown to occur at a hotspot (N822) of previously reported secondary KIT mutations in imatinib resistant GISTs. When co-expressed with V560D (imatinib sensitive) in vitro N822K showed moderate imatinib resistance. 16954519 PubMed Heinrich et al., 2006, J. Clin. Oncol. 3 accepted 2918 1263 29 4 55599340 55599340 T A ENST00000288135.5 75 GRCh37 Somatic 2017-07-27 15:55:41 UTC https://civicdb.org/links/evidence_items/2918 https://civicdb.org/links/variants/1263 https://civicdb.org/links/genes/29 false KIT 3815 Y823D Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports C Resistance 147 patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib (CSTI571-B2222). Specimens from 43 pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. Y823D was observed as a secondary KIT mutation in five patients with secondary imatinib resistance. The mutation was shown to occur at a hotspot (Y823) of previously reported secondary KIT mutations in imatinib resistant GISTs. When co-expressed with V560D (imatinib sensitive) in vitro Y823D showed "extreme" imatinib resistance. 16954519 PubMed Heinrich et al., 2006, J. Clin. Oncol. 3 accepted 2919 989 29 4 55599341 55599341 T G ENST00000288135.5 75 GRCh37 Somatic 2017-07-27 15:47:51 UTC https://civicdb.org/links/evidence_items/2919 https://civicdb.org/links/variants/989 https://civicdb.org/links/genes/29 false KIT 3815 C809G Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports C Resistance 147 patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib (CSTI571-B2222). Specimens from 43 pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. C809G was observed as a secondary KIT mutation in one patient with secondary imatinib resistance. In vitro, C809G showed imatinib resistance both in isolation and when coexpressed with K642E + N822H (the primary KIT mutations, found on the same allele, for this patient). 16954519 PubMed Heinrich et al., 2006, J. Clin. Oncol. 3 accepted 2920 1264 29 4 55599299 55599299 T G ENST00000288135.5 75 GRCh37 Somatic 2017-07-27 15:44:38 UTC https://civicdb.org/links/evidence_items/2920 https://civicdb.org/links/variants/1264 https://civicdb.org/links/genes/29 false KIT 3815 D820A Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports C Resistance 147 patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib (CSTI571-B2222). Specimens from 43 pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. D820A was observed as a secondary KIT mutation in one patient with secondary imatinib resistance. The mutation was shown to occur at a hotspot (D820) of previously reported secondary KIT mutations in imatinib resistant GISTs. A cell line derived from a separate patient with the same primary (V560D) and secondary (D820A) mutations showed moderately increased resistance to imatinib compared to reports for GIST lines with primary exon 11 KIT mutations alone. 16954519 PubMed Heinrich et al., 2006, J. Clin. Oncol. 3 accepted 2921 1265 29 4 55599333 55599333 A C ENST00000288135.5 75 GRCh37 Somatic 2017-07-27 15:39:17 UTC https://civicdb.org/links/evidence_items/2921 https://civicdb.org/links/variants/1265 https://civicdb.org/links/genes/29 false KIT 3815 D820G Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports C Resistance 147 patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib (CSTI571-B2222). Specimens from 43 pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. D820G was observed as a secondary KIT mutation in two patients with secondary imatinib resistance. The mutation was shown to occur at a hotspot (D820) of previously reported secondary KIT mutations in imatinib resistant GISTs. When co-expressed with V560D (imatinib sensitive) in vitro D820G showed "extreme" imatinib resistance. 16954519 PubMed Heinrich et al., 2006, J. Clin. Oncol. 3 accepted 2922 1266 29 4 55599333 55599333 A G ENST00000288135.5 75 GRCh37 Somatic 2017-07-27 15:46:46 UTC https://civicdb.org/links/evidence_items/2922 https://civicdb.org/links/variants/1266 https://civicdb.org/links/genes/29 false KIT 3815 D816H Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports C Resistance 147 patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib (CSTI571-B2222). Specimens from 43 pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. D816H was observed as a secondary KIT mutation in two patients with secondary imatinib resistance. The mutation was shown to occur at a hotspot (D816) of previously reported secondary KIT mutations in imatinib resistant GISTs. When co-expressed with V560D (imatinib sensitive) in vitro D816H showed "extreme" imatinib resistance. It was also highly resistant in isolation. 16954519 PubMed Heinrich et al., 2006, J. Clin. Oncol. 3 accepted 2923 983 29 4 55599320 55599320 G C ENST00000288135.5 75 GRCh37 Somatic 2017-07-27 15:45:59 UTC https://civicdb.org/links/evidence_items/2923 https://civicdb.org/links/variants/983 https://civicdb.org/links/genes/29 false KIT 3815 T670I Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports C Resistance 147 patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib (CSTI571-B2222). Specimens from 43 pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. T670I was observed as a secondary KIT mutation in one patient with secondary imatinib resistance. The mutation was shown to occur at a hotspot (T670) of previously reported secondary KIT mutations in imatinib resistant GISTs. When co-expressed with V560D (imatinib sensitive) in vitro T670I showed "extreme" imatinib resistance. It also showed resistance in isolation. 16954519 PubMed Heinrich et al., 2006, J. Clin. Oncol. 3 accepted 2924 1267 29 4 55595519 55595519 C T ENST00000288135.5 75 GRCh37 Somatic 2017-07-27 15:34:52 UTC https://civicdb.org/links/evidence_items/2924 https://civicdb.org/links/variants/1267 https://civicdb.org/links/genes/29 false DNMT3A 1788 Mutation Cancer 162 Nivolumab,Atezolizumab,Pembrolizumab Substitutes Predictive Supports B Resistance A subset of patients receiving PD1/PD-L1 inhibition appear to be "hyper-progressors," with a greatly accelerated rate of tumor growth and clinical deterioration compared to pre-therapy. The current study investigated potential genomic markers associated with "hyper-progression". Consecutive stage IV cancer patients who received immunotherapies (CTLA-4, PD-1/PD-L1 inhibitors or other [investigational] agents) and had their tumor evaluated by next-generation sequencing Amongst 155 patients, TTF (time to treatment failure) <2 months was seen in 4/5 individuals harbouring DNMT3A alteration. 28351930 PubMed Kato et al., 2017, Clin. Cancer Res. 2 accepted 2926 189 18 2 25455845 25565459 ENST00000264709.3 75 GRCh37 DNMT3A mutations occur in a variety of myeloid malignancies. These mutations are associated with adverse prognosis in acute myeloid leukemia (AML), particularly in the context of NPM1 and FLT3-ITD mutations, which often co-occur. Early results indicate AML patients with DNMT3A mutations may respond better to decitabine than those with wild-type. Shorter survival has been indicated in patients with T-cell acute lymphoblastic leukemia and myelodysplastic syndrome, however, larger cohorts are required to verify this finding. DNMT3A mutations have been suggested as a pre-leukemic lesion and found in older individuals with clonal hematopoiesis but no overt malignancy. Somatic 2017-07-25 20:22:46 UTC https://civicdb.org/links/evidence_items/2926 https://civicdb.org/links/variants/189 https://civicdb.org/links/genes/18 false ATM 472 Mutation Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome ATM point mutations were found in 8/57 patients with CLL and were associated with a shorter treatment-free interval, suggesting a more aggressive course. 21993670 PubMed Guarini et al., 2012, Haematologica 3 accepted 2927 178 69 11 108093559 108239826 ENST00000278616.4 75 GRCh37 Somatic 2017-07-25 17:37:53 UTC https://civicdb.org/links/evidence_items/2927 https://civicdb.org/links/variants/178 https://civicdb.org/links/genes/69 false BRAF 673 Amplification Colorectal Cancer 9256 Dabrafenib,Panitumumab Combination Predictive Supports C Resistance Paired pre-treatment and post-progression tumor biopsies from BRAF-mutant CRC patients treated with RAF inhibitor combinations were analyzed. Alterations in MAPK pathway genes were found in resistant tumors not present in matched pre-treatment tumors, including KRAS amplification, BRAF amplification, and a MEK1 mutation. 25673644 PubMed Ahronian et al., 2015, Cancer Discov 3 accepted 2929 1269 5 7 140434279 140624564 ENST00000288602.6 75 GRCh37 Somatic 2017-04-25 21:33:56 UTC https://civicdb.org/links/evidence_items/2929 https://civicdb.org/links/variants/1269 https://civicdb.org/links/genes/5 false NRAS 4893 Mutation Skin Melanoma 8923 Ribociclib,Binimetinib Combination Predictive Supports B Sensitivity/Response Inhibition of CDK4 and 6, regulators of the G1/S cell cycle checkpoint, arrests the cell cycle in the G1 phase, suppresses DNA synthesis, and inhibits cancer cell growth. There is an ongoing phase 1/2 trial of binimetinib with the CDK4/6 inhibitor ribociclib (LEE011) in mutant NRAS melanoma patients (NCT01781572). Early results from the 21 evaluable patients were very promising, with 7 patients achieving a partial response (33%) and 11 patients with stable disease (52%) 26987942 PubMed Vu et al., 2016, Pharmacol. Res. 3 accepted 2931 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2017-09-08 19:15:53 UTC https://civicdb.org/links/evidence_items/2931 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false IDH1 3417 Mutation Brain Glioma 0060108 Olaparib Predictive Supports D Sensitivity/Response Mutations in isocitrate dehydrogenase 1 and 2, which result in overproduction of 2-hydroxyglutarate (2HG). 2HG is considered to be an oncometabolite, or a metabolite that promotes carcinogenesis, and inhibitors of mutant isocitrate dehydrogenase are in development to target this process. The authors discovered that 2HG overproduction impairs homologous recombination used in DNA repair and sensitizes cancer cells to treatment with PARP inhibitors, another class of cancer drugs that are already in clinical use. 28148839 PubMed Sulkowski et al., 2017, Sci Transl Med 3 accepted 2933 645 26 2 209101803 209116275 ENST00000415913.1 75 GRCh37 Somatic 2017-05-11 15:31:32 UTC https://civicdb.org/links/evidence_items/2933 https://civicdb.org/links/variants/645 https://civicdb.org/links/genes/26 false ROS1 6098 G2032R Lung Adenocarcinoma 3910 Crizotinib Predictive Supports C Resistance Resistance to crizotinib developed in a patient with metastatic lung adenocarcinoma harboring a CD74-ROS1 rearrangement who had initially shown a dramatic response to treatment. A biopsy of a resistant tumor showed an acquired G2032R mutation in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the metastatic sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. 23724914 PubMed Awad et al., 2013, N. Engl. J. Med. NCT00585195 1 accepted 2934 1271 4941 6 117638347 117638347 C T ENST00000368508.3 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/2934 https://civicdb.org/links/variants/1271 https://civicdb.org/links/genes/4941 false MAP2K1 5604 K57N Lung Adenocarcinoma 3910 Prognostic Supports B Poor Outcome In a study of 6,024 lung adenocarcinomas, 36 conferred MEK1 mutations whereby 64% (n=23) were K57N and 19% (n=7) were Q56P. Median overall survival of MEK1-mutated tumors was not significantly different from KRAS-mutated tumors (14.9 vs 13.7 months) or BRAP-mutated tumors (14.9 vs. 20.9 months). MEK1-mutated tumors were significantly inferior compared to EGFR-mutated tumors (14.9 vs. 35.9 months; HR=2.64, p=0.01), ALK-rearranged tumors (14.9 vs. 35.9 months; HR, 2.64; P = 0.01), ROS1-rearranged tumors (14.9 vs. 76 months; HR, 4.00; P = 0.02), and RET-rearranged tumors (14.9 months vs. not reached; HR, 3.25; P = 0.03). 25351745 PubMed Arcila et al., 2015, Clin. Cancer Res. 3 accepted 2935 1272 31 15 66727455 66727455 G T ENST00000307102.5 75 GRCh37 Somatic 2021-05-25 23:42:52 UTC https://civicdb.org/links/evidence_items/2935 https://civicdb.org/links/variants/1272 https://civicdb.org/links/genes/31 false MAP2K1 5604 K57N Lung Adenocarcinoma 3910 Selumetinib Predictive Supports D Sensitivity/Response Mutational profiling of 207 lung adenocarcinomas identified in 2 of with activating mutation in exon 2 of MEK1 (K57N) in the nonkinase portion of the kinase. Neither of these two tumors harbored known mutations in other genes encoding components of the EGFR signaling pathway (i.e., EGFR, HER2, KRAS, PIK3CA, and BRAF). Expression of mutant, but not wild-type, MEK1 leads to constitutive activity of extracellular signal-regulated kinase (ERK)-1/2 in human 293T cells and to growth factor-independent proliferation of murine Ba/F3 cells. A selective MEK inhibitor, AZD6244, inhibits mutant-induced ERK activity in 293T cells and growth of mutant-bearing Ba/F3 cells. 18632602 PubMed Marks et al., 2008, Cancer Res. 2 accepted 2936 1272 31 15 66727455 66727455 G T ENST00000307102.5 75 GRCh37 Somatic 2021-06-08 21:01:44 UTC https://civicdb.org/links/evidence_items/2936 https://civicdb.org/links/variants/1272 https://civicdb.org/links/genes/31 false NRAS 4893 Mutation Skin Melanoma 8923 Binimetinib Predictive Supports B Sensitivity/Response NEMO is an ongoing, randomised, open-label phase 3 study of patients with advanced, unresectable, AJCC IIIC/IV NRAS-mutant melanoma. 402 patients that were previously untreated or progressed on or after previous immunotherapy were randomised to receive either binimetinib (269) or dacarbazine (133). The study's primary endpoint was progression free survival. Median follow-up was 1.7 months (IQR 1.4-4.1). Median progression-free survival was 2.8 months (95% CI 2.8-3.6) in the binimetinib group and 1.5 months (1.5-1.7) in the dacarbazine group, demonstrating improved progression-free survival of binimetinib compared with dacarbazine. 28284557 PubMed Dummer et al., 2017, Lancet Oncol. NCT01763164 5 accepted 2937 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2017-07-27 21:49:42 UTC https://civicdb.org/links/evidence_items/2937 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false EGFR 1956 Mutation Lung Cancer 1324 Gefitinib Predictive Supports B Sensitivity/Response In a study of 52 patients with recurrent lung cancer, 27 individuals had EGFR mutation including 2 point mutations in exon 18 (G719A and G1719C), 23 deletions in exon 19, two insertions in exon 19 (I744KIPVAI), on mutation in exon 20 (S768I), and 16 point mutations in exon 21 (L858R and E709H). Patients were treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib, and tumors harboring an EGFR mutation had an increased frequency of partial response (PR) and a lower rate of progressive disease (PD) (PR:22, PD:2 vs. PR:2, PD:17; P<0.0001) compared to wildtype EGFR patients. Patients with KRAS mutations also had a longer overall survival compared to wildtype EGFR patients (HR:2.526, 95% CI:1.314-4.858, P=0.0055). 17409929 PubMed Endoh et al., 2006, J Thorac Oncol 2 accepted 2939 442 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2017-09-08 19:30:25 UTC https://civicdb.org/links/evidence_items/2939 https://civicdb.org/links/variants/442 https://civicdb.org/links/genes/19 false CTAG1B 1485 Overexpression Multiple Myeloma 9538 Letetresgene Autoleucel Predictive Supports B Sensitivity/Response Clinical responses to NY-ESO-1/LAGE-1 TCR-engineered T-cells were observed in 16 of 20 patients (80%) with advanced multiple myeloma expressing NY-ESO-1 and/or LAGE-1 in this Phase 1/2a trial showing a median progression free survival of 19.1 months. 26193344 PubMed Rapoport et al., 2015, Nat. Med. 3 accepted 2940 1273 1278 X 153845865 153847522 ENST00000328435.2 75 GRCh37 N/A 2021-03-10 23:49:47 UTC https://civicdb.org/links/evidence_items/2940 https://civicdb.org/links/variants/1273 https://civicdb.org/links/genes/1278 false CTAG2 30848 Overexpression Multiple Myeloma 9538 Letetresgene Autoleucel Predictive Supports B Sensitivity/Response Clinical responses to NY-ESO-1/LAGE-1 TCR-engineered T-cells were observed in 16 of 20 patients (80%) with advanced multiple myeloma expressing NY-ESO-1 and/or LAGE-1 in this Phase 1/2a trial showing a median progression free survival of 19.1 months. 26193344 PubMed Rapoport et al., 2015, Nat. Med. 3 accepted 2941 1274 11492 X 153880246 153881853 ENST00000247306.4 75 GRCh37 N/A 2021-03-10 23:48:44 UTC https://civicdb.org/links/evidence_items/2941 https://civicdb.org/links/variants/1274 https://civicdb.org/links/genes/11492 false KRAS 3845 A146T Colorectal Cancer 9256 Cetuximab Predictive Supports D Resistance Preclinical data supporting resistance of Exon 4 mutations, in particular A146T, to cetuximab and sensitivity to PD0325901. This study involved treatment of mice bearing A146T KRAS xenografts treated with PD0325901 or cetuximab. 20570890 PubMed Janakiraman et al., 2010, Cancer Res. 3 accepted 2943 906 30 12 25378562 25378562 C T ENST00000256078.4 75 GRCh37 Somatic 2017-07-21 16:33:13 UTC https://civicdb.org/links/evidence_items/2943 https://civicdb.org/links/variants/906 https://civicdb.org/links/genes/30 false NTRK1 4914 Fusion Lung Non-small Cell Carcinoma 3908 Entrectinib Predictive Supports C Sensitivity/Response 1378 cases of NSCLC were screened. One patient (frequency 0.1%) with a NTRK1 gene rearrangement (SQSTM1-NTRK1 Fusion) was treated with entrectinib in a phase 1 study. The patient had resolution of prior dyspnea and pain within 3 weeks. CT scans showed a partial response and complete resolution of brain metastases. The patient has continued treatment for over 6 months with ongoing PR. 26565381 PubMed Farago et al., 2015, J Thorac Oncol NCT02097810 3 accepted 2947 419 3983 1 156844175 156851434 ENST00000524377.1 75 GRCh37 Somatic 2018-12-04 17:16:38 UTC https://civicdb.org/links/evidence_items/2947 https://civicdb.org/links/variants/419 https://civicdb.org/links/genes/3983 false NTRK1 4914 Fusion Cancer 162 Entrectinib Predictive Supports B Sensitivity/Response in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer. 28183697 PubMed Drilon et al., 2017, Cancer Discov 3 accepted 2948 419 3983 1 156844175 156851434 ENST00000524377.1 75 GRCh37 Somatic 2017-04-14 16:36:54 UTC https://civicdb.org/links/evidence_items/2948 https://civicdb.org/links/variants/419 https://civicdb.org/links/genes/3983 false NTRK3 4916 Fusion Cancer 162 Entrectinib Predictive Supports B Sensitivity/Response in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer. 28183697 PubMed Drilon et al., 2017, Cancer Discov 3 accepted 2949 1277 3985 Somatic 2017-04-14 16:36:47 UTC https://civicdb.org/links/evidence_items/2949 https://civicdb.org/links/variants/1277 https://civicdb.org/links/genes/3985 false NTRK1 4914 SQSTM1::NTRK1 Lung Non-small Cell Carcinoma 3908 Entrectinib Predictive Supports C Sensitivity/Response Two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer. 28183697 PubMed Drilon et al., 2017, Cancer Discov 3 accepted 2950 800 3983 Somatic 2017-04-14 16:37:02 UTC https://civicdb.org/links/evidence_items/2950 https://civicdb.org/links/variants/800 https://civicdb.org/links/genes/3983 false ROS1 6098 Rearrangement Cancer 162 Entrectinib Predictive Supports B Sensitivity/Response Two phase I studies included 119 patients with advanced or metastatic solid tumors, which included 28 patients with ROS1 rearrangements (n=28) where the overall safety and antitumor activity of entrectinib was examined. Entrectinib was shown to be safe and well tolerated. For phase 2, 14 ROS1-rearranged solid tumors were eligible and demonstrated an overall objective response rate of 86% (95% CI: 60–96) to entrectinib. Of the 14, 13 were Non-small cell lung cancer cases, 12 of which showed response with 2 of these patients demonstrated a complete response. A single melanoma case with a ROS1 rearrangement also showed a response to treatment. 28183697 PubMed Drilon et al., 2017, Cancer Discov 3 accepted 2951 269 4941 6 117609463 117747018 ENST00000368508.3 75 GRCh37 ROS1 is a receptor tyrosine kinase that frequently forms gene fusions in several cancer types. Approximately 2% of NSCLC patients harbor a ROS1 gene fusion. Several fusion partners have been described with a constant ROS1-breakpoint, maintaining the kinase domain (Solomon B, 2015). Following case-studies and retrospective analyses, an expansion cohort of a phase-1 study showed clinical benefit of crizotinib in ROS1 rearranged NSCLC. The benefit was independent of the type of ROS1-rearrangement (Shaw et. al.,2014). Somatic 2022-08-19 00:15:31 UTC https://civicdb.org/links/evidence_items/2951 https://civicdb.org/links/variants/269 https://civicdb.org/links/genes/4941 false ALK 238 Fusion Cancer 162 Entrectinib Predictive Supports B Sensitivity/Response Two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer. 28183697 PubMed Drilon et al., 2017, Cancer Discov 3 accepted 2952 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2017-04-14 16:36:22 UTC https://civicdb.org/links/evidence_items/2952 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false NTRK1 4914 Fusion Cancer 162 Larotrectinib Predictive Supports C Sensitivity/Response Results from a phase I study show that the TRK inhibitor LOXO-101 is well tolerated and effective, with patients whose tumors bear NTRK fusions responding well and durably to this targeted therapy. This publication reported results from an AACR meeting for an ongoing study that had enrolled six patients with NTRK fusions, three of whom could be evaluated at the time. Each had a different, heavily pretreated advanced disease: soft-tissue sarcoma; gastrointestinal stromal tumor (GIST); and MASC. All three patients experienced partial responses by 3-4 months with resolution of key tumour-related symptoms within two weeks. One of three patients experienced near-complete response by 8 months. 26603524 PubMed 2016, Cancer Discov 2 accepted 2953 419 3983 1 156844175 156851434 ENST00000524377.1 75 GRCh37 Somatic 2020-12-03 00:41:21 UTC https://civicdb.org/links/evidence_items/2953 https://civicdb.org/links/variants/419 https://civicdb.org/links/genes/3983 false NTRK1 4914 LMNA::NTRK1 e2-e11 Sarcoma 1115 Larotrectinib Predictive Supports C Sensitivity/Response LOXO-101 is an orally administered inhibitor of the TRK kinase and is highly selective only for the TRK family of receptors. The tumor of a 41-year-old woman with soft-tissue sarcoma metastatic to the lung was found to harbor an in-frame LMNA-NTRK1 (exon 2 & exon 11) gene fusion encoding a functional LMNA-TRKA fusion oncoprotein. This patient's tumors underwent rapid and substantial tumor regression, with an accompanying improvement in pulmonary dyspnea, oxygen saturation, and plasma tumor markers. 26216294 PubMed Doebele et al., 2015, Cancer Discov NCT02122913 2 accepted 2955 3224 3983 Somatic 2020-12-03 00:43:41 UTC https://civicdb.org/links/evidence_items/2955 https://civicdb.org/links/variants/3224 https://civicdb.org/links/genes/3983 false NTRK1 4914 Amplification Cancer 162 Entrectinib Predictive Does Not Support B Sensitivity/Response Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including CNS disease. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. No objective responses (per RECIST v1.1) were observed in patients whose tumors did not harbor gene fusions involving NTRK1/2/3, ROS1, or ALK, with the exception of 1 patient with an ALKF1245V mutant neuroblastoma. 28183697 PubMed Drilon et al., 2017, Cancer Discov 1 accepted 2958 1280 3983 1 156830686 156851434 ENST00000524377.1 75 GRCh37 Somatic 2021-03-10 23:23:18 UTC https://civicdb.org/links/evidence_items/2958 https://civicdb.org/links/variants/1280 https://civicdb.org/links/genes/3983 false NTRK3 4916 Amplification Cancer 162 Entrectinib Predictive Does Not Support B Sensitivity/Response Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including CNS disease. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. No objective responses (per RECIST v1.1) were observed in patients whose tumors did not harbor gene fusions involving NTRK1/2/3, ROS1, or ALK, with the exception of 1 patient with an ALKF1245V mutant neuroblastoma. Only 9 of 119 patients had NTRK Amplifications. 28183697 PubMed Drilon et al., 2017, Cancer Discov 1 accepted 2959 1281 3985 15 88418230 88799978 ENST00000394480.2 75 GRCh37 Somatic 2021-03-11 17:38:08 UTC https://civicdb.org/links/evidence_items/2959 https://civicdb.org/links/variants/1281 https://civicdb.org/links/genes/3985 false NTRK1 4914 LMNA::NTRK1 e11-e10 Colorectal Adenocarcinoma 0050861 Entrectinib Predictive Supports C Sensitivity/Response A gene fusion between exon 11 of LMNA and exon 10 of NTRK1 was observed in a patient with metastatic colorectal cancer after therapy with first-line FOLFOX, second-line FOLFIRI/cetuximab, and third-line irinotecan. The patient treated in a clinical trial with pan-TRK kinase inhibitor entrectinib. Treatment was well tolerated and led to a partial response (PR) with 30% tumor shrinkage of multiple liver metastases. Clinical response lasted 4 months. 26546295 PubMed Russo et al., 2016, Cancer Discov 3 accepted 2960 3225 3983 1 156084498 156108548 ENST00000368300.4 1 156844363 156851434 ENST00000524377.1 75 GRCh37 Somatic 2020-11-09 22:33:42 UTC https://civicdb.org/links/evidence_items/2960 https://civicdb.org/links/variants/3225 https://civicdb.org/links/genes/3983 false NTRK1 4914 LMNA::NTRK1 G595R and G667C Colorectal Adenocarcinoma 0050861 Entrectinib Predictive Supports C Resistance A gene fusion between exon 10 of NTRK1 and exon 11 of the LMNA genes was observed in a patient with metastatic colorectal cancer after therapy with first-line FOLFOX, second-line FOLFIRI/cetuximab, and third-line irinotecan. The patient treated in a clinical trial with pan-TRK kinase inhibitor entrectinib. Treatment was well tolerated and led to a partial response (PR) with 30% tumor shrinkage of multiple liver metastases. Clinical response lasted 4 months. Longitudinal analysis of ctDNA in plasma samples revealed a p.G595R- and p.G667C mutation in NTRK1 that were absent before treatment initiation but emerged 4 weeks upon initiation of treatment with entrectinib. These mutations were also validated using xenograft, in vitro and 3D-modeling. 26546295 PubMed Russo et al., 2016, Cancer Discov 4 accepted 2961 1282 3983 1 156846342 156849107 ENST00000524377.1 75 GRCh37 Somatic 2017-08-31 17:27:06 UTC https://civicdb.org/links/evidence_items/2961 https://civicdb.org/links/variants/1282 https://civicdb.org/links/genes/3983 false TP53 7157 Wildtype Cancer 162 Rebemadlin Predictive Supports D Sensitivity/Response MDM2 Inhibitor Nutlin-3a induced senescence in presence of functional TP53 in murine primary fibroblasts, oncogenically transformed fibroblasts, and fibrosarcoma cell lines. Cells lacking functional TP53 were completely insensitive to the drug. 17671205 PubMed Efeyan et al., 2007, Cancer Res. 4 accepted 2963 369 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 N/A 2017-05-11 15:58:03 UTC https://civicdb.org/links/evidence_items/2963 https://civicdb.org/links/variants/369 https://civicdb.org/links/genes/45 false TP53 7157 Wildtype Cancer 162 MDM2 Inhibitor AMGMDS3 Predictive Supports D Sensitivity/Response MDM2 Inhibitor screen in a panel of 260 cancer cell lines with well characterized TP53 status shows that only cancer cell lines with unaltered TP53 may be sensitive to MDM2 Inhibitor. 25730903 PubMed Saiki et al., 2015, Oncotarget 4 accepted 2964 369 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 N/A 2022-01-06 18:56:34 UTC https://civicdb.org/links/evidence_items/2964 https://civicdb.org/links/variants/369 https://civicdb.org/links/genes/45 false TP53 7157 Wildtype Leukemia 1240 RG7112 Predictive Supports B Sensitivity/Response Phase I Trial of RG7112 in 116 heavily pretreated patients with AML, ALL, CML, CLL, sCLL demonstrated sustained clinical improvement and induction of TP53 target genes in subset of patients with wild type TP53. 96 patients were tested for TP53 mutation and 19 cases of mutation were detected. No sustained clinical improvement or induction of TP53 target genes was observed in patients with mutant TP53. 26459177 PubMed Andreeff et al., 2016, Clin. Cancer Res. 3 accepted 2965 369 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 N/A 2018-10-17 12:27:06 UTC https://civicdb.org/links/evidence_items/2965 https://civicdb.org/links/variants/369 https://civicdb.org/links/genes/45 false TP53 7157 Deleterious Mutation Leukemia 1240 RG7112 Predictive Supports B Resistance Phase I Trial of MDM2 inhibitor RG7112 in 116 patients with AML, ALL, CML, CLL, sCLL demonstrated sustained clinical improvement and induction of TP53 target genes in subset of patients with wild type TP53. No sustained clinical improvement or induction of TP53 target genes was observed in patients with mutant TP53. 26459177 PubMed Andreeff et al., 2016, Clin. Cancer Res. 3 accepted 2966 221 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Deleterious mutations are mutations of TP53 with prior characterization demonstrating significant deleterious effect on TP53 protein function. Inactivating TP53 mutations prevent on target activity and efficacy of MDM2-TP53 interaction inhibitors. Somatic 2017-05-31 15:15:11 UTC https://civicdb.org/links/evidence_items/2966 https://civicdb.org/links/variants/221 https://civicdb.org/links/genes/45 false TP53 7157 Deleterious Mutation Cancer 162 MDM2 Inhibitor AMGMDS3 Predictive Supports D Resistance MDM2 Inhibitor screen in a panel of 260 cancer cell lines with well characterized TP53 status shows that only cancer cell lines with unaltered TP53 may be sensitive to MDM2 Inhibitor AMGMDS3, while those with p53 mutations demonstrated resistance. 25730903 PubMed Saiki et al., 2015, Oncotarget 4 accepted 2967 221 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Deleterious mutations are mutations of TP53 with prior characterization demonstrating significant deleterious effect on TP53 protein function. Inactivating TP53 mutations prevent on target activity and efficacy of MDM2-TP53 interaction inhibitors. Somatic 2017-05-10 22:11:43 UTC https://civicdb.org/links/evidence_items/2967 https://civicdb.org/links/variants/221 https://civicdb.org/links/genes/45 false TP53 7157 Deleterious Mutation Cancer 162 Rebemadlin Predictive Supports D Resistance MDM2 Inhibitor Nutlin-3a induced senescence in presence of functional TP53 in murine primary fibroblasts, oncogenically transformed fibroblasts, and fibrosarcoma cell lines. TP53 mutant cells lacking functional TP53 were completely insensitive to the drug. 17671205 PubMed Efeyan et al., 2007, Cancer Res. 4 accepted 2968 221 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Deleterious mutations are mutations of TP53 with prior characterization demonstrating significant deleterious effect on TP53 protein function. Inactivating TP53 mutations prevent on target activity and efficacy of MDM2-TP53 interaction inhibitors. Somatic 2017-05-11 16:06:05 UTC https://civicdb.org/links/evidence_items/2968 https://civicdb.org/links/variants/221 https://civicdb.org/links/genes/45 false DCC 1630 EXPRESSION Colorectal Cancer 9256 Prognostic Supports B Better Outcome Expression of DCC was a strong positive predictive factor for survival in both stage II and stage III colorectal carcinomas. In patients with stage II disease whose tumors expressed DCC, the five-year survival rate was 94.3 percent, whereas in patients with DCC-negative tumors, the survival rate was 61.6 percent (P<0.001). In patients with stage III disease, the respective survival rates were 59.3 percent and 33.2 percent (P=0.03). 8929264 PubMed Shibata et al., 1996, N. Engl. J. Med. 3 accepted 2972 1284 1396 Somatic 2017-07-27 22:02:39 UTC https://civicdb.org/links/evidence_items/2972 https://civicdb.org/links/variants/1284 https://civicdb.org/links/genes/1396 false CTNNB1 1499 T41A Desmoid Tumor 0080366 Diagnostic Supports B Positive Desmoid fibromatosis is a rare, nonmetastatic neoplasm marked by local invasiveness and relentless recurrence. Beta-Catenin deregulation has been commonly identified in sporadic desmoids. CTNNB1 mutations were observed in 117 of 138 (85%) of desmoids. Three discrete mutations in two codons of CTNNB1 exon 3 were identified: T41A (59%), S45F (33%), and S45P (8%). Five-year recurrence-free survival was significantly poorer in S45F-mutated desmoids (23%, P < 0.0001) versus either T41A (57%) or nonmutated tumors (65%). In conclusion, CTNNB1 mutations are highly common in desmoid tumors. Furthermore, patients harboring CTNNB1 (45F) mutations are at particular risk for recurrence and therefore may especially benefit from adjuvant therapeutic approaches. 18832571 PubMed Lazar et al., 2008, Am. J. Pathol. 4 accepted 2973 1285 1290 3 41266124 41266124 A G ENST00000349496.5 75 GRCh37 Somatic 2020-10-09 16:10:06 UTC https://civicdb.org/links/evidence_items/2973 https://civicdb.org/links/variants/1285 https://civicdb.org/links/genes/1290 false CTNNB1 1499 S45F Desmoid Tumor 0080366 Diagnostic Supports B Positive Desmoid fibromatosis is a rare, nonmetastatic neoplasm marked by local invasiveness and relentless recurrence. Beta-Catenin deregulation has been commonly identified in sporadic desmoids. CTNNB1 mutations were observed in 117 of 138 (85%) of desmoids. Three discrete mutations in two codons of CTNNB1 exon 3 were identified: T41A (59%), S45F (33%), and S45P (8%). Five-year recurrence-free survival was significantly poorer in S45F-mutated desmoids (23%, P < 0.0001) versus either T41A (57%) or nonmutated tumors (65%). In conclusion, CTNNB1 mutations are highly common in desmoid tumors. Furthermore, patients harboring CTNNB1 (S45F) mutations are at particular risk for recurrence and therefore may especially benefit from adjuvant therapeutic approaches. 18832571 PubMed Lazar et al., 2008, Am. J. Pathol. 4 accepted 2974 1286 1290 3 41266137 41266137 C T ENST00000349496.5 75 GRCh37 Somatic 2020-10-09 16:10:06 UTC https://civicdb.org/links/evidence_items/2974 https://civicdb.org/links/variants/1286 https://civicdb.org/links/genes/1290 false CTNNB1 1499 S45P Desmoid Tumor 0080366 Diagnostic Supports B Positive Desmoid fibromatosis is a rare, nonmetastatic neoplasm marked by local invasiveness and relentless recurrence. Beta-Catenin deregulation has been commonly identified in sporadic desmoids. CTNNB1 mutations were observed in 117 of 138 (85%) of desmoids. Three discrete mutations in two codons of CTNNB1 exon 3 were identified: T41A (59%), S45F (33%), and S45P (8%). In conclusion, CTNNB1 mutations are highly common in desmoid tumors. 18832571 PubMed Lazar et al., 2008, Am. J. Pathol. 3 accepted 2975 1287 1290 3 41266136 41266136 T C ENST00000349496.5 75 GRCh37 Somatic 2020-10-09 16:10:06 UTC https://civicdb.org/links/evidence_items/2975 https://civicdb.org/links/variants/1287 https://civicdb.org/links/genes/1290 false CTNNB1 1499 S45F Desmoid Tumor 0080366 Prognostic Supports B Poor Outcome Desmoid fibromatosis is a rare, nonmetastatic neoplasm marked by local invasiveness and relentless recurrence. Beta-Catenin deregulation has been commonly identified in sporadic desmoids. CTNNB1 mutations were observed in 117 of 138 (85%) of desmoids. Three discrete mutations in two codons of CTNNB1 exon 3 were identified: T41A (59%), S45F (33%), and S45P (8%). Five-year recurrence-free survival was significantly poorer in S45F-mutated desmoids (23%, P < 0.0001) versus either T41A (57%) or nonmutated tumors (65%). In conclusion, CTNNB1 mutations are highly common in desmoid tumors. Furthermore, patients harboring CTNNB1 (S45F) mutations are at particular risk for recurrence and therefore may especially benefit from adjuvant therapeutic approaches. 18832571 PubMed Lazar et al., 2008, Am. J. Pathol. 3 accepted 2976 1286 1290 3 41266137 41266137 C T ENST00000349496.5 75 GRCh37 Somatic 2020-10-09 16:10:06 UTC https://civicdb.org/links/evidence_items/2976 https://civicdb.org/links/variants/1286 https://civicdb.org/links/genes/1290 false ARID1A 8289 Loss-of-function Ovarian Clear Cell Carcinoma 0050934 Dasatinib Predictive Supports D Sensitivity/Response High-throughput drug screens in OCCC tumor cell model identified synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo. 27364904 PubMed Miller et al., 2016, Mol. Cancer Ther. 3 accepted 2982 1293 6559 1 27022524 27108595 ENST00000324856.7 75 GRCh37 Somatic 2018-07-06 20:29:40 UTC https://civicdb.org/links/evidence_items/2982 https://civicdb.org/links/variants/1293 https://civicdb.org/links/genes/6559 false ARID1A 8289 Loss-of-function Ovarian Clear Cell Carcinoma 0050934 GSK126 Predictive Supports D Sensitivity/Response Inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated ovarian cancer cells. ARID1A mutational status correlates with response to the EZH2 inhibitor. Significantly, EZH2 inhibition causes regression of ARID1A mutated ovarian tumors in vivo. 25686104 PubMed Bitler et al., 2015, Nat. Med. 4 accepted 2983 1293 6559 1 27022524 27108595 ENST00000324856.7 75 GRCh37 Somatic 2018-07-06 20:29:32 UTC https://civicdb.org/links/evidence_items/2983 https://civicdb.org/links/variants/1293 https://civicdb.org/links/genes/6559 false PIK3CA 5290 E545K Cervix Carcinoma 2893 Cisplatin,Pictilisib Combination Predictive Supports D Sensitivity/Response CaSki cells that are heterozygous for the PIK3CA-E545K mutation are more resistant to cisplatin or cisplatin plus radiation than either HeLa or SiHa cells that express only wild-type PIK3CA. Similarly, HeLa cells engineered to stably express PIK3CA-E545K were more resistant to cisplatin or cisplatin plus radiation than cells expressing only wild-type PIK3CA or with PIK3CA depleted. Cells expressing the PIK3CA-E545K mutation also had constitutive PI3K pathway activation and increased cellular migration and each of these phenotypes was reversed by treatment with the PI3K inhibitor GDC-0941/Pictilisib. In addition, GDC-0941 restored sensitivity of E545K mutant cell lines to cisplatin as combination treatment had a larger impact on cell survival than either drug alone. 27489350 PubMed Arjumand et al., 2016, Oncotarget 3 accepted 2984 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2021-01-05 00:33:46 UTC https://civicdb.org/links/evidence_items/2984 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false PIK3CA 5290 E545K Cervical Cancer 4362 Cisplatin Predictive Supports D Resistance Authors tested various cervical cancer cell lines (CaSki, SiHa and HeLa) for their responses to cisplatin, radiation therapy, and GDC-0941. CaSki cells that are heterozygous for the PIK3CA-E545K mutation were significantly more resistant to cisplatin or cisplatin plus radiation than either HeLa or SiHa cells that express only wild-type PIK3CA. Similarly, HeLa cells engineered to stably express PIK3CA E545K were more resistant to cisplatin or cisplatin plus radiation than cells expressing only wild-type PIK3CA or with PIK3CA depleted. Cells expressing the PIK3CA-E545K mutation also had constitutive PI3K pathway activation and increased cellular migration and each of these phenotypes was reversed by treatment with the PI3K inhibitor GDC-0941 (pictilisib). 27489350 PubMed Arjumand et al., 2016, Oncotarget 3 accepted 2985 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2022-01-06 00:52:21 UTC https://civicdb.org/links/evidence_items/2985 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false VHL 7428 W8* (c.24G>A) Renal Cell Carcinoma 4450 Oncogenic N/A C N/A A single case (named "3GT" in this study) with sporadic grade 3 renal cell carcinoma was observed with both W8* and G44D somatic variants. 11536052 PubMed Ma et al., 2001, Oncogene 1 accepted 2986 1294 58 3 10183555 10183555 G A ENST00000256474.2 75 GRCh37 Somatic 2021-03-06 06:51:02 UTC https://civicdb.org/links/evidence_items/2986 https://civicdb.org/links/variants/1294 https://civicdb.org/links/genes/58 false ALK 238 F1245V Neuroblastoma 769 Entrectinib Predictive Supports C Sensitivity/Response Clinical trial of entrectinib in patients with ALK/ROS/TRK altered tumors. One patient with an ALK F1245V-mutant neuroblastoma achieved a durable, confirmed partial response (PR) lasting 8.3 months. The patient remained on study treatment for more than 3.5 years because of clinical benefit. 28183697 PubMed Drilon et al., 2017, Cancer Discov 3 accepted 2987 1295 1 2 29436860 29436860 A C ENST00000389048.3 75 GRCh37 Somatic 2019-11-05 23:55:05 UTC https://civicdb.org/links/evidence_items/2987 https://civicdb.org/links/variants/1295 https://civicdb.org/links/genes/1 false CTNNB1 1499 Activating Mutation Melanoma 1909 Anti-PD-L1 Monoclonal Antibody,Anti-CTLA-4 Monoclonal Antibody Substitutes Predictive Supports D Resistance Activation of melanoma-cell-intrinsic WNT/β-catenin signalling pathway contributes to a lack of T-cell infiltration in melanoma. Molecular analysis of human metastatic melanoma samples revealed a correlation between activation of the WNT/β-catenin signalling pathway and absence of a T-cell gene expression signature. In autochthonous mouse melanoma models active β-catenin signalling results in T-cell exclusion and resistance to anti-PD-L1/anti-CTLA-4 monoclonal antibody therapy. 25970248 PubMed Spranger et al., 2015, Nature 4 accepted 2988 1296 1290 3 41240930 41281936 ENST00000349496.5 75 GRCh37 Somatic 2017-05-30 18:06:43 UTC https://civicdb.org/links/evidence_items/2988 https://civicdb.org/links/variants/1296 https://civicdb.org/links/genes/1290 false MERTK 10461 OVEREXPRESSION Melanoma 1909 UNC1062 Predictive Supports D Sensitivity/Response Highest MERTK expression was observed in metastatic melanomas, followed by primary melanomas, and lowest in benign nevi. Over half of melanoma cell lines overexpressed MERTK compared with normal human melanocytes; however, overexpression did not correlate with mutations in BRAF or RAS. MERTK inhibition via shRNA reduced MERTK-mediated downstream signaling, reduced colony formation by up to 59%, and diminished tumor volume by 60% in a human melanoma murine xenograft model. Treatment of melanoma cells with UNC1062, a novel MERTK-selective small-molecule tyrosine kinase inhibitor, reduced activation of MERTK-mediated downstream signaling, induced apoptosis in culture, reduced colony formation in soft agar, and inhibited invasion of melanoma cells. 23585477 PubMed Schlegel et al., 2013, J. Clin. Invest. 3 accepted 2991 1299 8331 2 112656056 112787138 ENST00000295408.4 75 GRCh37 Somatic 2017-05-03 16:17:14 UTC https://civicdb.org/links/evidence_items/2991 https://civicdb.org/links/variants/1299 https://civicdb.org/links/genes/8331 false TP53 7157 CONSERVED DOMAIN MUT Ovarian Cancer 2394 Prognostic Supports B Poor Outcome Patients with conserved domain p53 mutation (n=61) were compared with those with wild type or non-conserved domain p53 mutation (n=117) in a cohort of 178 invasive ovarian carcinoma patients who had undergone surgery. Overall survival was decreased in the cohort with conserved domian mutation (p=0.005). Conserved domain mutation was an independent factor in univariate (but not multivariate) analysis of overall survival with relative risk 1.70 (1.17-2.47, p<0.007). 11595686 PubMed Reles et al., 2001, Clin. Cancer Res. 3 accepted 2993 1300 45 17 7577062 7579398 ENST00000269305.4 75 This conserved domain mutation variant covers mutations in regions of p53 reported to be highly conserved during evolution. These regions span codons 117-143 (region II), 171-181 (region III), 234-258 (region (IV), and 270-286 (region V). Region I covers approximately codons 10 through 25 but does not appear in all studies on conserved domain mutations. There is overlap with these regions and reported regions of hotspot p53 mutations, where it is observed that hotspots for detrimental mutation correspond to more highly evolutionary conserved regions. While there is agreement and overlap between different reports, the literature does not seem to indicate an exact consensus on these regions of human p53 at this time, but the four highly conserved regions are part of the DNA binding domain, and are reported to exist within codons 97 to 292. Somatic 2018-07-06 14:54:27 UTC https://civicdb.org/links/evidence_items/2993 https://civicdb.org/links/variants/1300 https://civicdb.org/links/genes/45 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports A Sensitivity/Response On May 14, 2013, the U.S. Food and Drug Administration approved erlotinib (Tarceva) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. 24868098 PubMed Khozin et al., 2014, Oncologist 5 accepted 2994 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2017-05-18 20:18:55 UTC https://civicdb.org/links/evidence_items/2994 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 Exon 19 Deletion Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports A Sensitivity/Response On May 14, 2013, the U.S. Food and Drug Administration approved erlotinib (Tarceva) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. 24868098 PubMed Khozin et al., 2014, Oncologist 5 accepted 2995 133 19 7 55242415 55242513 ENST00000275493.2 75 GRCh37 Deletions within exon 19 of EGFR are most common in lung cancer. These deletions, in non-small cell lung cancer, have been shown to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib, afatinib, and erlotinib. There is also data to suggest that this event is a good prognostic marker in lung adenocarcinoma. Examples of exon 19 deletions include: p.746_A750delELREA, p.747_753delinsS, p.747_752delLREATS, and p.747_751delLREAT. Somatic 2017-05-11 21:11:19 UTC https://civicdb.org/links/evidence_items/2995 https://civicdb.org/links/variants/133 https://civicdb.org/links/genes/19 false EGFR 1956 Exon 19 Deletion Lung Non-small Cell Carcinoma 3908 Afatinib Predictive Supports A Sensitivity/Response Afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases has been approved in the US for the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC) who have tumours with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test 23982599 PubMed Dungo et al., 2013, Drugs 5 accepted 2996 133 19 7 55242415 55242513 ENST00000275493.2 75 GRCh37 Deletions within exon 19 of EGFR are most common in lung cancer. These deletions, in non-small cell lung cancer, have been shown to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib, afatinib, and erlotinib. There is also data to suggest that this event is a good prognostic marker in lung adenocarcinoma. Examples of exon 19 deletions include: p.746_A750delELREA, p.747_753delinsS, p.747_752delLREATS, and p.747_751delLREAT. Somatic 2017-05-18 19:40:29 UTC https://civicdb.org/links/evidence_items/2996 https://civicdb.org/links/variants/133 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Afatinib Predictive Supports A Sensitivity/Response Afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases has been approved in the US for the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC) who have tumours with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test 23982599 PubMed Dungo et al., 2013, Drugs 5 accepted 2997 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2017-05-18 20:22:52 UTC https://civicdb.org/links/evidence_items/2997 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Docetaxel,Selumetinib Combination Predictive Supports A Resistance A phase 3 study of selumetinib and docetaxel in KRAS mutant, previously treated NSCLC. 866 were enrolled and 510 randomized. Median progression-free survival was 3.9 months with selumetinib + docetaxel and 2.8 months with placebo + docetaxel. Median overall survival was 8.7 months with selumetinib + docetaxel and 7.9 months with placebo + docetaxel. Objective response rate was 20.1% with selumetinib + docetaxel and 13.7% with placebo + docetaxel. 28492898 PubMed Jänne et al., 2017, JAMA NCT01933932 5 accepted 2998 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2017-09-08 18:06:44 UTC https://civicdb.org/links/evidence_items/2998 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false TP53 7157 Mutation Lung Non-small Cell Carcinoma 3908 Prognostic Supports B N/A A pooled analysis to investigate the prognostic and predictive roles of TP53/KRAS and TP53/EGFR comutations (cm) in randomized trials of adjuvant chemotherapy compared to observational therapy encompassing a total of 3,553 patients. TP53/KRAS cm showed no prognostic effects but a borderline predictive effect (p=0,04) for negative effect of chemotherapy as compared to tp53/KRAS wt/wt. TP53/EGFR cm in was neither prognostic ( P = .83), nor significantly predictive ( P = .86). Similar results were observed for both groups for disease-free survival. 28453411 PubMed Shepherd et al., 2017, J. Clin. Oncol. 5 accepted 2999 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 Somatic 2018-07-12 18:40:57 UTC https://civicdb.org/links/evidence_items/2999 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false CD274 29126 Expression Head And Neck Squamous Cell Carcinoma 5520 Radiation Therapy Predictive Supports B Resistance Radiation-resistant cell lines exhibited upregulation and increased activation of Axl, PI3 kinase signalling as well as increased expression of PD-L1. In 3 cohorts of HPV-negative head and neck squamous cell carcinoma patient samples evaluated with different methods [reverse phase protein array (N=68), mRNA expression array (N=97) or immunohistochemistry (N=114), respectively], increased expression of PD-L1 was also correlated with local failure following radiotherapy as compared to the PD-L1–low expression group (P = 0.01, 1.9 × 10−3, and 9 × 10−4, respectively). 28476872 PubMed Skinner et al., 2017, Clin. Cancer Res. 4 accepted 3000 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2017-09-09 23:07:01 UTC https://civicdb.org/links/evidence_items/3000 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false MYC 4609 Overexpression Lung Small Cell Carcinoma 5409 Prexasertib,Olaparib,Cisplatin Combination Predictive Supports D Sensitivity/Response A preclinical study to evaluate the efficacy of targeting the overexpressed CHEK1 cell cycle chekpoint kinase, including both miRNA and Prexasertib-induced inhibition. Both in vitro and in vivo, Prexasertib had strong single agent efficacy and augmented the effect of Olaparib or Cisplatin in either combination, including platinum-resistant models. CHEK1 and MYC overexpression were predictors of response. 28490518 PubMed Sen et al., 2017, Cancer Res. 4 accepted 3003 1303 3737 Somatic 2017-12-18 20:28:22 UTC https://civicdb.org/links/evidence_items/3003 https://civicdb.org/links/variants/1303 https://civicdb.org/links/genes/3737 false FLT3 2322 D835V Acute Myeloid Leukemia 9119 Tandutinib Predictive Supports D Resistance Murine Ba/F3 cells with FLT3-D835V mutations were evaluated as non-responsive to MLN518 (Tandutinib). Cells with single FLT3 (D835V) mutants were resistant to MLN518(IC50 > 10uM) whereas cells with FLT3 (ITD) mutants were not resistant to MLN518 (IC50 0.55uM). 15256420 PubMed Clark et al., 2004, Blood 3 accepted 3007 1302 24 13 28592641 28592641 T A ENST00000241453.7 75 GRCh37 Somatic 2019-08-29 21:46:53 UTC https://civicdb.org/links/evidence_items/3007 https://civicdb.org/links/variants/1302 https://civicdb.org/links/genes/24 false FLT3 2322 D835V Acute Myeloid Leukemia 9119 Sunitinib Predictive Does Not Support D Sensitivity/Response Murine Ba/F3 cells with FLT3 D835V mutation were assessed as not sensitive to SU11248 (Sunitinib) with dose required to inhibit proliferation of cells to 50% of untreated controls ED50 = 110nM. 15304385 PubMed Yee et al., 2004, Blood 3 accepted 3008 1302 24 13 28592641 28592641 T A ENST00000241453.7 75 GRCh37 Somatic 2019-09-05 19:37:44 UTC https://civicdb.org/links/evidence_items/3008 https://civicdb.org/links/variants/1302 https://civicdb.org/links/genes/24 false FLT3 2322 D835V Acute Myeloid Leukemia 9119 Sunitinib,Cytarabine Combination Predictive Supports D Sensitivity/Response SU11248 + Cytarabin has a synergic effect on Murine Ba/F3 cells with FLT3 D835V mutation (Combination Index = 0.59 for ED50, Combination Index = 0.71 for ED75, Combination Index = 0.82 for ED90) 15304385 PubMed Yee et al., 2004, Blood 2 accepted 3009 1302 24 13 28592641 28592641 T A ENST00000241453.7 75 GRCh37 Somatic 2017-06-16 15:31:16 UTC https://civicdb.org/links/evidence_items/3009 https://civicdb.org/links/variants/1302 https://civicdb.org/links/genes/24 false FLT3 2322 D835V Acute Myeloid Leukemia 9119 Sunitinib,Daunorubicin Combination Predictive Supports D Sensitivity/Response SU11248 + Daunorubicin has a synergic effect on Murine Ba/F3 cells with FLT3 D835V mutation. (Combination Index = 0.82 for ED50, Combination Index = 0.72 for ED75, Combination Index = 0.64 for ED90) 15304385 PubMed Yee et al., 2004, Blood 2 accepted 3010 1302 24 13 28592641 28592641 T A ENST00000241453.7 75 GRCh37 Somatic 2017-06-16 15:28:27 UTC https://civicdb.org/links/evidence_items/3010 https://civicdb.org/links/variants/1302 https://civicdb.org/links/genes/24 false FLT3 2322 D835V Acute Myeloid Leukemia 9119 Quizartinib Predictive Does Not Support D Sensitivity/Response Murine Ba/F3 cell line has a restrictive sensitivity to Quizartinib (AC220), a second generation class II tyrosine kinase inhibitor (IC50 for proliferation = 172nM, IC50 for induction of apoptosis = 888nM). 23497317 PubMed Kampa-Schittenhelm et al., 2013, Mol. Cancer 4 accepted 3012 1302 24 13 28592641 28592641 T A ENST00000241453.7 75 GRCh37 Somatic 2021-03-18 06:02:16 UTC https://civicdb.org/links/evidence_items/3012 https://civicdb.org/links/variants/1302 https://civicdb.org/links/genes/24 false TP53 7157 Overexpression Ovarian Cancer 2394 Carboplatin,Cisplatin Substitutes Predictive Supports B Resistance In a study involving patients with invasive ovarian carcinoma who had undergone surgery, a subset of 73 patients were classified via response to platinum-based chemotherapy as sensitive or resistant/refractory and tested for p53 overexpression (>10% postive stained nuclei). 78% of p53 negative patients were classified as sensitive, in compariston to 39% of p53 positive patients (p=0.001). 11595686 PubMed Reles et al., 2001, Clin. Cancer Res. 3 accepted 3013 1306 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 N/A 2020-10-28 06:58:44 UTC https://civicdb.org/links/evidence_items/3013 https://civicdb.org/links/variants/1306 https://civicdb.org/links/genes/45 false TP53 7157 ALTERATION Ovarian Cancer 2394 Prognostic Supports B Poor Outcome In a study of invasive ovarian carcinoma patients who had undergone surgery, the p53 alteration variant was defined as p53 mutation or p53 overexpression by immunostain (>10% positive). Patients with p53 alterations showed increase in poor tumor cell differentiation (p<0.001) and increase in tumor cellular S-phase fraction (p<0.001). Out of 178 patients, p53 alteration (n=132) was associated with decreased overall survival in comparison to normal p53 (n=46), p=0.007. 11595686 PubMed Reles et al., 2001, Clin. Cancer Res. 4 accepted 3014 1307 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 P53 ALTERATION is a bucket type variant used in studies which is constructed by combining all cases of p53 mutation together with p53 overexpression. This includes cases which have p53 mutation or overexpression alone or as well as cases where both occur in combination. Somatic 2017-09-08 22:17:08 UTC https://civicdb.org/links/evidence_items/3014 https://civicdb.org/links/variants/1307 https://civicdb.org/links/genes/45 false EGFR 1956 Amplification Lung Non-small Cell Carcinoma 3908 Rociletinib,Osimertinib Substitutes Predictive Supports D Resistance Evidence of wild-type allele-mediated resistance, a novel concept of acquired resistance in response to mutation-selective inhibitor therapy in cancer treatment. This study reports that the Src-AKT pathway contributes to acquired resistance to third generation EGFR TKIs. In addition, amplification of EGFR wild-type alleles but not mutant alleles was sufficient to confer acquired resistance. 28202511 PubMed Nukaga et al., 2017, Cancer Res. 3 accepted 3015 190 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2017-05-30 18:38:32 UTC https://civicdb.org/links/evidence_items/3015 https://civicdb.org/links/variants/190 https://civicdb.org/links/genes/19 false EGFR 1956 Mutation Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports B Sensitivity/Response In a phase 3 clinical trial of non-small cell lung cancer (NSCLC) patients, a subset of patients with EGFR mutations (n=44) treated with gefitinib were associated with improved progression free survival (HR: 0.16, 95% CI: 0.05-0.49, P=0.001), and a higher objective response rate (ORR: 42.1% vs 21.1%, p=0.04) compared to patients treated with docetaxel. Of the 44 patients, 22 had an exon 19 deletion, 16 had an L858R mutation, one patient had an exon 20 T790M mutation, two had an exon G719A mutation and four had other mutations. 20038723 PubMed Douillard et al., 2010, J. Clin. Oncol. NCT00076388 3 accepted 3016 442 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2020-09-29 03:17:55 UTC https://civicdb.org/links/evidence_items/3016 https://civicdb.org/links/variants/442 https://civicdb.org/links/genes/19 false BRAF 673 V600E Lung Non-small Cell Carcinoma 3908 Dabrafenib,Trametinib Combination Predictive Supports A Sensitivity/Response Patients with BRAF V600E-mutant NSCLC (n=57) were enrolled into a phase 2, multicentre, non-randomised, open-label study, administering dabrafenib plus trametinib. The overall response rate was 36/57 (63.2%, [95% CI 49.3-75.6]) and the median progression-free survival was 9.7 months (95% CI 6.9-19.6). At data cutoff (11.6 months of follow-up), 18/36 (50%) confirmed responses were ongoing and 23/57 (40%) of patients had died. 27283860 PubMed Planchard et al., 2016, Lancet Oncol. NCT01336634 4 accepted 3017 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2017-06-29 14:37:21 UTC https://civicdb.org/links/evidence_items/3017 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false FGFR1 2260 Amplification Lung Non-small Cell Carcinoma 3908 Dovitinib Predictive Supports B Sensitivity/Response Clinical trial studied the efficacy of Dovitinib on 26 patients with FGFR1 amplifications. Objective response for the cohort was 11.5%, disease control rate was 50%. 11.5% of patients exhibited partial response, 38.5% exhibited stable disease. Median PFS was 2.9 months, median OS was 5 months, this trend was worse with increases in FGFR1 amplification above average. 27315356 PubMed Lim et al., 2016, Cancer 2 accepted 3027 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). Somatic 2017-07-25 20:12:41 UTC https://civicdb.org/links/evidence_items/3027 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false KIT 3815 V559D Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports C Sensitivity/Response A patient with an uncontrolled relapse of c-kit-positive mesenchymal tumor in descending part of the duodenum had received 400mg Imatinib daily for more than 10 years at the time of publication. He responded well to therapy (Karnofsky index 90%). KIT V559D (Exon 11) was identified in the diagnostic biopsy and indicated as a positive predictor of imatinib response with long term usage. 22114577 PubMed Cameron et al., 2011, Case Rep Oncol 3 accepted 3028 968 29 4 55593610 55593610 T A ENST00000288135.5 75 GRCh37 Somatic 2019-02-21 20:55:19 UTC https://civicdb.org/links/evidence_items/3028 https://civicdb.org/links/variants/968 https://civicdb.org/links/genes/29 false KIT 3815 V559D Cancer 162 Imatinib,PD-180970,Sunitinib,Dasatinib,Tandutinib Substitutes Predictive Supports D Sensitivity/Response KIT(V559D) were expressed in HEK-293 cells (in vitro). Imatinib, BMS-354825 (dasatinib), PD-180970, MLN-518 (tandutinib), and SU-11248 bind variant V559D with high affinity (Kd =< 20 nM), and inhibit KIT autophosphorylation. Despite similar binding affinities, the cellular activity of BMS-354825 was >10-fold greater than that of SU-11248 or PD-180970, and the authors hypothesize that additional pharmaceutical properties may contribute to the greater cellular potency. 16046538 PubMed Carter et al., 2005, Proc. Natl. Acad. Sci. U.S.A. 2 accepted 3029 968 29 4 55593610 55593610 T A ENST00000288135.5 75 GRCh37 Somatic 2021-06-09 18:48:02 UTC https://civicdb.org/links/evidence_items/3029 https://civicdb.org/links/variants/968 https://civicdb.org/links/genes/29 false FLT3 2322 D835V Acute Myeloid Leukemia 9119 Tyrphostin AG 1296,AS602868 Substitutes Predictive Supports D Sensitivity/Response Murine Ba/F3 cells with FLT3 D835V mutation were assessed as sensitive to both AS602868 and AG1296.(IC50 = 1.85uM and IC50 = 4.55uM, respectively) 17330097 PubMed Griessinger et al., 2007, Leukemia 3 accepted 3034 1302 24 13 28592641 28592641 T A ENST00000241453.7 75 GRCh37 Somatic 2018-04-30 18:49:51 UTC https://civicdb.org/links/evidence_items/3034 https://civicdb.org/links/variants/1302 https://civicdb.org/links/genes/24 false MET 4233 Overexpression Uveal Melanoma 6039 Trametinib,Selumetinib Substitutes Predictive Supports D Resistance In this study the authors screened for growth factors that elicited resistance in newly characterized metastatic uveal melanoma cell lines to clinical-grade MEK inhibitors, trametinib and selumetinib, showing that neuregulin 1 (NRG1) and hepatocyte growth factor (HGF) provide resistance to MEK inhibition. Trametinib enhances the responsiveness to NRG1 and sustained HGF-mediated activation of AKT. Targeting ERBB3 and cMET could overcome resistance to trametinib. 25952648 PubMed Cheng et al., 2015, Cancer Res. 3 accepted 3038 621 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 N/A 2020-10-20 06:08:29 UTC https://civicdb.org/links/evidence_items/3038 https://civicdb.org/links/variants/621 https://civicdb.org/links/genes/52 false AKT1 207 E17K Cancer 162 Capivasertib Predictive Supports B Sensitivity/Response AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363. 58 patients with advanced solid tumors were treated. In patients with AKT1 E17K-mutant tumors (n = 52) and a median of 5 lines of prior therapy, the median PFS was 5.5 months , 6.6 months and 4.2 months in patients with ER+ breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K-mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS as was the presence of coincident PI3K pathway hotspot mutations. Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS and response. Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. 28489509 PubMed Hyman et al., 2017, J. Clin. Oncol. 4 accepted 3039 4 2 14 105246551 105246551 C T ENST00000407796.2 75 GRCh37 AKT1 E17K is a recurrent mutation that has been observed in breast, colorectal, lung, and ovarian cancer. It has been convincingly shown to be an activating mutation resulting in PI3K/AKT/mTOR pathway activity. It has been suggested that this mutation decreases the cell's sensitivity to AKT1 allosteric kinase inhibitors. This, and other AKT1 mutations, are the subject of much research and development for therapeutics. Somatic 2017-06-09 18:44:10 UTC https://civicdb.org/links/evidence_items/3039 https://civicdb.org/links/variants/4 https://civicdb.org/links/genes/2 false PIK3CA 5290 Mutation Cancer 162 Capivasertib Predictive Supports B Sensitivity/Response In a study of 37 patients with AKT1 (E13K) mutations, 5 patients harbored a concurrent PI3K/mTOR pathway alteration. The PFS of patients with a concurrent PI3K/mTOR pathway alteration was significantly longer than those without when treated with AZD-5363 (median PFS, not reached v 4.3 months, respectively; HR, 0.21; P = 0.045). 28489509 PubMed Hyman et al., 2017, J. Clin. Oncol. 4 accepted 3040 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2017-07-18 19:33:49 UTC https://civicdb.org/links/evidence_items/3040 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false TP53 7157 R248Q Cancer 162 MDM2 Inhibitor AMGMDS3 Predictive Supports D Resistance Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R248Q loss of function mutation is present in 5 cell lines and all are insensitive to MDM2 Inhibitor AMGMDS3. 25730903 PubMed Saiki et al., 2015, Oncotarget 4 accepted 3042 117 45 17 7577538 7577538 C T ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R248 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, R248 mutations have been shown to confer worse overall survival. The R248Q mutation has also shown an increased invasive behavior in cell lines. This is specific to the 248Q variant. Somatic 2017-06-15 15:37:34 UTC https://civicdb.org/links/evidence_items/3042 https://civicdb.org/links/variants/117 https://civicdb.org/links/genes/45 false CTNNB1 1499 S45P Desmoid Tumor 0080366 Prognostic Supports B Better Outcome Desmoid fibromatosis is a rare, nonmetastatic neoplasm marked by local invasiveness and relentless recurrence. Beta-Catenin deregulation has been commonly identified in sporadic desmoids. CTNNB1 mutations were observed in 117 of 138 (85%) of desmoids. Three discrete mutations in two codons of CTNNB1 exon 3 were identified: T41A (59%), S45F (33%), and S45P (8%). Five-year recurrence-free survival was significantly poorer in S45F-mutated desmoids (23%, P < 0.0001) versus either T41A (57%) or nonmutated tumors (65%). Because of their low frequency, patients with S45P mutations were excluded from these analyses but showed a recurrence course similar to T41A or wild type patients. 18832571 PubMed Lazar et al., 2008, Am. J. Pathol. 1 accepted 3043 1287 1290 3 41266136 41266136 T C ENST00000349496.5 75 GRCh37 Somatic 2020-10-09 16:10:06 UTC https://civicdb.org/links/evidence_items/3043 https://civicdb.org/links/variants/1287 https://civicdb.org/links/genes/1290 false CTNNB1 1499 T41A Desmoid Tumor 0080366 Prognostic Supports B Better Outcome In an analysis of 138 desmoid fibromatosis tumors, which is a rare, nonmetastatic neoplasm marked by local invasiveness and relentless recurrence, 117 tumors (85%) had CTNNB1 mutations. Three discrete mutations in two codons of CTNNB1 exon 3 were identified: T41A (59%), S45F (33%), and S45P (8%). Five-year recurrence-free survival was significantly poorer in S45F-mutated desmoids (23%, P < 0.0001) versus either T41A (57%) or nonmutated tumors. 18832571 PubMed Lazar et al., 2008, Am. J. Pathol. 3 accepted 3044 1285 1290 3 41266124 41266124 A G ENST00000349496.5 75 GRCh37 Somatic 2020-10-09 16:10:06 UTC https://civicdb.org/links/evidence_items/3044 https://civicdb.org/links/variants/1285 https://civicdb.org/links/genes/1290 false GNAS 2778 R201H Thyroid Gland Follicular Carcinoma 3962 Radioactive Iodine Predictive Supports C Sensitivity/Response A 79 year old patient with prior history of graves' disease presented with follicular thyroid carcinoma. Two mutations NRAS p.Q61K and GNAS p.R201H were detected. The thyroid cancer manifested as a 13.5 cm mass. There were minimal lung, humerus and T9 spine metastases, and exhibited a very good response to the radioactive iodine treatment after he had underwent total thyroidectomy and bilateral neck dissection. They also screened other 23 fatal cases and revealed that none of them had GNAS p.R201H mutation. But two of them had NRAS p.Q61K mutation. 26788326 PubMed Lu et al., 2016, Endocrinol Diabetes Metab Case Rep 2 accepted 3045 1319 2319 Somatic 2017-07-20 14:59:22 UTC https://civicdb.org/links/evidence_items/3045 https://civicdb.org/links/variants/1319 https://civicdb.org/links/genes/2319 false BRAF 673 Non-V600 Colorectal Cancer 9256 Prognostic Supports B Better Outcome This study of 9,643 patients characterized clinical implications of non-V600 BRAF mutations in metastatic CRC. Of the patients with metastatic CRC that underwent NGS testing, 208 patients had non-V600 BRAF mutations (22% of BRAF mutations identified and 2.2% of total patients tested ). When compared to V600 BRAF mutations, tumors without V600 BRAF mutations were more prevalent in younger patients (58 v 68 years, respectively) and male patients (65% vs 46%, respectively). Additionally, non-V600 BRAF mutations were less prevalent in high-grade tumors (13% v 64%, respectively) and right-sided primary tumors (36% v 81%, respectively). Median overall survival was significantly longer in patients with non-V600 BRAF-mutant metastatic CRC compared with those with both V600E BRAF-mutant and wild-type BRAF metastatic CRC (60.7 v 11.4 v 43.0 months). 28486044 PubMed Jones et al., 2017, J. Clin. Oncol. 5 accepted 3046 2408 5 Somatic 2018-07-24 16:28:05 UTC https://civicdb.org/links/evidence_items/3046 https://civicdb.org/links/variants/2408 https://civicdb.org/links/genes/5 false PIK3CA 5290 H1047L or H1047R Invasive Tubular Breast Carcinoma 6587 Prognostic Supports B Poor Outcome In a retrospective analysis of 32 Western Chinese female patients with invasive ductal breast cancer, PIK3CA H1047L (n=1) or H1047R (n=8) was associated with worse survival and increased incidence of lymph node invasion. The incidence of lymph node invasion was 15/23 (65%) for the PIK3CA wildtype population and 7/9 (78%) for the subset of patients whose tumors harbored PIK3CA H1047L or H1047R. Authors note that age, tumor grade, tumor size, number of lymphatic nodes and IHC results did not show significant difference between PIK3CA-mutated and non-mutated samples. 28269754 PubMed Cheng et al., 2017, Cancer Biomark 1 accepted 3047 3766 37 Somatic 2022-03-31 23:51:19 UTC https://civicdb.org/links/evidence_items/3047 https://civicdb.org/links/variants/3766 https://civicdb.org/links/genes/37 false GNA11 2767 Mutation Uveal Melanoma 6039 Cabozantinib Predictive Supports B Sensitivity/Response In total, 77 patients with metastatic melanoma (62% cutaneous, 30% uveal, 8% mucosal) were admitted into a randomized phase II trial assessing the efficacy of Cabozantinib. Patients received cabozantinib 100 mg/d during a 12-week lead-in. Patients with stable disease (SD; RECIST) at week 12 were randomized to cabozantinib or placebo. During lead-in phase, 55% of evaluable patients showed reduction in target lesion size (59% uveal melanoma). Uveal melanoma cohort included 23 patients, 9 with GNAQ (n=5) and GNA11 (n=4) mutations. Responses were reported in mutational patients. In the uveal melanoma cohort, 61% of patients (14/23) had SD at week 12, and no patient had a PR, resulting in an overall disease control rate of 61%. The median PFS for the 23 patients with uveal melanoma was 4.8 months. 28103611 PubMed Daud et al., 2017, Br. J. Cancer 3 accepted 3049 506 2308 19 3094408 3124002 ENST00000078429.4 75 GRCh37 Somatic 2021-01-25 23:41:21 UTC https://civicdb.org/links/evidence_items/3049 https://civicdb.org/links/variants/506 https://civicdb.org/links/genes/2308 false NRAS 4893 Q61H Colorectal Cancer 9256 Cetuximab,Irinotecan Combination Predictive Supports C Resistance One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored NRAS Q61H was wildtype for KRAS, BRAF and PIK3CA. This patient was was a 73 year old male treated with cetuximab and irinotecan as 4th line therapy who experienced progressive disease and had PFS of 10 weeks and OS of 36 weeks. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 2 accepted 3690 893 36 1 115256528 115256528 T G ENST00000369535.4 75 GRCh37 Somatic 2020-11-10 22:13:24 UTC https://civicdb.org/links/evidence_items/3690 https://civicdb.org/links/variants/893 https://civicdb.org/links/genes/36 false NRAS 4893 G12D Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance In a retrospective study of 148 treatment naive metastatic colorectal cancer patients, patients with RAS mutations (n=10), including KRAS A146T, KRAS G13D, NRAS G12D and NRAS Q179*, treated with FOLFOX4 plus cetuximab were associated with decreased overall survival (16.3mo vs. 28.5mo, HR:0.43, 95% CI:0.20-0.89, P=0.020) and decreased progression free survival (7.2mo vs. 9.7mo, HR:0.56, 95% CI:0.27-1.16, P=0.11), as compared to patients with wild-type KRAS and NRAS. 25666295 PubMed Kaczirek et al., 2015, Clin Colorectal Cancer accepted 3693 878 36 1 115258747 115258747 C T ENST00000369535.4 75 GRCh37 Somatic 2017-07-20 15:51:07 UTC https://civicdb.org/links/evidence_items/3693 https://civicdb.org/links/variants/878 https://civicdb.org/links/genes/36 false KRAS 3845 Mutation Colorectal Cancer 9256 Cetuximab,Chemotherapy Combination Predictive Supports B Resistance This was a retrospective study of 605 patients with metastatic, chemotherapy refractory colorectal cancer treated with cetuximab + chemotherapy. Patients with KRAS mutant tumors (total [n = 253], codon 12 [n=183], 13 [n=47], 59 [n=1], 61 [n=13], 146 [n=9]) had a significantly lower response rate (17/253; 6.7%) compared to patients with KRAS wt tumors (126/352; 35.8%; OR: .13; P < .0001). Patients with KRAS mutant tumors also experienced significant lower disease control rate, shorter median progression free survival and overall survival. Association between KRAS mutation status and outcome was confirmed in multivariate analysis. Authors note that these patients were treated with cetuximab prior to widespread adoption of regular KRAS mutational status screening. Patients treated with cetuximab or panitumumab monotherapy were not included. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 4 accepted 3704 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2020-03-12 23:03:52 UTC https://civicdb.org/links/evidence_items/3704 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 G12A Colorectal Cancer 9256 Regorafenib Predictive Supports D Resistance In an in vitro study, a human colon adenocarcinoma SW48 cell line virally transduced to express KRAS G12A demonstrated resistance to regorafenib treatment (IC50: 330.13 nM vs. 114.28 nM, P<0.01, reported errantly as 3301.13nM in the source) compared to SW48 cells expressing KRAS wild-type. Resistance was determined by assessing cell viability. Authors concluded that KRAS G12A was more strongly resistant to regorafenib than KRAS wt and other KRAS G12/G13 mutations. 26161928 PubMed Camaj et al., 2015, Future Oncol 2 accepted 3710 148 30 12 25398284 25398284 C G ENST00000256078.4 75 GRCh37 KRAS G12A, like EGFR T790M, has been shown to be capable of driving acquired resistance to tyrosine kinase inhibitors in lung adenocarcinoma. Somatic 2020-08-30 20:42:40 UTC https://civicdb.org/links/evidence_items/3710 https://civicdb.org/links/variants/148 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Erlotinib,Teprotumumab Combination Predictive Supports B Sensitivity/Response In advanced-stage (IIIB or IV) non-small cell lung cancer patients treated with erlotinib daily and teprotumumab (R1507) weekly or every three weeks, patients whose tumors harbored KRAS mutations had similar progression free survival rates compared to patients with wt KRAS. Among patients given R1507 weekly, those whose tumors had KRAS mutations (n=16) had a 12-week progression free survival (PFS) rate of 25% compared to 30% for KRAS wt patients (n=27; p = 0.7436). For patients given R1507 (teprotumumab) every three weeks, 12-week PFS rate for patients with KRAS mt tumors (n=12) was 50% compared to 27% for patients with KRAS wt tumors (n=34; p=0.1350). Authors concluded that KRAS mutation was predictive of a favorable response to erlotinib + R1507 combination therapy. 22025157 PubMed Ramalingam et al., 2011, J. Clin. Oncol. NCT00760929 2 accepted 3713 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2020-12-29 22:44:02 UTC https://civicdb.org/links/evidence_items/3713 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Prognostic Supports B Poor Outcome Analysis was performed on the placebo group (n=451) of the Phase III study SATURN using erlotinib maintenance therapy for patients with advanced NSCLC who were selected for response or stable disease after first line chemotherpy. The study was not powered for prognostic tests, but it was still found that KRAS Mutant status was a significant negative prognostic factor on progression free survival. (HR, 1.50; 95% CI, 1.06 to 2.12; P=0.20) 21969500 PubMed Brugger et al., 2011, J. Clin. Oncol. 3 accepted 3715 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2017-09-08 18:09:22 UTC https://civicdb.org/links/evidence_items/3715 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false PIK3CA 5290 E545K Melanoma 1909 Vemurafenib Predictive Supports D Resistance An in vitro study of M229 (a human melanoma cell line) endogenously expressing wildtype PIK3CA and BRAF V600E (a known BRAF inhibitor sensitizing mutation) used PIK3CA E545K as a positive control for testing resistance to BRAF inhibition by vemurafenib. M229 cells virally transduced with PIK3CA E545K were significantly more resistant to vemurafenib-mediated growth suppression than cells transduced with empty vectors (50% vs 20% survival at the highest concentration, p <.0001). Furthermore, E545K appears to confer more resistance to vemurafenib than PIK3CA D350G and similar levels of resistance as E545G. Resistance was determined by assessing cell survival. 24265155 PubMed Shi et al., 2014, Cancer Discov 2 accepted 3722 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2018-07-19 20:25:43 UTC https://civicdb.org/links/evidence_items/3722 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false PIK3CA 5290 E545G Melanoma 1909 Vemurafenib Predictive Supports D Resistance An in vitro study of M229 (a human melanoma cell line) endogenously expressing wildtype PIK3CA and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that cells virally induced to stably over-express PIK3CA E545G were significantly more resistant to BRAF inhibition by vemurafenib than cells transduced with an empty vector (50% vs 20% survival at the highest concentration, p < .0001). Though statistics were not provided, E545G appears to confer similar levels of resistance to vemurafenib as the positive control variant, PIK3CA E545K. 24265155 PubMed Shi et al., 2014, Cancer Discov 2 accepted 3724 883 37 3 178936092 178936092 A G ENST00000263967.3 75 GRCh37 Somatic 2018-07-19 20:24:19 UTC https://civicdb.org/links/evidence_items/3724 https://civicdb.org/links/variants/883 https://civicdb.org/links/genes/37 false PIK3CA 5290 Exon 21 Mutation Colorectal Cancer 9256 Prognostic Does Not Support B Poor Outcome This study analyzed tumor and patient characteristics from 1,170 colorectal cancer patients derived from the prospective cohort studies: Nurses' Health Study and Health Professionals Follow Up Study. PIK3CA mutations were found in 16% (189/1170) of patients via pyrosequencing of FFPE samples. Of patients with PIK3CA mutations, 39% (73/189) had mutations in exon 21 (listed as exon 20 in the publication, as it was common at the time of its publication to exclude non-coding exon 1). The presence of an exon 21 mutation was not significantly associated with colorectal cancer-specific or overall survival when compared to patients with wt PIK3CA (multivariate, stage-stratified HR = 1.11 vs 1). Authors note that they had limited data on cancer treatment data, but assume that treatment regimens did not differ substantially based on PIK3CA mutation status given that patients were diagnosed prior to clinical availability of PIK3CA genotype data. They further note that treatment decisions were typically based on cancer stage, for which their analyses adjusted. 22357840 PubMed Liao et al., 2012, Clin. Cancer Res. 2 accepted 3729 105 37 3 178951882 178952495 ENST00000263967.3 75 GRCh37 PIK3CA Exon 21 Mutations (e.g., H1047R; often referred to as Exon 20 mutations if counting only coding exons) are among the most recurrent mutations in cancer, especially breast cancer. Of PIK3CA mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between Exon 21 and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2020-05-28 18:14:47 UTC https://civicdb.org/links/evidence_items/3729 https://civicdb.org/links/variants/105 https://civicdb.org/links/genes/37 false PIK3CA 5290 Mutation Colorectal Cancer 9256 Chemotherapy,Cetuximab Combination Predictive Does Not Support B Resistance This was a retrospective study of 605 patients with metastatic, chemotherapy refractory colorectal cancer treated with cetuximab + chemotherapy. Patients with KRAS wildtype, PIK3CA assessable tumors, and individual response data (n=339) were genotyped for PIK3CA mutations. Patients harboring PIK3CA mutant tumors (n=34) had a significantly lower response rate than did patients with wildtype PIK3CA (6/34 [17.7%] vs 115/305 [37.7%]; p =.015). Patients with mutant PIK3CA also experienced lower disease control rate in response to cetuximab treatment. However, there was no significant difference between patients with mutant or wildtype PIK3CA in progression free or overall survival (median PFS: 18 vs 24 weeks; median OS: 39 vs 51 weeks). Authors suggest that PIK3CA exon 21 mutations are more relevant to cetuximab response than PIK3CA mutations as a whole, as PIK3CA exon 10 mutations do not appear to effect cetuximab response (exons are listed as exon 20 and exon 9 in the source). 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 2 accepted 3732 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2020-12-07 02:26:25 UTC https://civicdb.org/links/evidence_items/3732 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Colorectal Cancer 9256 Vemurafenib Predictive Supports D Resistance In an in vitro study, a RKO cell line expressing BRAF V600E (a known vemurafenib sensitizing mutation) and PIK3CA H1047R co-mutation demonstrated reduced sensitivity to vemurafenib treatment. Resistance was determined by assessing cellular proliferation and AKT phosphorylation. 22180495 PubMed Yang et al., 2012, Cancer Res. 3 accepted 3733 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2020-06-18 22:20:16 UTC https://civicdb.org/links/evidence_items/3733 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false BRAF 673 V600E Colorectal Cancer 9256 FOLFOX-4 Regimen,Cetuximab Combination Predictive Supports B Resistance In a retrospective study of 148 treatment naive metastatic colorectal cancer patients, patients with BRAF V600E and wildtype NRAS/KRAS (n=14) mutation treated with FOLFOX4 plus cetuximab were associated with a decreased progression free survival (7.2mo vs. 9.7mo, HR:0.39, 95% CI:0.21-0.72, P=0.0017), and decreased overall survival (11.7mo vs. 28.5mo, HR:0.23, 95% CI:0.12-0.41, P<0.0001), as compared to patients with wildtype BRAF, NRAS and KRAS. 25666295 PubMed Kaczirek et al., 2015, Clin Colorectal Cancer 4 accepted 3739 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-11-20 23:11:26 UTC https://civicdb.org/links/evidence_items/3739 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Melanoma 1909 Vemurafenib Predictive Supports B Sensitivity/Response In a phase 2 clinical trial (NCT00949702) of 132 BRAF mutation positive metastatic melanoma patients treated with vemurafenib monotherapy, patients harboring BRAF V600E (n=123) or V600K (n=9) mutations were associated with a favorable objective response rate (53% per RECIST v1.1 criteria, 70/132), with 6% (8/132) and 47% (62/132) of patients achieving complete response and partial response, respectively. 23569304 PubMed Trunzer et al., 2013, J. Clin. Oncol. 4 accepted 3750 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-10-29 23:45:43 UTC https://civicdb.org/links/evidence_items/3750 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Melanoma 1909 Vemurafenib Predictive Supports B Sensitivity/Response In a clinical study (NCT01307397) of Polish, stage IIIC/IV, melanoma patients with metastases (n=75) harboring BRAF V600 mutation (as detected by cobas 4800 BRAF V600 Mutation Test), median overall survival was 61.9% (95% CI: 50.1-73.6) and median progression free survival was 7.4 months (95% CI: 5.5-9.2). Median duration of response was 7.4 months (95% CI: 5.7-9.2), with 3% (2/75) and 43% (29/75) of patients achieving a complete and partial response, respectively. 26557775 PubMed Rutkowski et al., 2015, Contemp Oncol (Pozn) 3 accepted 3755 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-10-29 23:51:37 UTC https://civicdb.org/links/evidence_items/3755 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Melanoma 1909 Vemurafenib Predictive Supports B Sensitivity/Response In a retrospective study of 300 stage IV melanoma patients, patients with BRAF V600E mutation (n=175) were associated with a 4.8% (8/167) complete response, a 58.1% (97/167) partial response and stable disease in 22.2% (37/167) of cases, while 15% (25/167) of patients harboring BRAF V600E experienced progressive disease. 25524477 PubMed Ugurel et al., 2015, Ann. Oncol. 3 accepted 3757 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-10-29 23:46:37 UTC https://civicdb.org/links/evidence_items/3757 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Skin Melanoma 8923 Dabrafenib,Trametinib Combination Predictive Supports B Sensitivity/Response In a clinical trial (NCT01597908) of 704 metastatic melanoma patients, patients harboring a BRAF V600E mutation and treated with vemurafenib (n=317) were associated with a 51% response rate, as compared to a 64% response rate (p<0.001) in V600E mutation positive patients treated with dabrafenib and trametinib combination therapy (n=312). Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). 25399551 PubMed Robert et al., 2015, N. Engl. J. Med. NCT01597908 4 accepted 3758 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-11-08 18:02:40 UTC https://civicdb.org/links/evidence_items/3758 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Childhood Pilocytic Astrocytoma 6812 Vemurafenib Predictive Supports C Sensitivity/Response In a case report, a 28 month old patient with a cervicomedullary low grade glioma compatible with pilocytic astrocytoma which was resected had a second lesion consistent with a ganglioglioma 3 years later. This mass progressed under treatment at which point PCR amplification of BRAF exon 15 and subsequent Sanger sequencing the initial biopsy revealed the tumor harbored a BRAF V600E mutation. Based on these results, vemurafenib monotherapy was started and radiological and clinical response was noted after 3 months of treatment, which was sustained after 6 months of therapy. Prior to vemurafenib treatment, the patient had undergone tracheotomy, was treated with standard chemotherapy and underwent another surgery, but had developed progressive disease. 25524464 PubMed del Bufalo et al., 2014, J Transl Med 3 accepted 3777 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-10-30 16:40:15 UTC https://civicdb.org/links/evidence_items/3777 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Ovarian Serous Carcinoma 0050933 Vemurafenib Predictive Supports C Sensitivity/Response A stage 4B, low-grade papillary serous ovarian adenocarcinoma patient, harboring a BRAF V600E mutation was associated with response to vemurafenib monotherapy. The patient was treated with standard chemotherapy, hormone therapy and bevacizumab prior to the identification of the BRAF V600E mutation; next, the patient was treated with paclitaxel and an anti-HER3 antibody and finally with vemurafenib, obtaining a partial response of greater than 1 year. 26490654 PubMed Combe et al., 2015, Invest New Drugs 3 accepted 3787 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-10-29 23:47:51 UTC https://civicdb.org/links/evidence_items/3787 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false EGFR 1956 Ex19 del L858R Lung Adenocarcinoma 3910 Erlotinib Predictive Supports B Sensitivity/Response The phase 3 (EURTAC) study consisted of of 173 non-small cell lung cancer patients who had not had prior chemotherapy for metastatic disease (although adjuvant or neoadjuvant chemotherapy was permitted) and included 160 patients with lung adenocarcinoma subtype. The patients had EGFR mutations (exon 19 deletions or L858R), and improved progression-free survival was reported in the erlotinib treated cohort as compared to the cohort that was treated with standard chemotherapy (9.7mo vs. 5.2mo, HR:0.37, 95%CI:0.25-0.54, P<0.0001, univariate analysis; HR:0.35, 95%CI:0.23-0.52, P<0.0001, multivariate analysis). 22285168 PubMed Rosell et al., 2012, Lancet Oncol. NCT00446225 4 accepted 3791 1854 19 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/3791 https://civicdb.org/links/variants/1854 https://civicdb.org/links/genes/19 false EGFR 1956 Mutation Lung Adenocarcinoma 3910 Prognostic Supports B Better Outcome Analysis was performed on the placebo group (n=451) of the Phase III study SATURN using erlotinib maintenance therapy for patients with advanced NSCLC who were selected for response or stable disease after first line chemotherapy. It was found that EGFR Mutant status was a significant positive prognostic factor for overall survival. (HR, 0.33; 95% CI, 0.19 to 0.59; P<0.01) 21969500 PubMed Brugger et al., 2011, J. Clin. Oncol. 3 accepted 3792 442 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/3792 https://civicdb.org/links/variants/442 https://civicdb.org/links/genes/19 false EGFR 1956 Mutation Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports B Sensitivity/Response In a phase II trial for Bronchioloalveolar carcinoma (BAC, or in situ pulmonary adenocarcinoma), EGFR exons 18-24 were analyzed in 7 patients who had shown a partial response to Erlotinib, and 10 patients who did not. EGFR mutations were seen in 5/7 responders but not in any of the non-responders, which was a significant result (p=0.003). 15329413 PubMed Pao et al., 2004, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 3794 442 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2017-10-12 21:41:18 UTC https://civicdb.org/links/evidence_items/3794 https://civicdb.org/links/variants/442 https://civicdb.org/links/genes/19 false EGFR 1956 L861Q Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports C Sensitivity/Response In a study, a group of 6 participants, 5 with stage IV and one with stage IIIB lung adenocarcinoma, were sequenced at EGFR exons 18 to 21. All patients had L861Q mutation and were treated with the 1st generation TKI gefitinib. 4 patients had partial response with progression free survival (PFS) of 4.3, 19.3, 10.0, 8.7 months; overall survival (OS) of 4.3, 34.9, 15.7, 15.7 months; and all 4 were alive at study end. One patient had stable disease, PFS 6.5 months, OS 15.2 months, and was not alive at study end. One patient had progressive disease as response, with PFS of 2.8 months, OS of 10.7 months, and was not alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 3 accepted 3802 1020 19 7 55259524 55259524 T A ENST00000275493.2 75 GRCh37 Somatic 2017-07-06 21:48:19 UTC https://civicdb.org/links/evidence_items/3802 https://civicdb.org/links/variants/1020 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Cancer 162 Multikinase Inhibitor AEE788,Gefitinib,Erlotinib Substitutes Predictive Supports D Resistance Experimental - EGFR T790M mutation has been associated with resistance to first generation EGFR tyrosine kinase inhibitors, including erlotinib and gefitinib. In an in vitro study, Ba/F3 cells stably expressing EGFR T790M demonstrated resistance to gefitinib and erlotinib and the tool construct AEE788. These cells had very high IC50 nmol/L values for all three inhibitors in comparison to other constructs (Gefitinib>2000, Erlotinib>2000, AEE788>2000), indicating resitance to all three inhibitors. 19147750 PubMed Kancha et al., 2009, Clin. Cancer Res. 3 accepted 3810 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2020-09-02 06:58:29 UTC https://civicdb.org/links/evidence_items/3810 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Cancer 162 Erlotinib,Gefitinib,Multikinase Inhibitor AEE788 Substitutes Predictive Supports D Sensitivity/Response EGFR L858R was expressed in Ba/F3 cells which do not contain endogenous EGFR, and conferred growth factor independance to the cells. Cells were plated and treated with 1st generation EGFR inhibitors Gefitinib, Erlotinib, or the the tool compound AEE788, and IC50 values were measured. L858R EGFR cells had very low IC50 nmol/L values for all three inhibitors in comparison to other constructs (Gefitinib=12, Erlotinib=6, AEE788=6), indicating sensitivity to all three constructs. 19147750 PubMed Kancha et al., 2009, Clin. Cancer Res. 3 accepted 3811 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2017-09-16 05:19:03 UTC https://civicdb.org/links/evidence_items/3811 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false ABL1 25 BCR::ABL F359V Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with F359V evaluated, 6/6 had complete hematologic responses and 4/7 had major cytogenetic responses. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 2 accepted 3815 892 4 9 133748414 133748414 T G ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 21:57:04 UTC https://civicdb.org/links/evidence_items/3815 https://civicdb.org/links/variants/892 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359V Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with F359V, 0/2 had a CHR and 1/2 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 3816 892 4 9 133748414 133748414 T G ENST00000318560.5 75 GRCh37 Somatic 2018-12-21 19:49:05 UTC https://civicdb.org/links/evidence_items/3816 https://civicdb.org/links/variants/892 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359V Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports C Reduced Sensitivity In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with F359V, 5/7 had MaHRs which was comparable to response rates among wild type patients, and 1/7 had MCyRs which which was lower than response rates among wild type patients. 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 3817 892 4 9 133748414 133748414 T G ENST00000318560.5 75 GRCh37 Somatic 2019-01-31 10:06:43 UTC https://civicdb.org/links/evidence_items/3817 https://civicdb.org/links/variants/892 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359V Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support B Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase) patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Of the 27 with F359V mutations, 14, 17, and 25 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 3819 892 4 9 133748414 133748414 T G ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:12:45 UTC https://civicdb.org/links/evidence_items/3819 https://civicdb.org/links/variants/892 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359V Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports C Resistance Prior to dasatinib treatment, two imatinib-resistant patients with chronic myeloid leukemia (CML) in chronic phase had the BCR-ABL1 fusion, one with the T315I, F359V, M244V, and G250E variants in 2/10, 6/10, 1/10, and 1/10 clones, respectively, and the other with F359V, F359V/F486S, F359V/L273M, and L273M variants in 6/10, 1/10, 2/10, and 1/10 clones, respectively. Clones were generated using peripheral blood RNA. The patients had no best cytogenetic responses and no or complete best hematologic responses to dasatinib. Two additional patients with CML, in myeloid blast crisis, had F359V in 1/10 and 9/10 clones. They had no hematologic and no cytogenetic responses. Overall, responses were poor compared to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 2 accepted 3820 892 4 9 133748414 133748414 T G ENST00000318560.5 75 GRCh37 Somatic 2020-03-11 21:01:14 UTC https://civicdb.org/links/evidence_items/3820 https://civicdb.org/links/variants/892 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359V Chronic Myeloid Leukemia 8552 Axitinib Predictive Does Not Support D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the F359V variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 933nM vs. 823 nM), indicating that the variant does not induce resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 3822 892 4 9 133748414 133748414 T G ENST00000318560.5 75 GRCh37 Somatic 2019-12-20 21:53:35 UTC https://civicdb.org/links/evidence_items/3822 https://civicdb.org/links/variants/892 https://civicdb.org/links/genes/4 false KRAS 3845 G12V Colorectal Cancer 9256 Panitumumab Predictive Supports C Resistance One patient participating in a large retrospective study of EGFR monoclonal antibodies in metastatic, treatment refractory colorectal cancer had a tumor which harbored KRAS G12V, was wildtype for NRAS, BRAF and PIK3CA, and had individual response data. This patient was was a 78 year old female treated with panitumumab monotherapy as 2nd line therapy who experienced progressive disease (PFS: 5 weeks). 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 3824 425 30 12 25398284 25398284 C A ENST00000256078.4 75 GRCh37 KRAS mutations are the most common mutations in pancreatic cancer occurring in > 90% of cases. Of these the G12D activating mutation is the most prevalent and results in a loss of GTPase activity which in turn leads to a constitutively active form of KRAS. This is enough to cause pre-cancerous pancreatic intraepithelial lesions Somatic 2020-12-01 23:53:15 UTC https://civicdb.org/links/evidence_items/3824 https://civicdb.org/links/variants/425 https://civicdb.org/links/genes/30 false BRAF 673 V600E Colorectal Cancer 9256 Panitumumab Predictive Supports C Resistance One patient participating in a large retrospective study of EGFR monoclonal antibodies in metastatic colorectal cancer had a tumor which harbored BRAF V600E, was wildtype for NRAS, KRAS and PIK3CA, and had individual response data. This patient was was a male treated with panitumumab monotherapy as 1st line therapy who experienced progressive disease (PFS: 7 weeks; OS: 10 weeks). 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 3827 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-12-02 00:05:58 UTC https://civicdb.org/links/evidence_items/3827 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false PIK3CA 5290 R88Q Colorectal Cancer 9256 Irinotecan,Cetuximab Combination Predictive Does Not Support C Resistance One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored PIK3CA R88Q, was wildtype for KRAS, BRAF and NRAS, and had individual response data. This patient was was a 56 year old female treated with cetuximab and irinotecan as 2nd line therapy who experienced a partial response (PFS: 32 weeks, OS: 32 weeks). 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 3832 929 37 3 178916876 178916876 G A ENST00000263967.3 75 GRCh37 Somatic 2020-11-25 23:18:29 UTC https://civicdb.org/links/evidence_items/3832 https://civicdb.org/links/variants/929 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Colorectal Cancer 9256 Cetuximab,Irinotecan Combination Predictive Supports C Resistance Five patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored PIK3CA H1047R (exon 21), were wildtype for KRAS, BRAF and NRAS, and had individual response data. All patients were treated with cetuximab and irinotecan, four as 3rd line therapy, one as 4th line. Patient characteristics are as follows: a 65 year old female who experienced stable disease (PFS: 33 weeks, OS: 37 weeks); a 56 year old female who experienced stable disease (PFS: 28 weeks, OS: 43 weeks); a 69 year old female who experienced progressive disease (PFS: 10 weeks, OS: 28 weeks); a 63 year old male who experienced progressive disease (PFS:11 weeks, OS: 18 weeks); a 60 year old female who experienced progressive disease (PFS: 12 weeks, OS: 34 weeks). Based off this information and clinical data compiled from the larger cohort, authors concluded that PIK3CA exon 21 (listed as exon 20 in source) mutations predict poor response to cetuximab. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 3841 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2020-11-25 22:45:19 UTC https://civicdb.org/links/evidence_items/3841 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false NRAS 4893 G13R Colorectal Cancer 9256 Panitumumab Predictive Supports C Resistance One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored NRAS G13R, was wildtype for KRAS, BRAF and PIK3CA, and had individual response data. This patient was was a 50 year old male treated with panitumumab monotherapy as 3rd line therapy (discontinued for toxic/biochemical reasons) who experienced stable disease (PFS: 22 weeks; OS: 74 weeks). Authors considered stable disease as both clinical benefit and non-response 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 1 accepted 3842 896 36 1 115258745 115258745 C G ENST00000369535.4 75 GRCh37 Somatic 2020-12-02 00:15:31 UTC https://civicdb.org/links/evidence_items/3842 https://civicdb.org/links/variants/896 https://civicdb.org/links/genes/36 false NRAS 4893 G12C Colorectal Cancer 9256 Chemotherapy,Cetuximab Combination Predictive Supports C Resistance Two patients participating in a large retrospective trial of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored NRAS G12C and were wild type for KRAS, PIK3CA, and BRAF. Both experienced stable disease, which the authors classified as non-response. The two patients whose tumors harbored NRAS G12C included a 63 year old female treated with cetuximab and irinotecan as a 3rd line treatment who had PFS of 34 weeks and OS of 55 weeks; and a 38 year old female treated with cetuximab, oxaliplatin and 5FU as a 2nd line therapy who had PFS of 12 weeks. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 3845 897 36 1 115258748 115258748 C A ENST00000369535.4 75 GRCh37 Somatic 2020-11-10 22:22:43 UTC https://civicdb.org/links/evidence_items/3845 https://civicdb.org/links/variants/897 https://civicdb.org/links/genes/36 false PIK3CA 5290 G1049R Colorectal Cancer 9256 Cetuximab Predictive Supports C Resistance One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored PIK3CA G1049R (exon 20), was wildtype for KRAS, BRAF and NRAS, and had individual response data. This patient was was a 69 year old male treated with cetuximab + FOLFIRI as 3rd line therapy who experienced progressive disease and had PFS of 13 weeks and OS of 36 weeks. Using this information and data from the larger cohort, authors concluded that PIK3CA exon 21 (listed as exon 20 in source) mutations predict poor response to cetuximab. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 3847 940 37 3 178952090 178952090 G C ENST00000263967.3 75 GRCh37 Somatic 2020-11-25 22:40:05 UTC https://civicdb.org/links/evidence_items/3847 https://civicdb.org/links/variants/940 https://civicdb.org/links/genes/37 false HRAS 3265 G13D Skin Squamous Cell Carcinoma 3151 Vemurafenib Predictive Supports C Resistance In a retrospective study of 23 patients with BRAF V600 mutation (a known vemurafenib sensitizing mutation) that developed cutaneous squamous-cell carcinoma upon treatment with vemurafenib monotherapy, a patient harboring HRAS G13D co-mutation (n=1) was reported to be resistant to vemurafenib treatment. 22256804 PubMed Su et al., 2012, N. Engl. J. Med. NCT00405587,NCT00949702,NCT01001299,NCT01006980 accepted 3851 274 2747 11 534285 534285 C T ENST00000451590.1 75 GRCh37 Somatic 2017-06-10 13:12:51 UTC https://civicdb.org/links/evidence_items/3851 https://civicdb.org/links/variants/274 https://civicdb.org/links/genes/2747 false HRAS 3265 G13D Colorectal Cancer 9256 Cetuximab Predictive Supports D Resistance In an in vitro study, Colo-320, SW48, and CaCO2 cell lines expressing HRAS G13D mutation were associated with resistance to cetuximab treatment, as compared to Colo-320, SW48, and CaCO2 cells expressing wild-type HRAS. 26561417 PubMed Boidot et al., 2016, Int J Colorectal Dis accepted 3852 274 2747 11 534285 534285 C T ENST00000451590.1 75 GRCh37 Somatic 2017-06-10 00:20:06 UTC https://civicdb.org/links/evidence_items/3852 https://civicdb.org/links/variants/274 https://civicdb.org/links/genes/2747 false KRAS 3845 A146T Colorectal Cancer 9256 Cetuximab,FOLFOX-4 Regimen Combination Predictive Supports B Resistance In a retrospective study of 148 treatment naive metastatic colorectal cancer patients, patients with RAS mutations and wildtype BRAF (n=10), including A146T (N=3), G15D (N=1), and V152M/NRAS V160A, treated with FOLFOX4 plus cetuximab were associated with decreased overall survival (16.3mo vs. 28.5mo, HR:0.43, 95% CI:0.20-0.89, P=0.020) and decreased progression free survival (7.2mo vs. 9.7mo, HR:0.56, 95% CI:0.27-1.16, P=0.11), as compared to patients with wild-type KRAS, NRAS and BRAF. 25666295 PubMed Kaczirek et al., 2015, Clin Colorectal Cancer 3 accepted 3858 906 30 12 25378562 25378562 C T ENST00000256078.4 75 GRCh37 Somatic 2017-07-21 16:34:00 UTC https://civicdb.org/links/evidence_items/3858 https://civicdb.org/links/variants/906 https://civicdb.org/links/genes/30 false KRAS 3845 Q61H Colorectal Cancer 9256 Cetuximab,Chemotherapy Combination Predictive Supports C Resistance Seven patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored KRAS Q61H (either c.183A > C or >T) and were wildtype for BRAF and PIK3CA mutations. A 73 year old man who was treated with cetixumab and irinotecan as a fourth line therapy experienced stable disease, with a PFS of 36 weeks and OS of 57 weeks. A 65 year old man who was treated with cetuximab and irinotecan as a 3rd line therapy experienced stable disease with a PFS of 32 weeks and an OS of 51 weeks. A 70 year old female who was treated with cetuximab, oxaliplatin and 5FU as a second line therapy experienced progressive disease after 4 weeks of treatment. A 66 year old male who was treated with cetuximab and irinotecan as a 4th line therapy experienced progression after 6 week and had an OS of 21 weeks. A 71 year old female who was treated with cetuximab and folfiri as a 3rd line therapy experienced progression after 8 weeks and had an OS of 116 weeks. A 77 year old male who was treated with cetuximab and irinotecan as a 4th line therapy experienced progression after 8 weeks and had an overall survival of 17 weeks. A 66 year old male who was treated with cetuximab and irinotecan as a 3rd line therapy experienced stable disease (11 weeks) and an OS of 14 weeks. In this study, authors considered stable disease to be non-response to treatment. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 3861 907 30 12 25380275 25380275 T G ENST00000256078.4 75 GRCh37 Somatic 2020-11-25 00:12:07 UTC https://civicdb.org/links/evidence_items/3861 https://civicdb.org/links/variants/907 https://civicdb.org/links/genes/30 false KRAS 3845 Q61H Colorectal Cancer 9256 Cetuximab Predictive Supports C Resistance In a colorectal cancer patient with a KRAS Q61H mutation, KRAS Q61H was reported to be refractory to cetuximab treatment. The patient was treated with cetuximab and irinotecan for 18 months, had a partial response to therapy and then experienced progressive disease with a re-biopsy of the tumor identifying a KRAS Q61H mutation. 22722830 PubMed Misale et al., 2012, Nature accepted 3862 907 30 12 25380275 25380275 T G ENST00000256078.4 75 GRCh37 Somatic 2017-07-21 16:34:30 UTC https://civicdb.org/links/evidence_items/3862 https://civicdb.org/links/variants/907 https://civicdb.org/links/genes/30 false EGFR 1956 Mutation Lung Cancer 1324 Erlotinib Predictive Supports B Sensitivity/Response In advanced-stage (IIIB or IV) non-small cell lung cancer patients treated with erlotinib, patients whose tumors harbored EGFR mutations (n=3) had a higher 12-week progression-free survival rate compared to wildtype EGFR patients (n=54; 100% vs. 25%, P=0.0064). 22025157 PubMed Ramalingam et al., 2011, J. Clin. Oncol. NCT00760929 2 accepted 3864 442 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2020-12-29 22:44:41 UTC https://civicdb.org/links/evidence_items/3864 https://civicdb.org/links/variants/442 https://civicdb.org/links/genes/19 false KRAS 3845 Q61L Colorectal Cancer 9256 Cetuximab,Chemotherapy Combination Predictive Supports C Resistance Two patients participating in a large retrospective trial of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored KRAS Q61L. One patient, a 67 year old male, whose tumor was wildtype for BRAF and PIK3CA, was treated with cetuximab and irinotecan as a fourth line therapy. Cetuximab was discontinued due to toxicity and the patient experienced stable disease for 17 weeks and an overall survival of 23 weeks following treatment. The other patient was a 44 year old female whose tumor was wildtype for PIK3CA, BRAF and NRAS. The patient was treated with cetuximab and irinotecan as a third line therapy, and experienced progressive disease 23 weeks following treatment; overall survival was 30 weeks. Both patients experienced progressive disease following treatment. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 3867 908 30 12 25380276 25380276 T A ENST00000256078.4 75 GRCh37 Somatic 2020-03-13 15:37:45 UTC https://civicdb.org/links/evidence_items/3867 https://civicdb.org/links/variants/908 https://civicdb.org/links/genes/30 false KRAS 3845 Q61R Colorectal Cancer 9256 Cetuximab,Irinotecan Combination Predictive Supports C Resistance Two patients participating in a large retrospective trial of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored KRAS Q61R and were wild type for PIK3CA, BRAF, and NRAS. Both were treated with cetuximab and irinotecan as 3rd line treatments. One patient was a 72 year old female who experienced progressive disease 12 weeks following treatment; OS was 20 weeks. The other patient was a 43 year old female who experienced stable disease for the duration of the study and did not progress. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 3870 909 30 12 25380276 25380276 T C ENST00000256078.4 75 GRCh37 Somatic 2020-03-13 15:40:42 UTC https://civicdb.org/links/evidence_items/3870 https://civicdb.org/links/variants/909 https://civicdb.org/links/genes/30 false KRAS 3845 Q61K Colorectal Cancer 9256 Chemotherapy,Cetuximab Combination Predictive Supports C Resistance Two patients participating in a large retrospective trial of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored KRAS Q61K. One patient was a 61 year old female whose tumor was wildtype for BRAF and PIK3CA. This patient was treated with cetuximab, oxaliplatin, and 5FU, as a second line therapy, and experienced progressive disease 6 weeks following cetuximab administration; overall survival was 90 weeks. The other patient was a 65 year old female whose tumor was wildtype for PIK3CA. The patient was treated with cetuximab and irinotecan as a third line therapy, and experienced progressive disease 10 week following cetuximab. Both patients experienced progressive disease following treatment. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 3872 910 30 12 25380277 25380277 G T ENST00000256078.4 75 GRCh37 Somatic 2020-03-13 15:37:09 UTC https://civicdb.org/links/evidence_items/3872 https://civicdb.org/links/variants/910 https://civicdb.org/links/genes/30 false KRAS 3845 G13D Colorectal Cancer 9256 Cetuximab Predictive Supports D Resistance In an in vitro study, a Lim1215 colorectal cancer cell line endogenously expressing KRAS G13D mutation demonstrated resistance to cetuximab treatment, compared to Lim1215 parental cells expressing wild-type KRAS. Resistance was determined by assessing cell viability. 22722830 PubMed Misale et al., 2012, Nature accepted 3878 81 30 12 25398281 25398281 C T ENST00000256078.4 75 GRCh37 While the KRAS G13 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort. This mutation, along with the mutations affecting the neighboring G12 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, results are conflicting with retrospective analyses suggesting a better response to EGFR-Inhibition. A recent prospective phase-II study (12 patients, Schirripa et. al. 2015) could not reproduce this finding and another prospective phase II trial is currently ongoing. Somatic 2017-07-21 17:03:59 UTC https://civicdb.org/links/evidence_items/3878 https://civicdb.org/links/variants/81 https://civicdb.org/links/genes/30 false KRAS 3845 G13D Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance This was a retrospective study of 691 cetuximab treated patients with metastatic colorectal cancer. Of those, 50 patients harbored KRAS G13D, were BRAF, NRAS and PIK3CA wt, and had individual response data. Nine patients had partial response, 19 had stable disease, and 22 progressed. Treatments included cetuximab + irinotecan (n=38), cetuximab + FOLFIRI (n=5), cetuximab monotherapy (n=4), cetuximab + oxaliplatin + 5FU (n=2), and cetuximab + irinotecan + oxaliplatin + 5FU (n=1). Median PFS was 16 weeks (3-101 weeks), median OS was 33 weeks (3-161 weeks), and median number of previous chemotherapy lines was 2 (0-4). Median age was 65 years old (34-78), and there were 29 males and 20 females. Authors concluded that KRAS mutation was strongly associated with poor response to cetuximab and suggested that mutation status of KRAS is the most informative compared to BRAF, NRAS, and PIK3CA exon 20 for predicting cetuximab response. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 3881 81 30 12 25398281 25398281 C T ENST00000256078.4 75 GRCh37 While the KRAS G13 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort. This mutation, along with the mutations affecting the neighboring G12 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, results are conflicting with retrospective analyses suggesting a better response to EGFR-Inhibition. A recent prospective phase-II study (12 patients, Schirripa et. al. 2015) could not reproduce this finding and another prospective phase II trial is currently ongoing. Somatic 2020-11-25 01:12:38 UTC https://civicdb.org/links/evidence_items/3881 https://civicdb.org/links/variants/81 https://civicdb.org/links/genes/30 false KRAS 3845 G13D Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance In a retrospective study of 148 treatment naive metastatic colorectal cancer patients, patients with RAS mutations (n=10), including KRAS A146T, KRAS G13D, NRAS G12D and NRAS Q179*, treated with FOLFOX4 plus cetuximab were associated with decreased overall survival (16.3mo vs. 28.5mo, HR:0.43, 95% CI:0.20-0.89, P=0.020) and decreased progression free survival (7.2mo vs. 9.7mo, HR:0.56, 95% CI:0.27-1.16, P=0.11), as compared to patients with wild-type KRAS and NRAS. 25666295 PubMed Kaczirek et al., 2015, Clin Colorectal Cancer accepted 3882 81 30 12 25398281 25398281 C T ENST00000256078.4 75 GRCh37 While the KRAS G13 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort. This mutation, along with the mutations affecting the neighboring G12 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, results are conflicting with retrospective analyses suggesting a better response to EGFR-Inhibition. A recent prospective phase-II study (12 patients, Schirripa et. al. 2015) could not reproduce this finding and another prospective phase II trial is currently ongoing. Somatic 2017-07-20 16:08:13 UTC https://civicdb.org/links/evidence_items/3882 https://civicdb.org/links/variants/81 https://civicdb.org/links/genes/30 false KRAS 3845 G13D Colorectal Cancer 9256 Regorafenib Predictive Supports D Resistance In an in vitro study, a human colon adenocarcinoma SW48 cell line expressing KRAS G13D mutation demonstrated resistance to regorafenib treatment (IC50: 172.23 nM vs. 114.28 nM, P<0.01) compared to SW48 cells expressing KRAS wild-type. Resistance was determined by assessing cell viability. Authors concluded that KRAS G13D is more resistant to regorafenib than KRAS wt, but more sensitive than common KRAS G12 mutations. 26161928 PubMed Camaj et al., 2015, Future Oncol 1 accepted 3889 81 30 12 25398281 25398281 C T ENST00000256078.4 75 GRCh37 While the KRAS G13 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort. This mutation, along with the mutations affecting the neighboring G12 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, results are conflicting with retrospective analyses suggesting a better response to EGFR-Inhibition. A recent prospective phase-II study (12 patients, Schirripa et. al. 2015) could not reproduce this finding and another prospective phase II trial is currently ongoing. Somatic 2020-09-24 22:26:30 UTC https://civicdb.org/links/evidence_items/3889 https://civicdb.org/links/variants/81 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports B Resistance In the placebo-controlled Phase III study SATURN, using erlotinib maintenance therapy for patients with advanced NSCLC who were selected for response or stable disease after first line chemotherapy, KRAS mutation was assessed. In the KRAS wildtype group, erlotinib showed a significant benefit for progression free survival (PFS) over placebo (HR, 0.70; 95% CI, 0.57 to 0.87, P<0.001). No statistically significant improvement in PFS was seen with erlotinib in the KRAS mutant group over placebo. Significant difference in PFS between erlotinib treated KRAS WT and MUT patients was not seen. Overall, in the intent to treat population erlotinib significantly improved PFS over placebo (HR, 0.71; 95% CI, 0.62 to 0.82; P<0.001). 21969500 PubMed Brugger et al., 2011, J. Clin. Oncol. 3 accepted 3895 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2017-09-08 18:12:11 UTC https://civicdb.org/links/evidence_items/3895 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Q61 Colorectal Cancer 9256 Chemotherapy,Cetuximab Combination Predictive Supports B Resistance This was a retrospective study of 605 patients with metastatic, chemotherapy refractory colorectal cancer treated with cetuximab + chemotherapy. Patients harboring KRAS codon 61 mutations (n=13) had a significantly lower response rate than did patients with KRAS wildtype tumors (0/13 vs 123/345; p= .0055). Authors consider KRAS codon 61 mutations as supporting resistance to cetuximab and suggest that it should be included in KRAS mutation screening. Authors note that these patients were treated with cetuximab prior to widespread adoption of regular KRAS mutational status screening. Patients treated with cetuximab monotherapy were not included. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 4 accepted 3917 203 30 12 25380275 25380277 ENST00000256078.4 75 GRCh37 Somatic 2020-03-13 01:23:24 UTC https://civicdb.org/links/evidence_items/3917 https://civicdb.org/links/variants/203 https://civicdb.org/links/genes/30 false KRAS 3845 G12V Colorectal Cancer 9256 Regorafenib Predictive Supports D Resistance In an in vitro study, a human colon adenocarcinoma SW48 cell line expressing KRAS G12V mutation demonstrated resistance to regorafenib treatment (IC50: 241.90 nM vs. 114.28 nM, P<0.01) compared to SW48 cells expressing KRAS wildtype. Resistance was determined by assessing cell viability. Regorafenib significantly reduced BRAF, Erk1/2 and Elk phosphorylation compared to wildtype, as assessed by western blot. Authors concluded that KRAS G12A was more resistant to regorafenib than KRAS wt, and intermediately resistant compared to other common KRAS mutations. 26161928 PubMed Camaj et al., 2015, Future Oncol 2 accepted 3924 425 30 12 25398284 25398284 C A ENST00000256078.4 75 GRCh37 KRAS mutations are the most common mutations in pancreatic cancer occurring in > 90% of cases. Of these the G12D activating mutation is the most prevalent and results in a loss of GTPase activity which in turn leads to a constitutively active form of KRAS. This is enough to cause pre-cancerous pancreatic intraepithelial lesions Somatic 2020-09-24 22:25:40 UTC https://civicdb.org/links/evidence_items/3924 https://civicdb.org/links/variants/425 https://civicdb.org/links/genes/30 false KRAS 3845 A146 Colorectal Cancer 9256 Cetuximab,Chemotherapy Combination Predictive Does Not Support B Resistance This was a retrospective study of 605 patients with metastatic, chemotherapy refractory colorectal cancer treated with cetuximab + chemotherapy. Patients harboring KRAS codon 146 mutant tumors (n=11) did not have a significantly lower response rate than did patients with KRAS wildtype tumors (2/11 [18.2%] vs 101/274 [36.9%]; p =0.34). Authors suggest that KRAS codon 146 mutations may not support resistance to cetuximab. Authors note that these patients were treated with cetuximab prior to widespread adoption of regular KRAS mutational status screening. Patients treated with cetuximab monotherapy were not included. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 3939 2979 30 Somatic 2021-07-23 05:13:40 UTC https://civicdb.org/links/evidence_items/3939 https://civicdb.org/links/variants/2979 https://civicdb.org/links/genes/30 false KRAS 3845 G12D Colorectal Cancer 9256 Regorafenib Predictive Supports D Resistance In an in vitro study, a human colon adenocarcinoma SW48 cell line expressing KRAS G12D mutation demonstrated resistance to regorafenib treatment (IC50: 195.01nM vs. 114.28 nM P<0.01) compared to SW48 cells expressing KRAS wild-type. Resistance was determined by assessing cell viability. Authors concluded that KRAS G12D was more resistant to regorafenib than KRAS wt, and intermediately resistant compared to other common KRAS G12/G13 mutations. 26161928 PubMed Camaj et al., 2015, Future Oncol 1 accepted 3946 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2020-09-24 22:26:57 UTC https://civicdb.org/links/evidence_items/3946 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false KRAS 3845 G12D Melanoma 1909 Vemurafenib Predictive Supports D Resistance In vitro studies of M229 (a human melanoma cell line) endogenously expressing wildtype KRAS and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that cells virally induced to stably over-express KRAS4a G12D or KRAS4b G12D were more resistant to vemurafenib (a BRAF inhibitor) than cells transduced with empty vectors (90% vs 10% survival). 24265155 PubMed Shi et al., 2014, Cancer Discov 2 accepted 3957 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2018-07-19 20:19:34 UTC https://civicdb.org/links/evidence_items/3957 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false KRAS 3845 G12D Ovarian Cancer 2394 Cetuximab Predictive Supports D Resistance In an in vitro study, a MCAS cell line expressing KRAS G12D mutation was associated with reduced sensitivity to cetuximab treatment as compared to RMUG-L and OMC-1 cells expressing wild-type KRAS. Resistance was determined by assessing cell growth. Further, in an in vivo experiment, KRAS G12D expressing MCAS xenografts in nude mice had reduced response to cetuximab, as compared to KRAS wild-type expressing RMUG-L xenografts. Resistance was determined by assessing tumor growth. 22246397 PubMed Sato et al., 2012, Oncol. Rep. 3 accepted 3958 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2020-08-20 14:48:23 UTC https://civicdb.org/links/evidence_items/3958 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false KRAS 3845 G12C Colorectal Cancer 9256 Cetuximab,Chemotherapy Combination Predictive Supports B Resistance This was a retrospective study of 691 cetuximab treated patients with metastatic, chemotherapy refractory colorectal cancer. Of those, 16 patients harbored KRAS G12C, were BRAF, NRAS and PIK3CA wt, and had individual response data. One patient had a partial response, 6 had stable disease, and 9 progressed. Treatments included cetuximab + irinotecan (n=15) and cetuximab + FOLFIRI (n=1). Median PFS was 11 weeks (6-65 weeks), median OS was 24 weeks (14-91 weeks), and median number of previous chemotherapy lines was 2 (1-6). Median age was 62 years old (46-73), and there were 8 males and 8 females. Using these data and data from the larger cohort, authors concluded that KRAS mutation was strongly associated with poor response to cetuximab and suggested that mutation status of KRAS is the most informative compared to BRAF, NRAS, and PIK3CA exon 20 for predicting cetuximab response. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 3967 78 30 12 25398285 25398285 C A ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2020-11-25 00:38:35 UTC https://civicdb.org/links/evidence_items/3967 https://civicdb.org/links/variants/78 https://civicdb.org/links/genes/30 false KRAS 3845 G12C Colorectal Cancer 9256 Regorafenib Predictive Supports D Resistance In an in vitro study, a human colon adenocarcinoma SW48 cell line expressing KRAS G12C mutation demonstrated resistance to regorafenib treatment (IC50: 386.22 nM vs. 114.28 nM, P<0.01) compared to SW48 cells expressing KRAS wild-type. Resistance was determined by assessing cell viability. In vivo, KRAS G12C expressing SW48 cells were injected into NOD/SCID mice. Treatment with regorafenib did not lead to a significant delay of tumor growth. Mice injected with KRAS wt cells did not significantly respond to regorafenib, although a trend was seen toward better response. IHC analysis of mouse tissue revealed no significant change in markers of proliferation (Ki67), angiogenesis (CD31) and apoptosis (TUNEL) in KRAS G12C expressing mice treated with regorafenib compared to KRAS wt expressing mice whose tumors displayed more pronounced changes. Authors concluded that G12C was more resistant to regorafenib than KRAS wt and other common KRAS G12/G13 mutants. 26161928 PubMed Camaj et al., 2015, Future Oncol 2 accepted 3973 78 30 12 25398285 25398285 C A ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2020-09-24 22:25:57 UTC https://civicdb.org/links/evidence_items/3973 https://civicdb.org/links/variants/78 https://civicdb.org/links/genes/30 false KRAS 3845 G12R Colorectal Cancer 9256 Cetuximab,Chemotherapy Combination Predictive Supports C Resistance Three patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored KRAS G12R, were wildtype for NRAS, BRAF and PIK3CA, and had individual response data. One patient experienced stable disease, and two patients experienced progressive disease. Patient characteristics were as follows: a 67 year old female treated with cetuximab + irinotecan as a 4th line treatment who experienced progressive disease and had PFS of 8 weeks and OS of 17 weeks; a 78 year old female treated with cetuximab + irinotecan as a 3rd line therapy who experienced progressive disease and had PFS of 3 weeks and OS of 10 weeks; and a 55 year old male treated with cetuximab + FOLFIRI as a 3rd line therapy who experienced stable disease and had PFS of 13 weeks and OS of 15 weeks. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 3987 530 30 12 25398285 25398285 C G ENST00000256078.4 75 GRCh37 Somatic 2020-11-25 00:59:25 UTC https://civicdb.org/links/evidence_items/3987 https://civicdb.org/links/variants/530 https://civicdb.org/links/genes/30 false KRAS 3845 G12R Colorectal Cancer 9256 Cetuximab Predictive Supports D Resistance In an in vitro study to identify cetuximab-resistant clones following continuous drug treatment, a resistant clone of the Lim1215 colorectal cancer cell line was identified to have the KRAS G12R mutation. No G12R was detected in the parental line despite high-resolution evaluation. Additionally, endogenously expressing KRAS G12R (knock-in) mutation demonstrated resistance to cetuximab treatment, compared to Lim1215 parental cells expressing wild-type KRAS. Resistance was determined by assessing cell viability. 22722830 PubMed Misale et al., 2012, Nature 4 accepted 3989 530 30 12 25398285 25398285 C G ENST00000256078.4 75 GRCh37 Somatic 2017-07-21 17:06:21 UTC https://civicdb.org/links/evidence_items/3989 https://civicdb.org/links/variants/530 https://civicdb.org/links/genes/30 false KRAS 3845 G12R Colorectal Cancer 9256 Regorafenib Predictive Supports D Resistance In an in vitro study, a human colon adenocarcinoma SW48 cell line expressing KRAS G12R mutation demonstrated resistance to regorafenib treatment (IC50: 181.77 nM vs. 114.28 nM, P<0.01) compared to SW48 cells expressing KRAS wild-type. Resistance was determined by assessing cell viability. Authors concluded that KRAS G12R was resistant to regorafenib compared to wildtype but was less resistant than other common KRAS G12/G13 mutations. 26161928 PubMed Camaj et al., 2015, Future Oncol 1 accepted 3991 530 30 12 25398285 25398285 C G ENST00000256078.4 75 GRCh37 Somatic 2020-09-24 22:27:16 UTC https://civicdb.org/links/evidence_items/3991 https://civicdb.org/links/variants/530 https://civicdb.org/links/genes/30 false KRAS 3845 G12S Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance This was a retrospective study of 691 cetuximab treated patients with metastatic, chemotherapy refractory colorectal cancer. Of those, 16 patients harbored KRAS G12S, were BRAF, NRAS and PIK3CA wt, and had individual response data. Nine patients had stable disease and seven progressed. Treatments included cetuximab + irinotecan (n=13), cetuximab + FOLFIRI (n=1), cetuximab+5FU (n=1), cetuximab + irinotecan + oxaliplatin + bevacizumab (n=1). Median PFS was 12 weeks (2-50 weeks), median OS was 25 weeks (10-135 weeks), and median number of previous chemotherapy lines was 2 (1-6). Median age was 59 years old (31-69), and there were 9 males and 7 females. Using these data and data from the larger cohort, authors concluded that KRAS mutation was strongly associated with poor response to cetuximab and suggested that mutation status of KRAS is the most informative compared to BRAF, NRAS, and PIK3CA exon 20 for predicting cetuximab response. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 4006 913 30 12 25398285 25398285 C T ENST00000256078.4 75 GRCh37 Somatic 2020-11-25 01:02:37 UTC https://civicdb.org/links/evidence_items/4006 https://civicdb.org/links/variants/913 https://civicdb.org/links/genes/30 false KRAS 3845 G12S Colorectal Cancer 9256 Regorafenib Predictive Supports D Resistance In an in vitro study, a human colon adenocarcinoma SW48 cell line expressing KRAS G12S mutation demonstrated resistance to regorafenib treatment (IC50: 264.23 nM vs. 114.28 nM, P<0.01) compared to SW48 cells expressing KRAS wild-type. Resistance was determined by assessing cell viability. Authors concluded that KRAS G12S was more resistant to regorafenib than KRAS wt, and intermediately resistant compared to other common KRAS G12/G13 mutations. 26161928 PubMed Camaj et al., 2015, Future Oncol 2 accepted 4012 913 30 12 25398285 25398285 C T ENST00000256078.4 75 GRCh37 Somatic 2020-09-24 22:26:08 UTC https://civicdb.org/links/evidence_items/4012 https://civicdb.org/links/variants/913 https://civicdb.org/links/genes/30 false FLT3 2322 D835V Acute Myeloid Leukemia 9119 Sunitinib Predictive Supports C Sensitivity/Response In a retrospective study of 15 acute myeloid leukemia patients, the patients with FLT3 D835 mutation (n=2) were associated with improved response to sunitinib treatment (2/2 vs. 2/7) compared to FLT3 wild-type patients. The FLT3 D835 mutation positive patients were treated with sunitinib after failure of standard chemotherapy. After 4wk of sunitinib therapy, one patient showed morphological response and the other patient showed partial response to sunitinib therapy. 15459012 PubMed Fiedler et al., 2005, Blood accepted 4022 1302 24 13 28592641 28592641 T A ENST00000241453.7 75 GRCh37 Somatic 2017-06-15 20:25:09 UTC https://civicdb.org/links/evidence_items/4022 https://civicdb.org/links/variants/1302 https://civicdb.org/links/genes/24 false AKT1 207 E17K Melanoma 1909 Vemurafenib Predictive Supports D Resistance In an in vitro study, a M229 cell line endogenously expressing BRAF V600E mutation (a known vemurafenib sensitizing mutation) and overexpressing AKT1 E17K mutation was associated with resistance to vemurafenib treatment, as compared to cells expressing BRAF V600E mutation and wildtype AKT1. Resistance was determined by assessing cell survival. 24265155 PubMed Shi et al., 2014, Cancer Discov 1 accepted 4029 4 2 14 105246551 105246551 C T ENST00000407796.2 75 GRCh37 AKT1 E17K is a recurrent mutation that has been observed in breast, colorectal, lung, and ovarian cancer. It has been convincingly shown to be an activating mutation resulting in PI3K/AKT/mTOR pathway activity. It has been suggested that this mutation decreases the cell's sensitivity to AKT1 allosteric kinase inhibitors. This, and other AKT1 mutations, are the subject of much research and development for therapeutics. Somatic 2021-11-12 18:53:34 UTC https://civicdb.org/links/evidence_items/4029 https://civicdb.org/links/variants/4 https://civicdb.org/links/genes/2 false PIK3CA 5290 N345K Colorectal Cancer 9256 Cetuximab Predictive Supports C Resistance Three patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored PIK3CA N345K, were wildtype for KRAS, BRAF and NRAS, and had individual response data. Patient characteristics are as follows: a 48 year old female treated with cetuximab + irinotecan as 3rd line therapy who experienced stable disease (PFS: 72 weeks, OS: 105 weeks); a 46 year old male treated with cetuximab monotherapy as 5th line therapy who experienced stable disease (PFS: 24 weeks, OS: 57 weeks); a 61 year old female treated with cetuximab + irinotecan as 3rd line therapy who experienced progressive disease (PFS: 12 weeks, OS: 45 weeks). The response rate was 0/3 and the clinical benefit rate was 2/3 according to author criteria. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 1 accepted 4047 930 37 3 178921553 178921553 T A ENST00000263967.3 75 GRCh37 Somatic 2020-11-25 23:07:52 UTC https://civicdb.org/links/evidence_items/4047 https://civicdb.org/links/variants/930 https://civicdb.org/links/genes/37 false AKT1 207 S473 Phosphorylation Colorectal Cancer 9256 Prognostic Does Not Support B Poor Outcome This retrospective study examines outcomes of 158 primary sporadic colorectal cancer patients who had undergone surgical resection and were treated with 5-fluorouracil based chemotherapy. Cytoplasmic overexpression of phosphorylated AKT (as assessed by IHC), was not associated with differences in disease specific survival compared to lower levels of p-AKT expression (n = 89 high, n = 69 low; p = 0.8737) or in relapse free survival (n=54 high, n = 42 low; p = 0.1974). Authors note some tumors harbored KRAS or PIK3CA mutations, but that the presence of mutations in either gene didn't correlate with levels of p-AKT expression. 17590872 PubMed Kato et al., 2007, Int. J. Cancer 3 accepted 4051 3257 2 Somatic 2021-02-02 23:36:39 UTC https://civicdb.org/links/evidence_items/4051 https://civicdb.org/links/variants/3257 https://civicdb.org/links/genes/2 false KRAS 3845 Exon 2 Mutation Rectum Cancer 1993 Prognostic Does Not Support B Poor Outcome This study examined outcomes of 240 rectum cancer patients treated with total mesorectal excision therapy. Tumor samples were obtained at the time of surgery and genotyped for KRAS exon 2 mutations (listed as exon 1 in the source, as it was common at the time of publication to exclude non-coding exon 1). KRAS exon 2 mutations were identified in 81 cases. The authors reported that no differences were found in overall survival between patients with and without KRAS exon 2 mutations (P > 0.1). 19903786 PubMed He et al., 2009, Clin. Cancer Res. 2 accepted 4052 75 30 12 25398208 25398329 ENST00000256078.4 75 GRCh37 Exon 2 mutations have been associated with reduced response rates or resistance to EGFR inhibitors in non-small cell lung and colorectal cancer. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. Somatic 2020-07-09 22:10:05 UTC https://civicdb.org/links/evidence_items/4052 https://civicdb.org/links/variants/75 https://civicdb.org/links/genes/30 false PDGFRA 5156 V561D Cancer 162 Sunitinib Predictive Does Not Support D Resistance In an in vitro study, Chinese hamster ovary cells expressing PDGFRA V561D mutation demonstrated sensitivity to sunitinib treatment (IC50<100), though this sensitivity was indistinguishable from Chinese hamster ovary cells expressing wild-type PDGFRA. Sensitivity was determined by assessing PDGFRA auto-phosphorylation. 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 2 accepted 4056 941 38 4 55141036 55141036 T A ENST00000257290.5 75 GRCh37 Somatic 2019-04-26 19:13:59 UTC https://civicdb.org/links/evidence_items/4056 https://civicdb.org/links/variants/941 https://civicdb.org/links/genes/38 false PDGFRA 5156 D842V Cancer 162 Sunitinib Predictive Supports D Resistance In an in vitro study, Chinese hamster ovary cells expressing PDGFRA D842V mutation demonstrated reduced sensitivity to sunitinib treatment (IC50>1000 vs. IC50<100), compared to Chinese hamster ovary cells expressing wild-type PDGFRA. Sensitivity was determined by assessing PDGFRA auto-phosphorylation. 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 2 accepted 4060 99 38 4 55152093 55152093 A T ENST00000257290.5 75 GRCh37 PDGFRA D842 mutations are characterized broadly as imatinib resistance mutations. This is most well characterized in gastrointestinal stromal tumors, but other cell lines containing these mutations have been shown to be resistant as well. Exogenous expression of the A842V mutation resulted in constitutive tyrosine phosphorylation of PDGFRA in the absence of ligand in 293T cells and cytokine-independent proliferation of the IL-3-dependent Ba/F3 cell line, both evidence that this is an activating mutation. In imatinib resistant cell lines, a number of other therapeutics have demonstrated efficacy. These include; crenolanib, sirolimus, and midostaurin (PKC412). Somatic 2019-04-26 18:51:24 UTC https://civicdb.org/links/evidence_items/4060 https://civicdb.org/links/variants/99 https://civicdb.org/links/genes/38 false KIT 3815 V560_L576DEL Gastrointestinal Stromal Tumor 9253 Regorafenib Predictive Supports D Sensitivity/Response A GIST430 patient derived cell line expressing KIT V560_L576del primary activating mutation demonstrated insensitivity to regorafenib (IC50: 191nmol/L) treatment. IC50 was determined by assessing cell viability. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 2 accepted 4061 1550 29 4 55593612 55593662 GRCh37 Somatic 2019-07-09 22:45:43 UTC https://civicdb.org/links/evidence_items/4061 https://civicdb.org/links/variants/1550 https://civicdb.org/links/genes/29 false KIT 3815 K550_K558del Gastrointestinal Stromal Tumor 9253 Sunitinib Predictive Supports C Resistance Patient 3 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) KIT K550_K558 deletion. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. The patient started on 50mg sunitinib on a schedule of two weeks on/two weeks off. This patient experienced stable disease less than 6 months; time to progresssion of 14 weeks and overall survival of 17 weeks (Table A1). 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 2 accepted 4062 949 29 4 55593582 55593608 AAACCCATGTATGAAGTACAGTGGAAG ENST00000288135.5 75 GRCh37 Somatic 2019-05-03 23:20:44 UTC https://civicdb.org/links/evidence_items/4062 https://civicdb.org/links/variants/949 https://civicdb.org/links/genes/29 false KIT 3815 Exon 11 Mutation Gastrointestinal Stromal Tumor 9253 Sunitinib Predictive Supports B Resistance In a phase I/II trial of sunitinib efficacy on imatinib resistant or intolerant gastrointestinal stromal tumor (GIST) patients (n=77), patients harboring primary (pre-imatinib treatment) KIT exon 11 mutant GISTs (n=44) treated with sunitinib experienced shorter progression free survival (5.1 vs 19.0 months, P = .0356) and overall survival (12.3 vs 30.5 months, P=0.0132) as compared to patients with wild-type KIT (n=9). 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 3 accepted 4072 66 29 4 55593582 55593708 ENST00000288135.5 75 GRCh37 c-KIT mutations in exon 11 lie within the juxtamembrane domain, and are very recurrent in gastrointestinal stromal tumors, often bearing a poorer prognosis than other KIT mutations. Cells harboring exon 11 mutations have shown sensitivity to the tyrosine kinase inhibitor imatinib, offering a better prognosis to patients treated with the drug in the first year. Small cohorts of melanoma patients harboring exon 11 KIT mutations have shown response to imatinib and sunitinib. Somatic 2019-05-03 23:01:49 UTC https://civicdb.org/links/evidence_items/4072 https://civicdb.org/links/variants/66 https://civicdb.org/links/genes/29 false KIT 3815 V560D Cancer 162 Sunitinib Predictive Does Not Support D Resistance In an in vitro study, Chinese hamster ovary cells expressing KIT V560D demonstrated comparable sensitivity to sunitinib treatment compared to cells expressing ligand activated wild-type KIT (IC50<100 nmol/L). Sensitivity was determined by assessing KIT auto-phosphorylation. 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 2 accepted 4077 971 29 4 55593613 55593613 T A ENST00000288135.5 75 GRCh37 Somatic 2019-04-26 19:23:51 UTC https://civicdb.org/links/evidence_items/4077 https://civicdb.org/links/variants/971 https://civicdb.org/links/genes/29 false KIT 3815 W557_K558del Gastrointestinal Stromal Tumor 9253 Sunitinib Predictive Supports C Resistance Patients 11, 69, and 73 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) KIT W557_K558 deletion. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. Patient 11 started on 25 mg sunitinib daily, for a two week on/two week off schedule. Patients 69 and 73 were on a 50 mg sunitib per day for four weeks on/ two weeks off. All three patients experienced stable disease for less than 6 months. Time to progression for patients 11, 69, and 73: 8, 22, and 10 weeks. Overall survival for patients 11, 69, and 73: 10, 38, and 19 weeks (Table A1). 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 3 accepted 4082 961 29 4 55593603 55593608 TGGAAG ENST00000288135.5 75 GRCh37 Somatic 2019-05-03 23:27:35 UTC https://civicdb.org/links/evidence_items/4082 https://civicdb.org/links/variants/961 https://civicdb.org/links/genes/29 false KIT 3815 W557_K558del Gastrointestinal Stromal Tumor 9253 Ponatinib,Imatinib Substitutes Predictive Supports D Sensitivity/Response In an in vitro study, an IL3 independent Ba/F3 cell line expressing KIT W557_K558del primary activating mutation demonstrated sensitivity to imatinib (IC50: 27nmol/L) and ponatinib (IC50: 3nmol/L) treatments. IC50 was determined by assessing cell viability. In mice treated in vivo with Ba/F3 cells expressing KIT W557_K558 mutation, tumor volume was significantly reduced in response to both ponatinib and imatinib treatments. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 3 accepted 4084 961 29 4 55593603 55593608 TGGAAG ENST00000288135.5 75 GRCh37 Somatic 2019-07-09 22:24:20 UTC https://civicdb.org/links/evidence_items/4084 https://civicdb.org/links/variants/961 https://civicdb.org/links/genes/29 false KIT 3815 W557_K558del Gastrointestinal Stromal Tumor 9253 Sunitinib,Regorafenib Substitutes Predictive Supports D Sensitivity/Response In an in vitro study, an IL3 independent Ba/F3 cell line expressing KIT W557_K558del primary activating mutation demonstrated sensitivity to sunitinib (IC50: 7 +/- 2nmol/L) and regorafenib (IC50: 30 +/- 14nmol/L) treatments. IC50 was determined by assessing cell viability. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 2 accepted 4087 961 29 4 55593603 55593608 TGGAAG ENST00000288135.5 75 GRCh37 Somatic 2019-07-09 23:06:12 UTC https://civicdb.org/links/evidence_items/4087 https://civicdb.org/links/variants/961 https://civicdb.org/links/genes/29 false KIT 3815 K558_V559del Gastrointestinal Stromal Tumor 9253 Sunitinib Predictive Supports C Resistance Patient 47 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) KIT K558_V559 deletion. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. The patient took 50 mg sunitinib per day on a treatment schedule of two weeks on/one week off. The patient experienced progressive disease. Time to progression was censored at 5 weeks, and overall survival was 60 weeks. 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 2 accepted 4095 964 29 4 55593606 55593611 AAGGTT ENST00000288135.5 75 GRCh37 Somatic 2019-05-03 23:51:41 UTC https://civicdb.org/links/evidence_items/4095 https://civicdb.org/links/variants/964 https://civicdb.org/links/genes/29 false KIT 3815 A502_Y503insAY Cancer 162 Sunitinib Predictive Does Not Support D Resistance In an in vitro study, Chinese hamster ovary cells expressing KIT A502_Y503INSAY demonstrated comparable sensitivity to sunitinib treatment compared to CHO cells expressing ligand activated wild-type KIT (IC50<100 nmol/L). Sensitivity was determined by assessing KIT auto-phosphorylation. 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 2 accepted 4100 1558 29 4 55592182 55592183 GCCTAT GRCh37 Somatic 2019-04-26 19:52:40 UTC https://civicdb.org/links/evidence_items/4100 https://civicdb.org/links/variants/1558 https://civicdb.org/links/genes/29 false KIT 3815 Exon 9 Mutation Gastrointestinal Stromal Tumor 9253 Regorafenib Predictive Supports C Reduced Sensitivity This phase II clinical trial of regorafenib (NCT01068769) examined the long term safety and efficacy of regorafenib monotherapy in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GISTs) who failed previous treatments with imatinib. In response to regorafenib monotherapy, patients whose GISTs harbored KIT exon 9 mutations experienced lower rates of clinical benefit (defined as complete response, partial response, or stable disease lasting >16 weeks) than patients whose GISTs harbored KIT exon 11 mutations or KIT/PDGFR wildtype SDH-deficient patients. Of 3 patients with KIT exon 9 mutant GISTs, 2 experienced clinical benefit (including one PR), and the median progression free survival was 5.7 months. 27371698 PubMed Ben-Ami et al., 2016, Ann. Oncol. NCT01068769 3 accepted 4104 509 29 4 55592023 55592216 ENST00000288135.5 75 GRCh37 In patients with gastrointestinal stromal tumors (GIST), imatinib has improved outcomes for patients with KIT mutations. However, acquired resistance to imatinib is common. Patients harboring exon 9 KIT mutations may benefit from higher imatinib doses (800mg/daily). Similarly, imatinib-refractory tumors showed sensitivity to sunitinib treatment. Improved responses to either treatment were not observed in patients with exon 11 mutations. Somatic 2019-03-09 13:38:02 UTC https://civicdb.org/links/evidence_items/4104 https://civicdb.org/links/variants/509 https://civicdb.org/links/genes/29 false BRAF 673 Exon 15 Mutation Gastrointestinal Stromal Tumor 9253 Regorafenib Predictive Does Not Support C Sensitivity/Response This phase II clinical trial of regorafenib (NCT01068769) examined the long term safety and efficacy of regorafenib monotherapy in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GISTs) who failed previous treatments with imatinib. One patient's GIST harbored a BRAF exon 15 mutation.This patient experienced progressive disease and a progression free survival of 1.6 months. 27371698 PubMed Ben-Ami et al., 2016, Ann. Oncol. NCT01068769 2 accepted 4121 2650 5 Somatic 2019-03-08 22:11:01 UTC https://civicdb.org/links/evidence_items/4121 https://civicdb.org/links/variants/2650 https://civicdb.org/links/genes/5 false KIT 3815 V560D Gastrointestinal Stromal Tumor 9253 Sunitinib Predictive Supports C Resistance Patient 72 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) KIT V560D mutation. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. The patient took 50 mg sunitinib per day on a treatment schedule of four weeks on/two weeks off. The patient experienced progressive disease. Time to progression and overall survival were 9 and 33 weeks. 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 3 accepted 4122 971 29 4 55593613 55593613 T A ENST00000288135.5 75 GRCh37 Somatic 2019-05-03 23:57:14 UTC https://civicdb.org/links/evidence_items/4122 https://civicdb.org/links/variants/971 https://civicdb.org/links/genes/29 false KIT 3815 P551_E554delPMYE Gastrointestinal Stromal Tumor 9253 Ponatinib Predictive Supports D Sensitivity/Response In an in vitro study, an IL3 independent Ba/F3 cell line expressing KIT P551_E554delPMYE primary activating mutation demonstrated sensitivity to ponatinib treatment (IC50: 15nM). IC50 was determined by assessing cell viability. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 3 accepted 4125 1497 29 4 55593585 55593596 GRCh37 Somatic 2019-07-09 22:14:42 UTC https://civicdb.org/links/evidence_items/4125 https://civicdb.org/links/variants/1497 https://civicdb.org/links/genes/29 false KIT 3815 V560D Gastrointestinal Stromal Tumor 9253 Imatinib,Ponatinib,Sunitinib,Regorafenib Substitutes Predictive Supports D Sensitivity/Response In an in vitro study, an IL3 independent Ba/F3 cell line expressing KIT V560D primary activating mutation demonstrated sensitivity to imatinib (IC50: 3nmol/L), sunitinib (IC50: 2nmol/L), regorafenib (IC50: 3nmol/L), and ponatinib (IC50: 2nmol/L) treatments. IC50 was determined by assessing cell viability. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 3 accepted 4127 971 29 4 55593613 55593613 T A ENST00000288135.5 75 GRCh37 Somatic 2019-07-09 22:10:31 UTC https://civicdb.org/links/evidence_items/4127 https://civicdb.org/links/variants/971 https://civicdb.org/links/genes/29 false KIT 3815 L576P Gastrointestinal Stromal Tumor 9253 Sunitinib Predictive Supports C Resistance Patient 29 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) KIT L576P mutation. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. The patient took 50 mg sunitinib per day on a treatment schedule of two weeks on/two weeks off. The patient experienced stable disease for less than 6 months. Time to progression and overall survival were 31 and 29 weeks. 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 2 accepted 4136 72 29 4 55593661 55593661 T C ENST00000288135.5 75 GRCh37 KIT L576P is an exon 11 mutation that lies within the juxtamembrane domain. It is one of the most recurrent KIT mutations in melanoma, and both in vitro and in vivo studies have shown sensitivity to imatinib. Somatic 2019-05-03 23:30:44 UTC https://civicdb.org/links/evidence_items/4136 https://civicdb.org/links/variants/72 https://civicdb.org/links/genes/29 false KIT 3815 Exon 9 Mutation Gastrointestinal Stromal Tumor 9253 Regorafenib Predictive Supports B Reduced Sensitivity This retrospective study of a phase 2 clinical trial (NCT01068769) examined regorafenib safety and efficacy in advanced gastrointestinal stromal tumor (GIST) patients who failed previous treatments with at least imatinib and sunitinib. Of 30 genotyped patients treated with regorafenib, those with KIT exon 9 mutant GISTs (n=3) experienced decreased progression free survival as compared to patients with KIT exon 11 mutated GISTs (n=19) or wildtype (lacking KIT or PDGFRA mutations) GISTs (n= 8). The difference in PFS was significant between Exon 9 and 11 mutant GISTs (P = .01). Median PFS for the whole cohort was 10.0 months. Regorafenib treatment induced clinical benefit (defined as complete response, partial response, stable disease <16 weeks) in 2/3 patients with KIT exon 9 mutant GISTs. 22614970 PubMed George et al., 2012, J. Clin. Oncol. 2 accepted 4139 509 29 4 55592023 55592216 ENST00000288135.5 75 GRCh37 In patients with gastrointestinal stromal tumors (GIST), imatinib has improved outcomes for patients with KIT mutations. However, acquired resistance to imatinib is common. Patients harboring exon 9 KIT mutations may benefit from higher imatinib doses (800mg/daily). Similarly, imatinib-refractory tumors showed sensitivity to sunitinib treatment. Improved responses to either treatment were not observed in patients with exon 11 mutations. Somatic 2019-05-15 06:23:15 UTC https://civicdb.org/links/evidence_items/4139 https://civicdb.org/links/variants/509 https://civicdb.org/links/genes/29 false KIT 3815 L576P Cancer 162 Imatinib,Dasatinib Substitutes Predictive Supports D Sensitivity/Response In an in vitro study, COS-7 cells expressing KIT L576P activating mutation demonstrated sensitivity to imatinib and dasatinib treatments. Sensitivity was determined by assessing reduced mutant KIT auto-phosphorylation via western blotting with addition of inhibitors. 25317746 PubMed Vita et al., 2014, JAMA Dermatol 2 accepted 4141 72 29 4 55593661 55593661 T C ENST00000288135.5 75 GRCh37 KIT L576P is an exon 11 mutation that lies within the juxtamembrane domain. It is one of the most recurrent KIT mutations in melanoma, and both in vitro and in vivo studies have shown sensitivity to imatinib. Somatic 2019-08-05 23:05:09 UTC https://civicdb.org/links/evidence_items/4141 https://civicdb.org/links/variants/72 https://civicdb.org/links/genes/29 false KIT 3815 D579del Gastrointestinal Stromal Tumor 9253 Sunitinib Predictive Supports C Resistance Patient 74 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) KIT D579 deletion. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. The patient took 50 mg sunitinib per day on a treatment schedule of four weeks on/two weeks off. The patient experienced stable disease for less than six months. Time to progression was censored at 10 weeks and overall survival was 85 weeks. 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 2 accepted 4142 977 29 4 55593669 55593671 GAT ENST00000288135.5 75 GRCh37 Somatic 2019-05-03 23:59:25 UTC https://civicdb.org/links/evidence_items/4142 https://civicdb.org/links/variants/977 https://civicdb.org/links/genes/29 false KIT 3815 WILDTYPE Gastrointestinal Stromal Tumor 9253 Regorafenib Predictive Supports B Sensitivity/Response This phase II clinical trial of regorafenib (NCT01068769) examined the long term safety and efficacy of regorafenib in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GISTs) who failed previous treatments with imatinib. Patients whose GISTs were wildtype for KIT and PDGFR and who were succinate dehydrogenase (SDH) deficient (n=6) experienced higher rates of clinical benefit (defined as complete response, partial response, or stable disease lasting >16 weeks) than patients whose GISTs were wildtype for KIT and PDGFR but were not SDH deficient (n=2). 6/6 patients with SDH deficient GISTs had clinical benefit (including 2 PRs), and their median PFS was 10 months vs 1.6 months for patients with non-SDH deficient GISTs. 27371698 PubMed Ben-Ami et al., 2016, Ann. Oncol. NCT01068769 2 accepted 4144 2651 29 4 55524085 55606881 ENST00000288135.5 75 GRCh37 Somatic 2020-12-03 18:33:01 UTC https://civicdb.org/links/evidence_items/4144 https://civicdb.org/links/variants/2651 https://civicdb.org/links/genes/29 true KIT 3815 K642E Melanoma 1909 Dasatinib Predictive Supports C Sensitivity/Response In a phase 2 clinical trial of 39 stage 3/4 chemotherapy-naive unresectable melanoma patients, a subungual melanoma patient harboring the KIT K642E mutation was reported to have a partial response to dasatinib monotherapy of 24 weeks with a 56% tumor reduction. 21523734 PubMed Kluger et al., 2011, Cancer accepted 4147 978 29 4 55594221 55594221 A G ENST00000288135.5 75 GRCh37 Somatic 2019-11-22 11:37:57 UTC https://civicdb.org/links/evidence_items/4147 https://civicdb.org/links/variants/978 https://civicdb.org/links/genes/29 false KIT 3815 N822K Gastrointestinal Stromal Tumor 9253 Ponatinib Predictive Does Not Support D Resistance A preclinical study tested the effect of a tyrosine kinase inhibitor (TKI) on Ba/F3 cell lines with primary ponatinib-sensitizing del 557-558 mutation, which induced IL-3 independent growth, and secondary mutation N822K. The cells were tested for Ponatinib resistance. Ba/F3 cells with del 557-558 and N822K mutations did not show resistance towards Ponatinib (IC50 for growth inhibition: 3 nM) compared to Ba/F3 cells with del 557-558 alone (IC50: 3 nM). Ponatinib inhibited KIT phosphorylation at moderate concentrations. The results suggest that N822K does not induce Ponatinib resistance. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 3 accepted 4167 1263 29 4 55599340 55599340 T A ENST00000288135.5 75 GRCh37 Somatic 2019-07-19 22:07:46 UTC https://civicdb.org/links/evidence_items/4167 https://civicdb.org/links/variants/1263 https://civicdb.org/links/genes/29 false KIT 3815 N822K Gastrointestinal Stromal Tumor 9253 Regorafenib Predictive Supports D Resistance A preclinical study tested the effects of tyrosine kinase inhibitor (TKI) on Ba/F3 cell lines with primary regorafenib-sensitizing mutation del 557-558, which induced IL-3 independent growth, and secondary mutation N822K. The cells were tested for Regorafenib resistance. Ba/F3 cells with del 557-558 and N822K mutations did show resistance towards Regorafenib (IC50 for growth inhibition: 131 +- 9 nM) compared to Ba/F3 cells with the del 557-558 mutation (IC50 for growth inhibition: 30 +- 14 nM). Regorafenib inhibited KIT phosphorylation only at high concentrations. The results suggest that N822K does induce Regorafenib resistance. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 3 accepted 4169 1263 29 4 55599340 55599340 T A ENST00000288135.5 75 GRCh37 Somatic 2019-07-19 21:59:27 UTC https://civicdb.org/links/evidence_items/4169 https://civicdb.org/links/variants/1263 https://civicdb.org/links/genes/29 false BRAF 673 V600K Melanoma 1909 Vemurafenib Predictive Supports B Sensitivity/Response In a retrospective study of 300 stage IV melanoma patients, patients with BRAF V600K mutation (n=18) were associated with a 5.6% (1/18) complete response, a 22.2% (4/18) partial response and stable disease in 44.4% (8/18) of cases; however, 27.8% (5/18) of patients harboring BRAF V600K experienced progressive disease and patients with BRAF V600E mutation achieved a more impressive clinical benefit, as compared to patients with BRAF V600K mutation (P=0.016). 25524477 PubMed Ugurel et al., 2015, Ann. Oncol. 3 accepted 4180 563 5 7 140453136 140453137 AC TT ENST00000288602.6 75 GRCh37 Somatic 2020-07-24 21:23:51 UTC https://civicdb.org/links/evidence_items/4180 https://civicdb.org/links/variants/563 https://civicdb.org/links/genes/5 false BRAF 673 V600K Skin Melanoma 8923 Dabrafenib,Trametinib Combination Predictive Supports B Sensitivity/Response In a clinical trial (NCT01597908) of 704 metastatic melanoma patients, patients harboring a BRAF V600K mutation and treated with vemurafenib (n=34) were associated with a 44% response rate, as compared to a 65% response rate in V600E mutation positive patients treated with dabrafenib and trametinib combination therapy (n=34). 25399551 PubMed Robert et al., 2015, N. Engl. J. Med. NCT01597908 3 accepted 4181 563 5 7 140453136 140453137 AC TT ENST00000288602.6 75 GRCh37 Somatic 2018-07-06 14:05:18 UTC https://civicdb.org/links/evidence_items/4181 https://civicdb.org/links/variants/563 https://civicdb.org/links/genes/5 false EGFR 1956 R108K High Grade Glioma 3070 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line expressing EGFR R108K demonstrated increased sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing EGFR wild-type. Variant function was assessed by EGFR auto-phosphorylation. Sensitivity was assessed by cell viability assay using stable transfection of each variant and increasing concentrations of erlotinib (0–10 uM). 17177598 PubMed Lee et al., 2006, PLoS Med. 3 accepted 4186 994 19 7 55211080 55211080 G A ENST00000275493.2 75 GRCh37 Somatic 2020-08-28 05:34:57 UTC https://civicdb.org/links/evidence_items/4186 https://civicdb.org/links/variants/994 https://civicdb.org/links/genes/19 false EGFR 1956 T263P High Grade Glioma 3070 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line expressing EGFR T263P demonstrated increased sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing EGFR wild-type. Variant function was assessed by EGFR auto-phosphorylation. Sensitivity was assessed by cell viability assay using stable transfection of each variant and increasing concentrations of erlotinib (0–10 uM). 17177598 PubMed Lee et al., 2006, PLoS Med. 3 accepted 4187 995 19 7 55221743 55221743 A C ENST00000275493.2 75 GRCh37 Somatic 2020-08-28 05:43:54 UTC https://civicdb.org/links/evidence_items/4187 https://civicdb.org/links/variants/995 https://civicdb.org/links/genes/19 false EGFR 1956 A289V High Grade Glioma 3070 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line expressing EGFR A289V demonstrated increased sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing EGFR wild-type. Variant function was assessed by EGFR auto-phosphorylation. Sensitivity was assessed by cell viability assay using stable transfection of each variant and increasing concentrations of erlotinib (0–10 uM). 17177598 PubMed Lee et al., 2006, PLoS Med. 3 accepted 4188 996 19 7 55221822 55221822 C T ENST00000275493.2 75 GRCh37 Somatic 2017-08-25 01:11:47 UTC https://civicdb.org/links/evidence_items/4188 https://civicdb.org/links/variants/996 https://civicdb.org/links/genes/19 false EGFR 1956 G719 Lung Non-small Cell Carcinoma 3908 Erlotinib,Gefitinib Substitutes Predictive Supports B Sensitivity/Response EGFR G719 mutations have been associated with increased sensitivity to first generation EGFR tyrosine kinase inhibitors, including erlotinib and gefitinib. In a study of patients treated with erlotinib or gefitinib, a subset of patients with EGFR mutation at codons G719 or L861 (n=30) was associated with improved response rate (47.5% vs 16.5%, P<0.001) median progression free survival (5.0 vs 2.0 months, P<0.001), and overall survival (15.0 vs. 10.4 months, P =0.030), compared to patients with wild-type EGFR (n=272). For the subset of patients with G719, the response rate was 53.3% (8 of 15), median PFS was 8.1 months, and median overall survival was 16.4 months. 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 3 accepted 4189 718 19 7 55241707 55241708 ENST00000275493.2 75 GRCh37 This is a "bucket" variant for evidence that refers generically to missense variants happening at this position such as: G719A, G719D, G719S. Somatic 2021-01-25 23:51:36 UTC https://civicdb.org/links/evidence_items/4189 https://civicdb.org/links/variants/718 https://civicdb.org/links/genes/19 false EGFR 1956 G719S Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line expressing EGFR G719S demonstrated increased sensitivity to erlotinib treatment comparable to Ba/F3 cells expressing a known sensitizing mutation (EGFR L858R). Sensitivity was determined by assessing cell proliferation, the IC50 of erlotinib for EGFR G719S and EGFR L858R expressing cells were 16 nmol/L and 6 nmol/L, respectively. 19147750 PubMed Kancha et al., 2009, Clin. Cancer Res. accepted 4190 134 19 7 55241707 55241707 G A ENST00000275493.2 75 GRCh37 While not as recurrent as the L858R mutation, EGFR G719S has also been shown to be an activating mutation. In lung cancer cell lines, it also confers sensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib. Somatic 2017-09-16 11:44:01 UTC https://civicdb.org/links/evidence_items/4190 https://civicdb.org/links/variants/134 https://civicdb.org/links/genes/19 false EGFR 1956 V742A Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line expressing EGFR V742A demonstrated increased sensitivity to erlotinib treatment comparable to Ba/F3 cells expressing a known sensitizing mutation (EGFR L858R). Sensitivity was determined by assessing cell proliferation, the IC50 of erlotinib for EGFR V742A and EGFR L858R expressing cells were 21 nmol/L and 6 nmol/L, respectively. 19147750 PubMed Kancha et al., 2009, Clin. Cancer Res. accepted 4197 1001 19 7 55242455 55242455 T C ENST00000275493.2 75 GRCh37 Somatic 2017-09-16 11:38:33 UTC https://civicdb.org/links/evidence_items/4197 https://civicdb.org/links/variants/1001 https://civicdb.org/links/genes/19 false EGFR 1956 E746_A750del Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports C Sensitivity/Response Mutational profiling was performed on EGFR exons 18-24 from a group of 10 retrospectively chosen patients who had shown partial response or clinical improvement in response to gefitinib. Of 7 tumors with EGFR mutations, 4 were del E746-A750. 3 had adenocarcinoma with bronchioloalveolar carcinoma (BAC) features, with response duration and overall survival of 8 and 15 months, 5+ and 5+ months (treatment ongoing at study end) and 28 and 30+ months (alive at study end), and one former smoker with adenocarcinoma with BAC features, who had response duration of 5+ months with treatment ongoing at study end. 15329413 PubMed Pao et al., 2004, Proc. Natl. Acad. Sci. U.S.A. 4 accepted 4198 1002 19 7 55242465 55242479 GGAATTAAGAGAAGC ENST00000275493.2 75 GRCh37 Somatic 2020-04-17 23:04:18 UTC https://civicdb.org/links/evidence_items/4198 https://civicdb.org/links/variants/1002 https://civicdb.org/links/genes/19 false EGFR 1956 Mutation Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports C Sensitivity/Response In the placebo-controlled Phase III study SATURN, using erlotinib maintenance therapy for patients with advanced NSCLC who were selected for response or stable disease after first line chemotherapy, EGFR mutation was assessed. In patients with EGFR mutation, erlotinib maintenance reduced progression and death significantly with median progression free survival (PFS) of 44.6 vs. 13 weeks over placebo. Erlotinib also significantly improved PFS in EGFR wildtype patients, but EGFR mutant tumors treated with erlotinib had significant better PFS than EGFR wildtype. Overall, in the intent to treat population erlotinib significantly improved PFS over placebo (HR, 0.71; 95% CI, 0.62 to 0.82; P<0.001). 21969500 PubMed Brugger et al., 2011, J. Clin. Oncol. 4 accepted 4201 442 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2017-09-08 19:36:35 UTC https://civicdb.org/links/evidence_items/4201 https://civicdb.org/links/variants/442 https://civicdb.org/links/genes/19 false EGFR 1956 E746_T751>I Lung Adenocarcinoma 3910 Gefitinib Predictive Supports C Sensitivity/Response Mutational profiling was performed on EGFR exons 18-24 from a group of 10 retrospectively chosen lung cancer patients who had shown partial response or clinical imporvement in response to gefitinib. Of 7 tumors with EGFR mutations, 1 was del E746-T751insI. The patient was a female never smoker who had adenocarcinoma with bronchioloalveolar carcinoma features, and demonstrated response for 9 months, with overall survival 14 months. 15329413 PubMed Pao et al., 2004, Proc. Natl. Acad. Sci. U.S.A. 2 accepted 4209 1003 19 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/4209 https://civicdb.org/links/variants/1003 https://civicdb.org/links/genes/19 false EGFR 1956 G719D Lung Non-small Cell Carcinoma 3908 Gefitinib,Erlotinib Substitutes Predictive Supports C Sensitivity/Response In a study, 2 participants with stage IV lung adenocarcinoma were sequenced at EGFR exons 18 to 21. Both patients were found to have G719D mutation and were treated with the 1st generation TKIs gefitinib or erlotinib. The first patient (M, 81, smoker) was treated with gefitinib and had a partial response, progression free survival (PFS) of 21.7 months, overall survival (OS) of 22.5 months and was alive at study end. The second patient (M, 76, smoker) was treated with erlotinib and had stable disease as response, PFS of 2.6 months, OS of 2.6 months and was alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 3 accepted 4210 1420 19 7 55241708 55241708 G A GRCh37 Somatic 2017-07-06 21:54:48 UTC https://civicdb.org/links/evidence_items/4210 https://civicdb.org/links/variants/1420 https://civicdb.org/links/genes/19 false EGFR 1956 L747P Lung Non-small Cell Carcinoma 3908 Erlotinib,Gefitinib Substitutes Predictive Does Not Support C Sensitivity/Response In a study, 2 participants with stage IV adenocarcinoma were sequenced at EGFR exons 18 to 21. Both patients were found to have L747P mutation and were treated with the 1st generation TKIs gefitinib or erlotinib. The first patient (M, 62, nonsmoker) was treated with gefitinib and had progressive disease, progression free survival (PFS) of 1.0 months, overall survival (OS) of 7.7 months and was not alive at study end. The second patient (M, 39, nonsmoker) was treated with erlotinib and had progressive disease as response, PFS of 2.3 months, OS of 7.2 months and was alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 2 accepted 4220 1891 19 7 55242469 55242470 TT CC ENST00000275493.2 75 GRCh37 Somatic 2020-08-11 04:00:57 UTC https://civicdb.org/links/evidence_items/4220 https://civicdb.org/links/variants/1891 https://civicdb.org/links/genes/19 false EGFR 1956 V774A Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports C Sensitivity/Response In a study, 1 participant with stage IV adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have V774A mutation, and was treated with the 1st generation TKI gefitinib. The patient (F, 51, nonsmoker) had a partial response, progression free survival (PFS) of 6.9 months, overall survival (OS) of 29.7 months and was alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 3 accepted 4226 1892 19 7 55249023 55249023 T C ENST00000275493.2 75 GRCh37 Somatic 2017-07-06 22:40:50 UTC https://civicdb.org/links/evidence_items/4226 https://civicdb.org/links/variants/1892 https://civicdb.org/links/genes/19 false EGFR 1956 V774M Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Does Not Support C Sensitivity/Response In a study, 1 participant with stage IV squamous cell lung carcinoma was sequenced at EGFR exons 18 to 21 and was found to have V774M mutation, and was treated with the 1st generation TKI erlotinib. The patient (M, 80, smoker) had progressive disease as response, progression free survival (PFS) of 1.6 months, overall survival (OS) of 6.7 months and was not alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 2 accepted 4231 1894 19 7 55249022 55249022 G A ENST00000275493.2 75 GRCh37 Somatic 2017-07-06 22:41:56 UTC https://civicdb.org/links/evidence_items/4231 https://civicdb.org/links/variants/1894 https://civicdb.org/links/genes/19 false EGFR 1956 K806E Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Does Not Support C Sensitivity/Response In a study, 1 participant with stage IIIB lung adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have K806E mutation, and was treated with the 1st generation TKI gefitinib. The patient (M, 77, nonsmoker) had progressive disease as response, progression free survival (PFS) of 1.6 months, overall survival (OS) of 28.1 months and was alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 2 accepted 4239 1895 19 7 55249118 55249118 A G ENST00000275493.2 75 GRCh37 Somatic 2017-07-06 21:59:56 UTC https://civicdb.org/links/evidence_items/4239 https://civicdb.org/links/variants/1895 https://civicdb.org/links/genes/19 false EGFR 1956 N826Y Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Does Not Support C Sensitivity/Response In a study, 1 participant with stage IV lung adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have N826Y mutation, and was treated with the 1st generation TKI gefitinib. The patient (F, 46, nonsmoker) had progressive disease as response, progression free survival (PFS) of 3.3 months, overall survival (OS) of 13.9 months and was not alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 2 accepted 4244 1896 19 7 55259418 55259418 A T ENST00000275493.2 75 GRCh37 Somatic 2017-07-06 22:37:30 UTC https://civicdb.org/links/evidence_items/4244 https://civicdb.org/links/variants/1896 https://civicdb.org/links/genes/19 false EGFR 1956 V834I Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports C Sensitivity/Response In a study, 1 participant with stage IIIB lung adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have V834I mutation, and was treated with the 1st generation TKI gefitinib. The patient (F, 79, nonsmoker) had a partial response, progression free survival (PFS) of 5.0 months, overall survival (OS) of 15.0 months and was not alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 3 accepted 4248 1897 19 Somatic 2017-07-06 22:45:46 UTC https://civicdb.org/links/evidence_items/4248 https://civicdb.org/links/variants/1897 https://civicdb.org/links/genes/19 false EGFR 1956 L838P Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports C Sensitivity/Response In a study, 1 participant with stage IV lung adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have L838P mutation, and was treated with the 1st generation TKI gefitinib. The patient (F, 66, nonsmoker) had a partial response, progression free survival (PFS) of 15.2 months, overall survival (OS) of 29.3 months and was not alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 3 accepted 4252 1457 19 7 55259455 55259455 T C ENST00000275493.2 75 GRCh37 Somatic 2017-07-06 22:31:55 UTC https://civicdb.org/links/evidence_items/4252 https://civicdb.org/links/variants/1457 https://civicdb.org/links/genes/19 false EGFR 1956 N842S Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Does Not Support C Sensitivity/Response In a study, 1 participant with stage IV lung adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have N842S mutation, and was treated with the 1st generation TKI gefitinib. The patient (F, 73, nonsmoker) progressive disease as response, progression free survival (PFS) of 0.9 months, overall survival (OS) of 9.7 months and was not alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 2 accepted 4256 1899 19 7 55259467 55259467 A G ENST00000275493.2 75 GRCh37 Somatic 2017-07-06 22:36:46 UTC https://civicdb.org/links/evidence_items/4256 https://civicdb.org/links/variants/1899 https://civicdb.org/links/genes/19 false EGFR 1956 T847I Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Does Not Support C Sensitivity/Response In a study, 1 participant with stage IIIB lung adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have T847I mutation, and was treated with the 1st generation TKI gefitinib. The patient (M, 77, smoker) progressive disease as response, progression free survival (PFS) of 1.1 months, overall survival (OS) of 1.1 months and was not alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 2 accepted 4260 1463 19 7 55259482 55259482 C T GRCh37 Somatic 2017-07-06 22:38:38 UTC https://civicdb.org/links/evidence_items/4260 https://civicdb.org/links/variants/1463 https://civicdb.org/links/genes/19 false EGFR 1956 V851I Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Does Not Support C Sensitivity/Response In a study, 1 participant with stage IV lung adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have V851I mutation, and was treated with the 1st generation TKI gefitinib. The patient (F, 69, nonsmoker) progressive disease as response, progression free survival (PFS) of 0.7 months, overall survival (OS) of 1.6 months and was not alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common mutations (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 2 accepted 4264 1466 19 7 55259493 55259493 G A GRCh37 Somatic 2020-08-19 18:37:43 UTC https://civicdb.org/links/evidence_items/4264 https://civicdb.org/links/variants/1466 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Cancer 162 Erlotinib Predictive Supports D Sensitivity/Response MCF-7 cells were transduced with YFP tagged EGFR with E746_A750delELREA mutation, or YFP EGFR wildtype, and stained for ectopic YFP EGFR and phospho-Akt as a readout for EGFR pathway activity. Increased p-Akt stain was seen with ectopic mutant EGFR over wildtype cells. Parallel erlotinib incubations of cells with wildtype EGFR induced recompartmentalization of ectopic EGFR protien only at high concentration (10uM). Addition of erlotinib to mutant EGFR cell incubations reduced p-Akt signal and induced recompartmentalization of ectopic EGFR protien at considerably lower conecntration (100 nM) erlotinib. These results indicate the EGFR L858R variant as a growth pathway driver targetable by erlotinib. 17877814 PubMed de Gunst et al., 2007, Mol. Cancer 3 accepted 4265 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2017-09-08 20:57:09 UTC https://civicdb.org/links/evidence_items/4265 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L747_P753delinsS Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line expressing EGFR L747_P753>S demonstrated increased sensitivity to erlotinib treatment comparable to Ba/F3 cells expressing a known sensitizing mutation (EGFR L858R). Sensitivity was determined by assessing cell proliferation, the IC50 of erlotinib for EGFR L747_P753>S and EGFR L858R expressing cells were 5 nmol/L and 6 nmol/L, respectively. 19147750 PubMed Kancha et al., 2009, Clin. Cancer Res. accepted 4266 1012 19 7 55242470 55242487 TAAGAGAAGCAACATCTC ENST00000275493.2 75 GRCh37 Somatic 2017-09-16 11:34:48 UTC https://civicdb.org/links/evidence_items/4266 https://civicdb.org/links/variants/1012 https://civicdb.org/links/genes/19 false EGFR 1956 S768I Lung Adenocarcinoma 3910 Erlotinib Predictive Supports C Resistance In stage IV lung adenocarcinoma patients (n=2) harboring EGFR S768I mutation, EGFR S768I was associated with progressive disease after 1 month of erlotinib monotherapy; the patient was previously treated with standard chemotherapy. 22895145 PubMed Lund-Iversen et al., 2012, J Thorac Oncol accepted 4273 562 19 7 55249005 55249005 G T ENST00000275493.2 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/4273 https://civicdb.org/links/variants/562 https://civicdb.org/links/genes/19 false EGFR 1956 S768I Cancer 162 Erlotinib,Gefitinib Substitutes Predictive Does Not Support D Sensitivity/Response In an in vitro study, a Ba/F3 cell line expressing EGFR S768I demonstrated reduced sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing a known sensitizing mutation (EGFR L858R). Sensitivity was determined by assessing cell proliferation, the IC50 of erlotinib for EGFR S768I and EGFR L858R expressing cells were 250 nmol/L and 6 nmol/L, respectively. Gefitinib was similarly tested and IC50 of 315 nanomolar was obtained, indicating non-response and potential resistance 19147750 PubMed Kancha et al., 2009, Clin. Cancer Res. 3 accepted 4274 562 19 7 55249005 55249005 G T ENST00000275493.2 75 GRCh37 Somatic 2020-08-13 17:11:54 UTC https://civicdb.org/links/evidence_items/4274 https://civicdb.org/links/variants/562 https://civicdb.org/links/genes/19 false EGFR 1956 D770_N771insSVD Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line expressing EGFR D770_N771insSVD demonstrated reduced sensitivity to erlotinib treatment (IC50=3.187�M), comparable to Ba/F3 cells expressing EGFR L858R and T790M co-mutation (T790M is a known resistant mutation to 1st and 2nd generation EGFR tyrosine kinase inhibitors; IC50=4.155�M). Resistance was determined by assessing cell proliferation, EGFR, AKT and ERK phosphorylation. 24353160 PubMed Yasuda et al., 2013, Sci Transl Med accepted 4275 1445 19 7 55249013 55249014 GCGTGGACA ENST00000275493.2 GRCh37 Somatic 2018-02-11 10:47:15 UTC https://civicdb.org/links/evidence_items/4275 https://civicdb.org/links/variants/1445 https://civicdb.org/links/genes/19 false EGFR 1956 H773_V774insH Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line expressing EGFR H773_V774insH demonstrated reduced sensitivity to erlotinib treatment (IC50=3.902�M), comparable to Ba/F3 cells expressing EGFR L858R and T790M co-mutation (T790M is a known resistant mutation to 1st and 2nd generation EGFR tyrosine kinase inhibitors; IC50=4.155�M). Resistance was determined by assessing cell proliferation, EGFR, AKT and ERK phosphorylation. 24353160 PubMed Yasuda et al., 2013, Sci Transl Med accepted 4276 1446 19 7 55249021 55249022 CAC ENST00000275493.2 75 GRCh37 Somatic 2018-02-11 11:11:05 UTC https://civicdb.org/links/evidence_items/4276 https://civicdb.org/links/variants/1446 https://civicdb.org/links/genes/19 false EGFR 1956 R831H Malignant Mesothelioma 1790 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a COS-7 cell line expressing EGFR R831H demonstrated increased sensitivity to erlotinib treatment, compared to COS-7 cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation. 20942962 PubMed Foster et al., 2010, World J Surg Oncol accepted 4279 1017 19 7 55259434 55259434 G A ENST00000275493.2 75 GRCh37 Somatic 2018-01-18 23:34:24 UTC https://civicdb.org/links/evidence_items/4279 https://civicdb.org/links/variants/1017 https://civicdb.org/links/genes/19 false EGFR 1956 L838V Cancer 162 Gefitinib,Erlotinib Substitutes Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line expressing EGFR L838V demonstrated reduced sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing a known sensitizing mutation (EGFR L858R). Sensitivity was determined by assessing cell proliferation, the IC50 of erlotinib for EGFR L838V and EGFR L858R expressing cells were 160 nmol/L and 6 nmol/L, respectively. Similarly, gefitinib was tested and 187 nanomolar IC50 was seen, suggesting lack of sensitivity and potential resistance. 19147750 PubMed Kancha et al., 2009, Clin. Cancer Res. 2 accepted 4280 1018 19 7 55259454 55259454 C G ENST00000275493.2 75 GRCh37 Somatic 2022-03-10 03:19:29 UTC https://civicdb.org/links/evidence_items/4280 https://civicdb.org/links/variants/1018 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to reversible tyrosine kinase inhibitor drugs. Cells with an EGFR L858R mutation demonstrated an improved response to erlotinib (IC50: 40nM vs. 110nM) compared to EGFR wild type cells. 18408761 PubMed Li et al., 2008, Oncogene 2 accepted 4284 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2020-08-10 20:18:02 UTC https://civicdb.org/links/evidence_items/4284 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Cancer 162 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a MCF-7 cell line expressing EGFR L858R mutation demonstrated sensitivity to erlotinib treatment, compared to MCF-7 cells expressing EGFR wild-type. Sensitivity was determined by assessing YFP signal-EGFR relocation. 21132006 PubMed Harada et al., 2011, Oncogene 2 accepted 4285 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2020-10-30 00:04:28 UTC https://civicdb.org/links/evidence_items/4285 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, Ba/F3 and NCI-H3255 cell lines expressing EGFR L858R demonstrated increased sensitivity to erlotinib treatment (IC50=0.006 and 0.068 µM). Sensitivity was determined by assessing cell proliferation, EGFR, AKT and ERK phosphorylation, levels of BIM (a marker of EGFR TKI-induced cell killing) and cell viability. 24353160 PubMed Yasuda et al., 2013, Sci Transl Med 3 accepted 4286 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2021-02-03 23:41:03 UTC https://civicdb.org/links/evidence_items/4286 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, CHO and NCI-H3255 cells expressing EGFR L858R mutation were associated with sensitivity to erlotinib treatment. Sensitivity was determined by assessing cell density. 27612423 PubMed Ray et al., 2016, Oncotarget accepted 4287 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2020-12-03 18:33:01 UTC https://civicdb.org/links/evidence_items/4287 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 true EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Resistance This study analyzed patients with non small cell lung cancer (NSCLC) who were positive for EML4-ALK fusions (ALK+) and progressed on crizotinib monotherapy. One patient was biopsied twice following crizotinib progression and once pre-treatment. This patient was a 27 year old female with one pack year who experienced partial response on crizotinib as 4th line therapy. The patient's pre-crizotinib biopsy was ALK+ and lacked the EGFR mutation. A biopsy taken after 63 days on crizotinib showed EGFR L858R mutation and lacked ALK gene rearrangement by FISH (ALK Loss). Of note, a second post-treatment biopsy (after 113 on crizotinib) showed ALK rearrangement but lacked EGFR mutation. The authors interpreted the emergence of an ALK negative tumor (first post-critozitinib biopsy) as evidence of a separate oncogenic driver (EGFR L858R). 22235099 PubMed Doebele et al., 2012, Clin. Cancer Res. 3 accepted 4288 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2021-02-04 23:26:26 UTC https://civicdb.org/links/evidence_items/4288 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Adenocarcinoma 3910 Erlotinib Predictive Supports B Sensitivity/Response In a prospective study of 46 Caucasian, advanced lung adenocarcinoma patients harboring EGFR mutations, first-line erlotinib treatment was assessed. Average PFS and OS for these 46 patients was 11 months (95% CI: 9.7-12.3 months) and 23 months (95% CI: 21.3-28.6+ months), respectively. A PFS rate of 81% at three months met the primary endpoint of presumed superiority over chemotherapy. Clinical benefit (CR+PR+SD) rate was 81%. Fifteen patients harbored EGFR L858R mutations, which was the only mutation found in exon 21. The authors note similar response profiles for exon 19 (27/46) and exon 21 mutations (15/46) to the overall population. 27032107 PubMed De Grève et al., 2016, PLoS ONE NCT00339586 2 accepted 4290 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/4290 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Adenocarcinoma 3910 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, Ba/F3 cell line expressing EGFR L858R was associated with sensitivity to erlotinib treatment (IC50 26.9 ± 12.4). Sensitivity was determined by assessing cell viability, AKT and ERK phosphorylation, and EGFR auto-phosphorylation. 27102076 PubMed Konduri et al., 2016, Cancer Discov 2 accepted 4291 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2020-10-30 00:03:38 UTC https://civicdb.org/links/evidence_items/4291 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Adenocarcinoma 3910 Cetuximab Predictive Does Not Support D Sensitivity/Response In an in vitro study, Ba/F3 cell line expressing EGFR L858R did not show sensitivity to cetuximab treatment, while cells expressing EGFR-RAD51 fusion were sensitive. Sensitivity was determined by assessing cell viability, AKT and ERK phosphorylation and EGFR auto-phosphorylation. 27102076 PubMed Konduri et al., 2016, Cancer Discov 3 accepted 4292 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2020-11-23 19:32:07 UTC https://civicdb.org/links/evidence_items/4292 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Small Cell Carcinoma 5409 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study using NCI-H3255 cells (EGFR L858R mutation), inhibition of EGFR phosphorylation was used as an assay to determine sensitivity to EGFR tyrosine kinase inhibitors. NCI-H3255 cells demonstrated increased sensitivity to erlotinib (IC50: 8 and 11 nM) compared to EGFRwt NCI-H2073 cells (IC50: 108 nM; 95%CI 52-223 nM). 24893891 PubMed Cross et al., 2014, Cancer Discov 2 accepted 4293 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2021-02-03 22:58:02 UTC https://civicdb.org/links/evidence_items/4293 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Osimertinib Predictive Supports D Sensitivity/Response In an in vitro study using NCI-H3255 cells (EGFR L858R mutation), inhibition of EGFR phosphorylation was used as an assay to determine sensitivity to EGFR tyrosine kinase inhibitors. NCI-H3255 cells demonstrated increased sensitivity to AZD9291 (IC50: 60 and 49 nM) compared to EGFRwt NCI-H2073 cells (IC50: 1865 nM; 95%CI 872-3988 nM). In vivo experiments with NCI-H3255 xenograft models showed drastic tumour volume reduction upon treatment with 5mg/kg/day AZD9291. 24893891 PubMed Cross et al., 2014, Cancer Discov 2 accepted 4294 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2021-02-03 23:04:17 UTC https://civicdb.org/links/evidence_items/4294 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L858R High Grade Glioma 3070 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line expressing EGFR L858R demonstrated increased sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing EGFR wild-type. Variant function was assessed by EGFR auto-phosphorylation. Sensitivity was assessed by cell viability assay using stable transfection of each variant and increasing concentrations of erlotinib (0–10 uM). 17177598 PubMed Lee et al., 2006, PLoS Med. 3 accepted 4295 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2020-08-28 05:37:45 UTC https://civicdb.org/links/evidence_items/4295 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 L861 Lung Non-small Cell Carcinoma 3908 Gefitinib,Erlotinib Substitutes Predictive Supports B Sensitivity/Response EGFR L861 mutations have been associated with increased sensitivity to first generation EGFR tyrosine kinase inhibitors, including erlotinib and gefitinib. In a study of patients treated with erlotinib or gefitinib, a subset of patients with EGFR mutation at codons G719 or L861 (n=30) was associated with improved response rate (47.5% vs 16.5%, P<0.001) median progression free survival (5.0 vs 2.0 months, P<0.001), and overall survival (15.0 vs. 10.4 months, P =0.030), compared to patients with wild-type EGFR (n=272). 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 3 accepted 4298 1866 19 Somatic 2017-07-06 18:11:13 UTC https://civicdb.org/links/evidence_items/4298 https://civicdb.org/links/variants/1866 https://civicdb.org/links/genes/19 false EGFR 1956 L861Q High Grade Glioma 3070 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line expressing EGFR L861Q demonstrated increased sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing EGFR wild-type. Variant function was assessed by EGFR auto-phosphorylation. Sensitivity was assessed by cell viability assay using stable transfection of each variant and increasing concentrations of erlotinib (0–10 uM). 17177598 PubMed Lee et al., 2006, PLoS Med. 3 accepted 4299 1020 19 7 55259524 55259524 T A ENST00000275493.2 75 GRCh37 Somatic 2020-08-28 05:36:55 UTC https://civicdb.org/links/evidence_items/4299 https://civicdb.org/links/variants/1020 https://civicdb.org/links/genes/19 false EGFR 1956 E868G Malignant Mesothelioma 1790 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a COS-7 cell line expressing EGFR E868G demonstrated increased sensitivity to erlotinib treatment, compared to COS-7 cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation. 20942962 PubMed Foster et al., 2010, World J Surg Oncol accepted 4301 1482 19 7 55259545 55259545 A G ENST00000275493.2 75 GRCh37 Somatic 2018-01-18 23:34:00 UTC https://civicdb.org/links/evidence_items/4301 https://civicdb.org/links/variants/1482 https://civicdb.org/links/genes/19 false ABL1 25 BCR::ABL M244V Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support B Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 46 patients with M244V mutations, 20, 27, and 45 achieved a CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 4302 1021 4 9 133738330 133738330 A G ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 21:10:31 UTC https://civicdb.org/links/evidence_items/4302 https://civicdb.org/links/variants/1021 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M244V Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance In this phase II multinational study, 60 imatinib-resistant patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with M244V, 4/5 had MaHRs which was higher than response rates among wild type patients, and 2/5 had MCyRs which was comparable to response rates among wild type patients. 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 4304 1021 4 9 133738330 133738330 A G ENST00000318560.5 75 GRCh37 Somatic 2020-04-26 21:39:32 UTC https://civicdb.org/links/evidence_items/4304 https://civicdb.org/links/variants/1021 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M244V Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the M244V secondary variant in 12/12 bacterial clones generated using peripheral blood RNA. They had complete best hematologic and no cytogenetic responses to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 2 accepted 4305 1021 4 9 133738330 133738330 A G ENST00000318560.5 75 GRCh37 Somatic 2020-07-31 22:15:18 UTC https://civicdb.org/links/evidence_items/4305 https://civicdb.org/links/variants/1021 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M244V Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with M244V evaluated, 2/2 had complete hematologic responses and 2/3 had major cytogenetic responses. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 2 accepted 4307 1021 4 9 133738330 133738330 A G ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 21:36:39 UTC https://civicdb.org/links/evidence_items/4307 https://civicdb.org/links/variants/1021 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M244V Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with M244V evaluated, 3/3 had CHR and 2/3 had MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 2 accepted 4308 1021 4 9 133738330 133738330 A G ENST00000318560.5 75 GRCh37 Somatic 2018-12-21 19:47:40 UTC https://civicdb.org/links/evidence_items/4308 https://civicdb.org/links/variants/1021 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L248V Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with L248V evaluated, 3/3 had complete hematologic responses and 2/3 had major cytogenetic responses. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 2 accepted 4310 1022 4 9 133738342 133738342 C G ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 21:38:12 UTC https://civicdb.org/links/evidence_items/4310 https://civicdb.org/links/variants/1022 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L248V Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed decreased incorporation when harboring fusions with the L248V variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1393nM vs. 823 nM), indicating resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 4311 1022 4 9 133738342 133738342 C G ENST00000318560.5 75 GRCh37 Somatic 2019-12-20 21:56:07 UTC https://civicdb.org/links/evidence_items/4311 https://civicdb.org/links/variants/1022 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G250E Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with G250E evaluated, 1/1 had a complete hematologic response and 2/2 had major cytogenetic responses. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 2 accepted 4313 1023 4 9 133738349 133738349 G A ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 21:38:57 UTC https://civicdb.org/links/evidence_items/4313 https://civicdb.org/links/variants/1023 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G250E Chronic Myeloid Leukemia 8552 Bosutinib Predictive Supports C Reduced Sensitivity This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with G250E, 3/6 had a CHR and 0/5 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 2 accepted 4314 1023 4 9 133738349 133738349 G A ENST00000318560.5 75 GRCh37 Somatic 2018-12-21 19:46:18 UTC https://civicdb.org/links/evidence_items/4314 https://civicdb.org/links/variants/1023 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G250E Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support B Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Of 60 patients with G250E mutations, 20, 29, and 56 achieved a CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 4316 1023 4 9 133738349 133738349 G A ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 21:13:56 UTC https://civicdb.org/links/evidence_items/4316 https://civicdb.org/links/variants/1023 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G250E Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports C Reduced Sensitivity In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with G250E, 6/9 had MaHRs which was comparable to response rates among wild type patients, and 1/9 had MCyRs which was lower than response rates among wild type patients. 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 4318 1023 4 9 133738349 133738349 G A ENST00000318560.5 75 GRCh37 Somatic 2019-01-31 10:02:38 UTC https://civicdb.org/links/evidence_items/4318 https://civicdb.org/links/variants/1023 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G250E Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed higher incorporation when harboring fusions with the G250E variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1295nM vs. 823 nM), indicating resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 4320 1023 4 9 133738349 133738349 G A ENST00000318560.5 75 GRCh37 Somatic 2019-12-20 21:55:38 UTC https://civicdb.org/links/evidence_items/4320 https://civicdb.org/links/variants/1023 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Q252H Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the Q252H variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1155nM vs. 823 nM), indicating resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 4323 1024 4 9 133738356 133738356 G C ENST00000318560.5 75 GRCh37 Somatic 2019-12-20 21:49:45 UTC https://civicdb.org/links/evidence_items/4323 https://civicdb.org/links/variants/1024 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Q252H Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Of 6 patients with Q252H mutations, 1, 1, and 3 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. The authors identify Q252H as one of 4 variants with a low CCyR but advise caution when interpreting these results due to low sample size. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 4327 1024 4 9 133738356 133738356 G C ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:20:31 UTC https://civicdb.org/links/evidence_items/4327 https://civicdb.org/links/variants/1024 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253H Chronic Myeloid Leukemia 8552 Axitinib Predictive Does Not Support D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the Y253H variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 867nM vs. 823 nM), indicating that the variant does not induce resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 4329 1025 4 9 133738357 133738357 T C ENST00000318560.5 75 GRCh37 Somatic 2019-12-30 03:07:46 UTC https://civicdb.org/links/evidence_items/4329 https://civicdb.org/links/variants/1025 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253H Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with Y253H evaluated, 1/1 had a complete hematologic response and 1/1 had a major cytogenetic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 2 accepted 4331 1025 4 9 133738357 133738357 T C ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 21:41:21 UTC https://civicdb.org/links/evidence_items/4331 https://civicdb.org/links/variants/1025 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253H Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with Y253H evaluated, 5/6 had CHR and 4/6 had MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 3 accepted 4332 1025 4 9 133738357 133738357 T C ENST00000318560.5 75 GRCh37 Somatic 2018-12-21 19:44:53 UTC https://civicdb.org/links/evidence_items/4332 https://civicdb.org/links/variants/1025 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253H Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance In this phase II multinational study, 60 imatinib-resistant patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with Y253H, 5/6 had MaHRs which was higher than response rates among wild type patients and 2/6 had MCyRs which was comparable to response rates among wild type patients. 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 4334 1025 4 9 133738357 133738357 T C ENST00000318560.5 75 GRCh37 Somatic 2020-04-26 21:41:00 UTC https://civicdb.org/links/evidence_items/4334 https://civicdb.org/links/variants/1025 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253H Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support B Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 23 patients with the Y253H mutation, 14, 15, and 20 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 4335 1025 4 9 133738357 133738357 T C ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:23:03 UTC https://civicdb.org/links/evidence_items/4335 https://civicdb.org/links/variants/1025 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253H Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the Y253H secondary variant in 11/11 bacterial clones generated using peripheral blood RNA. They had complete response as best hematologic response and complete response as best cytogenetic response to dasatinib which were improved compared to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 4 accepted 4336 1025 4 9 133738357 133738357 T C ENST00000318560.5 75 GRCh37 Somatic 2020-07-31 22:56:57 UTC https://civicdb.org/links/evidence_items/4336 https://civicdb.org/links/variants/1025 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253F Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with Y253F evaluated, 1/1 had a complete hematologic response and 0/1 had a major cytogenetic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 1 accepted 4340 1026 4 9 133738358 133738358 A T ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:07:49 UTC https://civicdb.org/links/evidence_items/4340 https://civicdb.org/links/variants/1026 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253F Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the Y253F variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1275nM vs. 823 nM), indicating resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 4345 1026 4 9 133738358 133738358 A T ENST00000318560.5 75 GRCh37 Somatic 2019-12-20 21:52:05 UTC https://civicdb.org/links/evidence_items/4345 https://civicdb.org/links/variants/1026 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Bosutinib Predictive Supports C Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with E255K, 0/1 had a CHR and 0/1 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 4347 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2018-12-21 19:43:38 UTC https://civicdb.org/links/evidence_items/4347 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with E255K evaluated, 2/2 had complete hematologic responses and 1/2 had a major cytogenetic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 1 accepted 4348 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2018-07-12 21:42:24 UTC https://civicdb.org/links/evidence_items/4348 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support B Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 16 patients with E255K mutations, 6, 9, and 14 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 4350 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2018-07-19 21:24:03 UTC https://civicdb.org/links/evidence_items/4350 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports C Reduced Sensitivity In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with E255K, 4/6 had MaHRs which was comparable to response rates among wild type patients, and 0/6 had MCyRs which was lower than response rates among wild type patients. 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 4352 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2019-01-31 10:00:00 UTC https://civicdb.org/links/evidence_items/4352 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the E255K secondary variant in 12/12 bacterial clones generated using peripheral blood RNA. They had complete best hematologic and minimal best cytogenetic responses to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 4353 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2020-02-18 05:21:22 UTC https://civicdb.org/links/evidence_items/4353 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the E255K variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1282nM vs. 823 nM), indicating resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 4355 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2019-12-20 22:05:44 UTC https://civicdb.org/links/evidence_items/4355 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL D276G Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with D276G evaluated, 1/1 had a complete hematologic responses and 0/1 had a major cytogenetic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 1 accepted 4357 1027 4 9 133747520 133747520 A G ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:09:18 UTC https://civicdb.org/links/evidence_items/4357 https://civicdb.org/links/variants/1027 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL D276G Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 8 patients with D276G mutations, 3, 4, and 7 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 4359 1027 4 9 133747520 133747520 A G ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:26:20 UTC https://civicdb.org/links/evidence_items/4359 https://civicdb.org/links/variants/1027 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL D276G Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporations when harboring fusions with the D276G variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1105nM vs. 823 nM), indicating resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 4360 1027 4 9 133747520 133747520 A G ENST00000318560.5 75 GRCh37 Somatic 2019-12-20 22:05:28 UTC https://civicdb.org/links/evidence_items/4360 https://civicdb.org/links/variants/1027 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Bosutinib Predictive Supports C Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with T315I, 2/7 had a CHR and 0/6 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 2 accepted 4362 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2018-12-21 19:58:04 UTC https://civicdb.org/links/evidence_items/4362 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Bosutinib Predictive Supports C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with T315I evaluated, 1/2 had a complete hematologic response and 0/3 had major cytogenetic responses. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 2 accepted 4364 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2018-07-12 21:49:00 UTC https://civicdb.org/links/evidence_items/4364 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports B Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 21 patients with T315I mutations, 0, 2, and 6 achieved CCyR, MCyR, and CHR to dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. Of the 63 variants considered, the authors associate T315I, F317L, and V299L with resistance to dasatinib or lower levels of response due to clinical resistance and low in vitro sensitivity. They suggest considering alternative treatment options for patients with these variants. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 4365 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2018-07-19 21:50:47 UTC https://civicdb.org/links/evidence_items/4365 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports C Sensitivity/Response In this study, enzymatic profiling, crystal structures, and proliferation assays using Ba/F3 with the BCR-ABL1 variant showed higher sensitivity to axitinib in fusions with the T315I variant of ABL1 compared to wildtype ABL1 (IC50 of 21nM vs. 217 nM in resazurin assay; IC50 of 98 nM vs. 823 nM in tritiated thymidine assay). Bone marrow mononuclear cells (BM MNCs) were isolated from a chronic myeloid leukemia patients with the BCR-ABL1 T315I variant who was pretreated with imatinib, dasatinib, and chemotherapy. This patient's cells were sensitive to Ponatinib and Axitinib and insensitive to Nilotinib, Imatinib, and Dasatinib according to drug sensitivity scoring in proliferation assays. The patient was given axitinib monotherapy resulting in a significant decrease in T315I transcript levels in bone marrow (P<0.05). The authors note this as an example of a drug specifically targeting the secondary mutant resistant form of a protein. 25686603 PubMed Pemovska et al., 2015, Nature 4 accepted 4369 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2019-12-30 05:01:49 UTC https://civicdb.org/links/evidence_items/4369 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports C Resistance Prior to dasatinib treatment, two imatinib-resistant patients with chronic myeloid leukemia in accelerated phase had the BCR-ABL1 fusion with the T315I secondary variant in 8/10 and 10/10 bacterial clones generated using peripheral blood RNA. They had none as best hematologic response and none as best cytogenetic response to dasatinib which were worse compared to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 4373 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2020-07-31 22:47:06 UTC https://civicdb.org/links/evidence_items/4373 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Acute Lymphoblastic Leukemia 9952 Dasatinib Predictive Supports C Resistance In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with T315I, 0/5 had MaHRs and 0/5 had MCyRs which were lower than response rates among wild type patients. 17264298 PubMed Guilhot et al., 2007, Blood 2 accepted 4376 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2019-01-31 09:58:59 UTC https://civicdb.org/links/evidence_items/4376 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with F317L evaluated, 3/3 had major cytogenetic responses. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 3 accepted 4381 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2018-07-12 21:49:37 UTC https://civicdb.org/links/evidence_items/4381 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Bosutinib Predictive Supports C Reduced Sensitivity This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with F317L, 4/8 had a CHR and 1/7 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 4382 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2019-02-04 19:04:25 UTC https://civicdb.org/links/evidence_items/4382 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the F317L variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1220nM vs. 823 nM), indicating resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 4390 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2019-12-20 22:04:32 UTC https://civicdb.org/links/evidence_items/4390 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M351T Chronic Myeloid Leukemia 8552 Bosutinib Predictive Supports C Reduced Sensitivity This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with M351T, 1/1 had a CHR and 0/1 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 4394 1029 4 9 133748391 133748391 T C ENST00000318560.5 75 GRCh37 Somatic 2018-12-21 19:40:58 UTC https://civicdb.org/links/evidence_items/4394 https://civicdb.org/links/variants/1029 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M351T Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support B Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 54 patients with M351T mutations, 25, 28, and 51 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 4 accepted 4396 1029 4 9 133748391 133748391 T C ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:30:20 UTC https://civicdb.org/links/evidence_items/4396 https://civicdb.org/links/variants/1029 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M351T Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports C Reduced Sensitivity In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with M351T, 3/6 had MaHRs which was comparable to response rates among wild type patients, and 1/6 had MCyRs which was lower than response rates among wild type patients. 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 4397 1029 4 9 133748391 133748391 T C ENST00000318560.5 75 GRCh37 Somatic 2020-04-26 21:31:49 UTC https://civicdb.org/links/evidence_items/4397 https://civicdb.org/links/variants/1029 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M351T Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, four imatinib-resistant patients with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the M351T and M351S; M351T; M351T; and M351T secondary variants in 8/9 and 1/9; 4/10; 10/10; and 11/11 bacterial clones, respectively. Clones were generated using peripheral blood RNA. They had complete response as best hematologic response and complete (n = 3) or partial (n = 1) responses as best cytogenetic response to dasatinib. An additional patient, in myeloid blast crisis, had the M351T variant in 10/10 clones with complete response as best hematologic response and complete response as best cytogenetic response to dasatinib. An additional patient in accelerated phase had the M351T and M351A variants in 6/10 and 1/10 clones, respectively, with complete response as best hematologic response and none as best cytogenetic response to dasatinib. Overall, responses among these patients were comparable to those among patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 4398 1029 4 9 133748391 133748391 T C ENST00000318560.5 75 GRCh37 Somatic 2020-07-31 22:35:34 UTC https://civicdb.org/links/evidence_items/4398 https://civicdb.org/links/variants/1029 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E355G Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with E355G evaluated, 2/2 had complete hematologic responses and 1/2 had major cytogenetic responses. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 1 accepted 4400 1487 4 9 133748403 133748403 A G ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 21:52:26 UTC https://civicdb.org/links/evidence_items/4400 https://civicdb.org/links/variants/1487 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E355G Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with E355G, 2/4 had MaHRs and 2/4 had MCyRs which were comparable to response rates among wild type. 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 4402 1487 4 9 133748403 133748403 A G ENST00000318560.5 75 GRCh37 Somatic 2020-04-26 21:28:55 UTC https://civicdb.org/links/evidence_items/4402 https://civicdb.org/links/variants/1487 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E355G Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support B Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 19 patients with E355G mutations, 4, 9, and 17 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 2 accepted 4403 1487 4 9 133748403 133748403 A G ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 22:01:49 UTC https://civicdb.org/links/evidence_items/4403 https://civicdb.org/links/variants/1487 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E355G Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, three imatinib-resistant patients with chronic myeloid leukemia had the BCR-ABL1 fusion with the E355G secondary variant in one or more bacterial clones. Clones were generated using peripheral blood RNA. The first two, in chronic and accelerated phases, had minimal or no best cytogenetic responses but had complete or no evidence of leukemia best hematologic responses, respectively. Of these, the first had E355G and E355G/Q252R variants in 8/10 and 1/10 clones, respectively, and the second had E355G, E355G/L324Q, and L324Q variants in 6/10, 1/10, and 3/10 clones, respectively. The third patient, in lymphoid blast crisis with the E355G variant in 10/10 clones, had complete best hematologic and partial best cytogenetic responses to dasatinib. All responses were comparable to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 4404 1487 4 9 133748403 133748403 A G ENST00000318560.5 75 GRCh37 Somatic 2020-02-18 05:48:39 UTC https://civicdb.org/links/evidence_items/4404 https://civicdb.org/links/variants/1487 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L387M Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 5 patients with L387M mutations, 4, 4, and 5 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 4406 1488 4 9 133750328 133750328 T A ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:32:24 UTC https://civicdb.org/links/evidence_items/4406 https://civicdb.org/links/variants/1488 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L387M Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with L387M, L387M/F192L, and E450G variants in 7/10, 2/10, and 1/10 clones, respectively. Clones were generated using peripheral blood RNA. The patient had minimal best cytogenetic and complete best hematologic responses to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 4407 1488 4 9 133750328 133750328 T A ENST00000318560.5 75 GRCh37 Somatic 2020-02-18 21:52:26 UTC https://civicdb.org/links/evidence_items/4407 https://civicdb.org/links/variants/1488 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL H396R Chronic Myeloid Leukemia 8552 Bosutinib Predictive Supports C Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with H396R, 0/1 had a CHR and 0/1 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 4410 1030 4 9 133750356 133750356 A G ENST00000318560.5 75 GRCh37 Somatic 2018-12-21 19:39:39 UTC https://civicdb.org/links/evidence_items/4410 https://civicdb.org/links/variants/1030 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL H396R Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with H396R evaluated, 1/1 had a complete hematologic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 1 accepted 4411 1030 4 9 133750356 133750356 A G ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 22:03:33 UTC https://civicdb.org/links/evidence_items/4411 https://civicdb.org/links/variants/1030 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL H396R Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support B Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 33 patients with H396R mutations, 13, 17, and 30 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 4413 1030 4 9 133750356 133750356 A G ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:34:21 UTC https://civicdb.org/links/evidence_items/4413 https://civicdb.org/links/variants/1030 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL H396R Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the H396R variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1247nM vs. 823 nM), indicating resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 4417 1030 4 9 133750356 133750356 A G ENST00000318560.5 75 GRCh37 Somatic 2019-12-20 22:05:08 UTC https://civicdb.org/links/evidence_items/4417 https://civicdb.org/links/variants/1030 https://civicdb.org/links/genes/4 false PIK3CA 5290 E542K Colorectal Cancer 9256 Cetuximab Predictive Does Not Support C Resistance This was a retrospective study of 691 cetuximab treated patients with metastatic colorectal cancer. Of those, 7 patients harbored PIK3CA E542K (exon 10), were wt for BRAF, NRAS and PIK3CA, and had individual response data. Two patients had partial response, three had stable disease, and two progressed, resulting in a response rate of 2/7 and a clinical benefit rate of 5/7 according to author criteria. Treatments included cetuximab + irinotecan (n=5), cetuximab + FOLFIRI (n=1), and cetuximab monotherapy (n=1). Median PFS was 34 weeks (17-48 weeks), median OS was 46 weeks (27-91 weeks), and median number of previous chemotherapy lines was 2 (0-4). Median age was 59 years old (53-74), and there were 6 females and one male. Using these and data from the larger cohort, authors concluded that PIK3CA exon 10 (listed as exon 9 in source) mutations are associated with weak or no resistance to cetuximab. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 4424 103 37 3 178936082 178936082 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K variants are the second most recurrent PIK3CA mutations in breast cancer and are highly recurrent mutations in many other cancer types. Colorectal cancer patients with the PIK3CA E545K variant, and possibly other variants in the E545 region, may indicate poor prognosis relative to patients with other PIK3CA variants or wild-type PIK3CA. The literature also suggests that E545/E542 variants may confer resistance to EGFR inhibitors (e.g., cetuximab). An FDA approved treatment regimen including a targeted PIK3CA inhibitor is available for specific subtypes of breast cancer. While PIK3CA variants are highly prevalent in many other cancer types, targeted therapies for PIK3CA variants are still in early clinical trial phases in other cancer types. Somatic 2020-11-25 22:28:05 UTC https://civicdb.org/links/evidence_items/4424 https://civicdb.org/links/variants/103 https://civicdb.org/links/genes/37 false KRAS 3845 G12A Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance This was a retrospective study of 691 cetuximab treated patients with metastatic colorectal cancer. Of those, 22 patients harbored KRAS G12A, were BRAF, NRAS and PIK3CA wt, and had individual response data. Three patients had partial response, 12 had stable disease, and seven progressed. Treatments included cetuximab + irinotecan (n=18), cetuximab monotherapy (n=1), cetuximab + FOLFIRI (n=2), and cetuximab + oxaliplatin + 5FU (n=1). Median PFS was 18 weeks (1-34 weeks), median OS was 35 weeks (1-143 weeks), and median number of previous chemotherapy lines was 2 (0-5). Median age was 62 years old (22-77) and there were 11 males and 11 females. Using these data and data from the larger cohort, authors concluded that KRAS mutation was strongly associated with poor response to cetuximab and suggested that mutation status of KRAS is the most informative compared to BRAF, NRAS, and PIK3CA exon 20 for predicting cetuximab response. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 4429 148 30 12 25398284 25398284 C G ENST00000256078.4 75 GRCh37 KRAS G12A, like EGFR T790M, has been shown to be capable of driving acquired resistance to tyrosine kinase inhibitors in lung adenocarcinoma. Somatic 2020-11-25 00:51:56 UTC https://civicdb.org/links/evidence_items/4429 https://civicdb.org/links/variants/148 https://civicdb.org/links/genes/30 false PIK3CA 5290 H1047L Colorectal Cancer 9256 Irinotecan,Cetuximab Combination Predictive Supports C Resistance Two patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored PIK3CA H1047L (exon 21), were wildtype for NRAS, BRAF and PIK3CA, and had individual response data. Both were males treated with cetuximab + irinotecan as 3rd line therapy and experienced progressive disease. One patient was 73 years old with a PFS of 11 weeks and an OS of 31 weeks. The other patient was 61 years old with a PFS and OS of 4 weeks. Authors concluded from this information and data from larger cohort that PIK3CA exon 21 (listed as exon 20 in source) mutations predict poor response to cetuximab. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 4432 1151 37 3 178952085 178952085 A T ENST00000263967.3 75 GRCh37 Somatic 2020-11-25 23:01:27 UTC https://civicdb.org/links/evidence_items/4432 https://civicdb.org/links/variants/1151 https://civicdb.org/links/genes/37 false ABL1 25 BCR::ABL L364I Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the L364I secondary variant in 9/12 bacterial clones generated using peripheral blood RNA. They had complete best hematologic and no cytogenetic responses to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 4434 2902 4 Somatic 2020-07-31 22:12:35 UTC https://civicdb.org/links/evidence_items/4434 https://civicdb.org/links/variants/2902 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Acute Lymphoblastic Leukemia 9952 Dasatinib Predictive Supports C Sensitivity/Response Prior to dasatinib treatment, one imatinib-resistant patient with acute lymphoblastic leukemia had the BCR-ABL1 fusion with no secondary variants in at least ten bacterial clones generated using peripheral blood RNA. They had NEL (no evidence of leukemia) best hematologic and minor best cytogenetic responses to dasatinib. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 4436 1 4 22 23522397 23632600 ENST00000305877.8 9 133729451 133763063 ENST00000318560.5 75 GRCh37 The BCR-ABL fusion protein, commonly referred to as the Philadelphia chromosome, is one of the most studied fusion genes in cancer. It has widely been considered the initiating event in chronic myelogenous leukemia (CML). However, despite its ability to initiate disease in mice, its status as an initiating mutation is in dispute. In what is commonly used as the poster-child for targeted therapeutics, the development and use of imatinib in the clinic has led to profound improvements in the prognosis of the disease. However, imatinib resistance is still seen in patients with mutations in the ABL kinase domain of the fusion, most notably the T315I variant. In patients resistant to imatinib, either acquired or otherwise, second generation BCR-ABL TKI's (dasatinib and nilotinib) have seen some success in delivering a tumor response. Third generation ABL1 inhibitor ponatinib is the only FDA approved drug with activity against T315I . However due to risk of life-threatening blood clots and severe narrowing of blood vessels ponatinib is ONLY approved for T315I-positive CML or T315I-positive Ph+ ALL or in cases of CML, Ph+ ALL with resistance or intolerance to other approved ABL1 inhibitors. Somatic 2020-02-08 03:39:55 UTC https://civicdb.org/links/evidence_items/4436 https://civicdb.org/links/variants/1 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F486S Chronic Myeloid Leukemia 8552 Axitinib Predictive Does Not Support D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the F486S variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 897nM vs. 823 nM), indicating baseline sensitivity. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 4438 1152 4 9 133755488 133755488 T C ENST00000318560.5 75 GRCh37 Somatic 2019-12-20 21:55:11 UTC https://civicdb.org/links/evidence_items/4438 https://civicdb.org/links/variants/1152 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F486S Chronic Myeloid Leukemia 8552 Bosutinib Predictive Supports C Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with F486S, 0/1 had a CHR and 0/1 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 4440 1152 4 9 133755488 133755488 T C ENST00000318560.5 75 GRCh37 Somatic 2018-12-21 19:25:05 UTC https://civicdb.org/links/evidence_items/4440 https://civicdb.org/links/variants/1152 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255V Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the E255V variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1350nM vs. 823 nM), indicating resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 4441 1173 4 9 133738364 133738364 A T ENST00000318560.5 75 GRCh37 Somatic 2019-12-20 21:54:56 UTC https://civicdb.org/links/evidence_items/4441 https://civicdb.org/links/variants/1173 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255V Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with E255V evaluated, 1/1 had a complete hematologic response and 1/1 had a major cytogenetic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 2 accepted 4443 1173 4 9 133738364 133738364 A T ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 21:43:47 UTC https://civicdb.org/links/evidence_items/4443 https://civicdb.org/links/variants/1173 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255V Chronic Myeloid Leukemia 8552 Bosutinib Predictive Supports C Reduced Sensitivity This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with E255V, 1/1 had a CHR and 0/1 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 4444 1173 4 9 133738364 133738364 A T ENST00000318560.5 75 GRCh37 Somatic 2018-12-21 19:38:50 UTC https://civicdb.org/links/evidence_items/4444 https://civicdb.org/links/variants/1173 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255V Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support B Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 11 patients with E255V mutations, 4, 4, and 9 achieved a CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 4447 1173 4 9 133738364 133738364 A T ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:36:12 UTC https://civicdb.org/links/evidence_items/4447 https://civicdb.org/links/variants/1173 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255V Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Three chronic myeloid leukemia patients had the BCR-ABL1 fusion with the E255V secondary variant in one or more bacterial clones generated using peripheral blood RNA. They had no best cytogenetic responses but had complete (n = 2) or minor best hematologic responses to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. The first patient, in chronic phase, had E255V, E255V/Q447R, E255V/T345A, and E255V/T345A/H396R variants in 6/10, 2/10, 1/10, and 1/10 clones, respectively. The second patient, in chronic phase, had E255V and E255K variants in 10/11 and 1/11 clones, respectively. The third patient, in myeloid blast crisis, had E255V and E292V variants in 10/12 and 2/12 clones, respectively. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 4448 1173 4 9 133738364 133738364 A T ENST00000318560.5 75 GRCh37 Somatic 2020-02-18 05:40:57 UTC https://civicdb.org/links/evidence_items/4448 https://civicdb.org/links/variants/1173 https://civicdb.org/links/genes/4 false KIT 3815 P551_E554delPMYE Gastrointestinal Stromal Tumor 9253 Imatinib,Regorafenib,Sunitinib Substitutes Predictive Does Not Support D Sensitivity/Response In an in vitro study, an IL3 independent Ba/F3 cell line expressing KIT P551_E554delPMYE primary activating mutation demonstrated insensitivity to regorafenib (IC50: 141nmol/L), imatinib (IC50: 90nmol/L), and sunitinib (IC50: 42nmol/L) treatments. In comparison, sensitizing KIT mutation del550-557 showed IC50 22, 13 and 5 nmol/L for these drugs respectively. IC50 was determined by assessing cell viability. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 3 accepted 4455 1497 29 4 55593585 55593596 GRCh37 Somatic 2019-07-09 23:03:28 UTC https://civicdb.org/links/evidence_items/4455 https://civicdb.org/links/variants/1497 https://civicdb.org/links/genes/29 false KIT 3815 V559D Gastrointestinal Stromal Tumor 9253 Ponatinib,Imatinib,Regorafenib Substitutes Predictive Supports D Sensitivity/Response In an in vitro kinase study, a KIT V559D primary activating mutant kinase demonstrated sensitivity to imatinib (IC50: 36nmol/L vs. 640nmol/L), regorafenib (IC50: 57nmol/L vs. 533nmol/L), and ponatinib (IC50: 0.8nmol/L vs. 6nmol/L) treatments compared to the wild-type KIT. IC50 was determined by assessing kinase activity. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 2 accepted 4459 968 29 4 55593610 55593610 T A ENST00000288135.5 75 GRCh37 Somatic 2019-07-09 22:59:36 UTC https://civicdb.org/links/evidence_items/4459 https://civicdb.org/links/variants/968 https://civicdb.org/links/genes/29 false PIK3CA 5290 S158L Colorectal Cancer 9256 Cetuximab,Irinotecan Combination Predictive Supports C Resistance One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored PIK3CA S158L, was wildtype for KRAS, BRAF and NRAS, and had individual response data. This patient was was a 53 year old male treated with cetuximab + irinotecan as 3rd line therapy who experienced progressive disease (PFS: 1 week; OS: 3 weeks). 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 3 accepted 4463 1499 37 3 178917598 178917598 C T ENST00000263967.3 75 GRCh37 Somatic 2020-11-25 23:15:18 UTC https://civicdb.org/links/evidence_items/4463 https://civicdb.org/links/variants/1499 https://civicdb.org/links/genes/37 false PIK3CA 5290 E81K Colorectal Cancer 9256 Cetuximab,Fluorouracil,Oxaliplatin Combination Predictive Does Not Support C Resistance Two patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored PIK3CA E81K, were wildtype for NRAS, BRAF and PIK3CA, and had individual response data. Both were treated with cetuximab + oxaliplatin + 5FU as 2nd line therapy and experienced stable disease, resulting in a response rate of 0/2 and a clinical benefit rate of 2/2 according to author criteria. One patient was a 57 year old female with a PFS of 24 weeks and an OS of 100 weeks. The other patient was a 60 year old male with a PFS of 23 weeks. 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 2 accepted 4464 1500 37 3 178916854 178916854 G A ENST00000263967.3 75 GRCh37 Somatic 2020-12-02 02:41:36 UTC https://civicdb.org/links/evidence_items/4464 https://civicdb.org/links/variants/1500 https://civicdb.org/links/genes/37 false PIK3CA 5290 R93W Colorectal Cancer 9256 Cetuximab,Fluorouracil,Oxaliplatin Combination Predictive Supports C Resistance One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored PIK3CA R93W, was wildtype for KRAS, BRAF and NRAS, and had individual response data. This patient was was a 56 year old male treated with cetuximab + oxaliplatin + 5FU as 2nd line therapy who experienced progressive disease (PFS: 8 weeks). 20619739 PubMed De Roock et al., 2010, Lancet Oncol. 2 accepted 4467 1178 37 3 178916890 178916890 C T ENST00000263967.3 75 GRCh37 Somatic 2020-11-25 23:11:49 UTC https://civicdb.org/links/evidence_items/4467 https://civicdb.org/links/variants/1178 https://civicdb.org/links/genes/37 false EGFR 1956 R776C Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line expressing EGFR R776C demonstrated increased sensitivity to erlotinib treatment comparable to Ba/F3 cells expressing a known sensitizing mutation (EGFR L858R). Sensitivity was determined by assessing cell proliferation, the IC50 of erlotinib for EGFR V742A and EGFR L858R expressing cells were 47 nmol/L and 6 nmol/L, respectively. 19147750 PubMed Kancha et al., 2009, Clin. Cancer Res. accepted 4468 1181 19 7 55249028 55249028 C T ENST00000275493.2 75 GRCh37 Somatic 2017-09-16 10:56:35 UTC https://civicdb.org/links/evidence_items/4468 https://civicdb.org/links/variants/1181 https://civicdb.org/links/genes/19 false BRAF 673 D594G Colorectal Cancer 9256 Cetuximab,Irinotecan Combination Predictive Supports C Resistance In a retrospective study of 53, KRAS exon 2 wild-type, metastatic colorectal cancer patients, patients harboring BRAF G466A (n=1), G469A (n=2), D594G (n=1), or V600E (n=2) mutations were reported to be non-responders to cetuximab in combination with irinotecan, (BRAF mutation positive: responders vs. non-responders = 0 vs. 6; BRAF wild-type: responders vs. non-responders 30 vs. 17; P=0.004), as compared to patients with wild-type BRAF. 26989027 PubMed Hsu et al., 2016, Oncotarget 3 accepted 4472 611 5 7 140453154 140453154 T C ENST00000288602.6 75 GRCh37 This BRAF mutation has a markedly reduced kinase activity and leads to paradoxical MEK-pathway activation via CRAF binding. Somatic 2019-08-30 15:24:58 UTC https://civicdb.org/links/evidence_items/4472 https://civicdb.org/links/variants/611 https://civicdb.org/links/genes/5 false ABL1 25 L298V Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with L298V evaluated, 1/1 had a complete hematologic response and 0/1 had a major cytogenetic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 1 accepted 4475 1506 4 9 133747585 133747585 C G ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:10:17 UTC https://civicdb.org/links/evidence_items/4475 https://civicdb.org/links/variants/1506 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F311I Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with F311I evaluated, 1/1 had a complete hematologic response and 1/1 had a major cytogenetic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 2 accepted 4478 1507 4 9 133748270 133748270 T A ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 21:46:17 UTC https://civicdb.org/links/evidence_items/4478 https://civicdb.org/links/variants/1507 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359C Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with F359C, 2/2 had a CHR and 1/2 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 4480 1184 4 9 133748415 133748415 T G ENST00000318560.5 75 GRCh37 Somatic 2018-12-21 19:36:56 UTC https://civicdb.org/links/evidence_items/4480 https://civicdb.org/links/variants/1184 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359C Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with F359C, 2/2 had MaHRs and 2/2 had MCyRs which were comparable to response rates among wild type patients. 17264298 PubMed Guilhot et al., 2007, Blood 2 accepted 4481 1184 4 9 133748415 133748415 T G ENST00000318560.5 75 GRCh37 Somatic 2020-04-26 21:31:13 UTC https://civicdb.org/links/evidence_items/4481 https://civicdb.org/links/variants/1184 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359C Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 5 patients with F359C mutations, 3, 3, and 4 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 4482 1184 4 9 133748415 133748415 T G ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:37:49 UTC https://civicdb.org/links/evidence_items/4482 https://civicdb.org/links/variants/1184 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359C Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with G250E and F359C variants in 3/10 and 5/10 clones, respectively. Clones were generated using peripheral blood RNA. The patient had complete best cytogenetic and complete best hematologic responses to dasatinib which were improved compared to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 4 accepted 4483 1184 4 9 133748415 133748415 T G ENST00000318560.5 75 GRCh37 Somatic 2020-02-08 03:42:33 UTC https://civicdb.org/links/evidence_items/4483 https://civicdb.org/links/variants/1184 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E453Q Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with E453Q evaluated, 1/1 had a complete hematologic response and 1/1 had a major cytogenetic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 2 accepted 4486 1509 4 9 133753888 133753888 G C ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 22:07:49 UTC https://civicdb.org/links/evidence_items/4486 https://civicdb.org/links/variants/1509 https://civicdb.org/links/genes/4 false ARID1A 8289 Q456* Ovarian Clear Cell Carcinoma 0050934 Dasatinib Predictive Supports D Sensitivity/Response In an in vitro study, a HCT116 cell line expressing ARID1A Q456* mutation demonstrated increased sensitivity to dasatinib treatment, compared to HCT116 cells expressing wild-type ARID1A. Sensitivity was determined by assessing cell survival. 27364904 PubMed Miller et al., 2016, Mol. Cancer Ther. accepted 4487 1510 6559 1 27057658 27057658 C T ENST00000324856.7 75 GRCh37 Somatic 2020-12-03 18:33:01 UTC https://civicdb.org/links/evidence_items/4487 https://civicdb.org/links/variants/1510 https://civicdb.org/links/genes/6559 true BRAF 673 V600D Melanoma 1909 Vemurafenib Predictive Supports D Sensitivity/Response In an in vitro study, WM2664, a BRAF V600D expressing cell line, demonstrated improved sensitivity to vemurafenib treatment, compared to BRAF wild-type expressing cells. Sensitivity was determined by assessing cell proliferation (WM2664, GI50: 1.5uM; vs. BRAF expressing cells (n=9) GI50: 10-41uM). 18287029 PubMed Tsai et al., 2008, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 4488 11 5 7 140453135 140453136 CA AT ENST00000288602.6 75 GRCh37 Patients harboring mutations in valine 600 residue of BRAF have been shown to be sensitive to dabrafenib. For more information on the V600 locus, see the V600E entry. Somatic 2020-08-20 14:49:36 UTC https://civicdb.org/links/evidence_items/4488 https://civicdb.org/links/variants/11 https://civicdb.org/links/genes/5 false BRAF 673 V600D Melanoma 1909 Vemurafenib Predictive Supports D Sensitivity/Response In an in vitro study, the WM2664 and WM239A cell lines expressing BRAF V600D were associated with increased sensitivity to vemurafenib treatment, as compared to cell lines expressing BRAF wild-type. Sensitivity was determined by proliferation assay. In addition, vemurafenib treatment strongly inhibited MEK and ERK phosphorylation in WM2664 cells. 20551065 PubMed Yang et al., 2010, Cancer Res. 4 accepted 4489 11 5 7 140453135 140453136 CA AT ENST00000288602.6 75 GRCh37 Patients harboring mutations in valine 600 residue of BRAF have been shown to be sensitive to dabrafenib. For more information on the V600 locus, see the V600E entry. Somatic 2020-11-21 22:43:17 UTC https://civicdb.org/links/evidence_items/4489 https://civicdb.org/links/variants/11 https://civicdb.org/links/genes/5 false EGFR 1956 H773_V774insNPH Lung Adenocarcinoma 3910 Erlotinib Predictive Supports C Resistance A 61 year old male never smoker with EGFR H773_V774insNPH mutant lung adenocarcinoma was treated with fourth line erlotinib and had progressive disease as best response, progression free survival of 1.6 months, and overall survival of 4.4 months. 24353160 PubMed Yasuda et al., 2013, Sci Transl Med 3 accepted 4493 1513 19 7 55249012 55249013 AACCCCCAC ENST00000275493.2 GRCh37 Somatic 2021-02-18 01:46:30 UTC https://civicdb.org/links/evidence_items/4493 https://civicdb.org/links/variants/1513 https://civicdb.org/links/genes/19 false EGFR 1956 D770_N771insGL Lung Adenocarcinoma 3910 Erlotinib Predictive Supports C Resistance 2 patients with EGFR D770_N771insGL mutant lung adenocarcinoma were treated with first line erlotinib. A 45 year old male never smoker had progressive disease as best response with +24% change to target lesions, progression free survival of 3.8 months, and still alive at study end after 39.3 months. A 79 year old female never smoker had progressive disease as best response with +13% change to target lesions, progression free survival of 6 months and overall survival of 14 months. 24353160 PubMed Yasuda et al., 2013, Sci Transl Med 4 accepted 4494 1514 19 7 55249012 55249013 GGGTTA ENST00000275493.2 GRCh37 Somatic 2021-02-18 01:50:42 UTC https://civicdb.org/links/evidence_items/4494 https://civicdb.org/links/variants/1514 https://civicdb.org/links/genes/19 false EGFR 1956 A864T Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line expressing EGFR A864T demonstrated increased sensitivity to erlotinib treatment comparable to Ba/F3 cells expressing a known sensitizing mutation (EGFR L858R). Sensitivity was determined by assessing cell proliferation, the IC50 of erlotinib for EGFR A864T and EGFR L858R expressing cells were 49 nmol/L and 6 nmol/L, respectively. 19147750 PubMed Kancha et al., 2009, Clin. Cancer Res. accepted 4495 1187 19 7 55259532 55259532 G A ENST00000275493.2 75 GRCh37 Somatic 2017-09-15 00:32:16 UTC https://civicdb.org/links/evidence_items/4495 https://civicdb.org/links/variants/1187 https://civicdb.org/links/genes/19 false EGFR 1956 N826S Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line expressing EGFR N826S demonstrated reduced sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing a known sensitizing mutation (EGFR L858R). Sensitivity was determined by assessing cell proliferation, the IC50 of erlotinib for EGFR N826S and EGFR L858R expressing cells were 505 nmol/L and 6 nmol/L, respectively. 19147750 PubMed Kancha et al., 2009, Clin. Cancer Res. accepted 4496 1188 19 7 55259419 55259419 A G ENST00000275493.2 75 GRCh37 Somatic 2017-09-14 22:50:58 UTC https://civicdb.org/links/evidence_items/4496 https://civicdb.org/links/variants/1188 https://civicdb.org/links/genes/19 false EGFR 1956 A763_Y764insFQEA Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, Ba/F3 and BID007 cell lines expressing EGFR A763_Y764insFQEA demonstrated increased sensitivity to erlotinib treatment (IC50=0.048�M and 0.082�M, respectively), comparable to Ba/F3 and NCI-H3255 cells expressing EGFR L858R (a known sensitizing mutation to EGFR tyrosine kinase inhibitors; IC50=0.006�M and 0.068�M, respectively). Sensitivity was determined by assessing cell proliferation, EGFR, AKT and ERK phosphorylation, levels of BIM (a marker of EGFR TKI-induced cell killing) and cell viability. 24353160 PubMed Yasuda et al., 2013, Sci Transl Med accepted 4497 1515 19 7 55248992 55248993 TCCAGGAAGCCT ENST00000275493.2 GRCh37 Somatic 2018-02-11 11:29:18 UTC https://civicdb.org/links/evidence_items/4497 https://civicdb.org/links/variants/1515 https://civicdb.org/links/genes/19 false AKT1 207 Q79K Melanoma 1909 Vemurafenib Predictive Supports D Resistance In an in vitro study, a M229 cell line endogenously expressing BRAF V600E mutation (a known vemurafenib sensitizing mutation) and overexpressing AKT1 Q79K mutation was associated with resistance to vemurafenib treatment, as compared to cells expressing BRAF V600E mutation and wildtype AKT1. Resistance was determined by assessing cell survival. 24265155 PubMed Shi et al., 2014, Cancer Discov 2 accepted 4498 169 2 14 105243048 105243048 G T ENST00000407796.2 75 GRCh37 Somatic 2021-11-12 18:57:05 UTC https://civicdb.org/links/evidence_items/4498 https://civicdb.org/links/variants/169 https://civicdb.org/links/genes/2 false EGFR 1956 VIII High Grade Glioma 3070 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line expressing EGFR vIII demonstrated increased sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing EGFR wild-type. Variant function was assessed by EGFR auto-phosphorylation. Sensitivity was assessed by cell viability assay using stable transfection of each variant and increasing concentrations of erlotinib (0–10 uM). 17177598 PubMed Lee et al., 2006, PLoS Med. 3 accepted 4500 312 19 7 55087058 55223523 ENST00000275493.2 75 GRCh37 The EGFRvIII variant is an oncogenic mutation that has been reported in several cancers including glioblastoma multiforme, breast, lung, head and neck, ovarian and prostate. In high-grade gliomas, EGFRvIII has been reported in about 30% of cases with EGFR amplification. The EGFRvIII mutation leads to deletion of the receptor ectodomain exons 2-7. The presence of this variant has been linked with clinical response to EGFR TKI. (Arteaga and Engelmann, 2014) Somatic 2020-08-28 05:45:28 UTC https://civicdb.org/links/evidence_items/4500 https://civicdb.org/links/variants/312 https://civicdb.org/links/genes/19 false KIT 3815 T670I Gastrointestinal Stromal Tumor 9253 Regorafenib Predictive Supports D Resistance A preclinical study tested the effects of a tyrosine kinase inhibitor (TKI) on Ba/F3 cell lines with representative primary regorafenib-sensitizing mutation del 557-558, which induced IL-3 independent growth, and secondary mutation T670I. The cells were tested for Regorafenib resistance. Ba/F3 cells with del 557-558/T670I mutations (IC50 = 132 +- 25 nM) did show resistance towards Regorafenib compared to Ba/F3 cells with del 557-558 alone (IC50 = 30 +- 14 nM). In addition, Ba/F3 cells were mutagenized with N-ethyl-N-nitrosourea and incubated with varying concentrations of Regorafenib. In Regorafenib incubated cells, T670I mutations were seen in approximately 10% of the resistant cell populations. The results suggest that T670I does induce regorafenib resistance in del 557-558/T670I cells. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 4 accepted 4510 1267 29 4 55595519 55595519 C T ENST00000288135.5 75 GRCh37 Somatic 2019-07-22 22:28:42 UTC https://civicdb.org/links/evidence_items/4510 https://civicdb.org/links/variants/1267 https://civicdb.org/links/genes/29 false AKT3 10000 E17K Melanoma 1909 Vemurafenib Predictive Supports D Resistance An in vitro study of M229 (a human melanoma cell line) endogenously expressing wildtype AKT3 and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that cells virally induced to stably over-express AKT3 E17K were significantly more resistant to BRAF inhibition via vemurafenib than cells transduced with empty vectors (40% vs 20% survival, p = .0033). 24265155 PubMed Shi et al., 2014, Cancer Discov 3 accepted 4521 1227 7936 1 243859016 243859016 C T ENST00000366539.1 75 GRCh37 Somatic 2018-07-19 20:06:20 UTC https://civicdb.org/links/evidence_items/4521 https://civicdb.org/links/variants/1227 https://civicdb.org/links/genes/7936 false ABL1 25 BCR::ABL L384M Chronic Myeloid Leukemia 8552 Axitinib Predictive Does Not Support D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the L384M variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 916nM vs. 823 nM), indicating baseline sensitivity. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 4525 1230 4 9 133750319 133750319 C A ENST00000318560.5 75 GRCh37 Somatic 2019-12-20 21:54:40 UTC https://civicdb.org/links/evidence_items/4525 https://civicdb.org/links/variants/1230 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L384M Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports C Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, a majority of patients with and without ABL1 mutation had comparable complete hematologic response, major cytogenetic response, complete cytogenetic response (CCyR), and major molecular response. However, out of 2 patients with the L384M mutation, 0 achieved CCyR with dasatinib monotherapy. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 1 accepted 4527 1230 4 9 133750319 133750319 C A ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:59:30 UTC https://civicdb.org/links/evidence_items/4527 https://civicdb.org/links/variants/1230 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359I Chronic Myeloid Leukemia 8552 Axitinib Predictive Does Not Support D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the F359I variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 975nM vs. 823 nM), indicating that the variant does not induce resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 4529 1523 4 9 133748414 133748414 T A ENST00000318560.5 75 GRCh37 Somatic 2019-12-20 21:50:50 UTC https://civicdb.org/links/evidence_items/4529 https://civicdb.org/links/variants/1523 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359I Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with F359I evaluated, 1/1 had a complete hematologic response and 1/1 had a major cytogenetic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 2 accepted 4530 1523 4 9 133748414 133748414 T A ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 21:56:10 UTC https://civicdb.org/links/evidence_items/4530 https://civicdb.org/links/variants/1523 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359I Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with F359I evaluated, 2/2 had CHR and 2/2 had MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 2 accepted 4531 1523 4 9 133748414 133748414 T A ENST00000318560.5 75 GRCh37 Somatic 2018-12-21 19:35:51 UTC https://civicdb.org/links/evidence_items/4531 https://civicdb.org/links/variants/1523 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359I Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support B Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 12 patients with F359I mutations, 7, 10, and 12 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 4532 1523 4 9 133748414 133748414 T A ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:38:33 UTC https://civicdb.org/links/evidence_items/4532 https://civicdb.org/links/variants/1523 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359I Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the F359I secondary variant in 9/9 bacterial clones generated using peripheral blood RNA. They had complete best hematologic and no cytogenetic responses to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 4533 1523 4 9 133748414 133748414 T A ENST00000318560.5 75 GRCh37 Somatic 2020-02-18 21:24:28 UTC https://civicdb.org/links/evidence_items/4533 https://civicdb.org/links/variants/1523 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M343T Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the M343T variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1175nM vs. 823 nM), indicating resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 4534 1524 4 9 133748367 133748367 T C ENST00000318560.5 75 GRCh37 Somatic 2019-12-20 22:04:50 UTC https://civicdb.org/links/evidence_items/4534 https://civicdb.org/links/variants/1524 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317V Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the F317V variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1320nM vs. 823 nM), indicating resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 4535 1525 4 9 133748288 133748288 T G ENST00000318560.5 75 GRCh37 Somatic 2019-12-20 21:54:22 UTC https://civicdb.org/links/evidence_items/4535 https://civicdb.org/links/variants/1525 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL V299L Chronic Myeloid Leukemia 8552 Bosutinib Predictive Supports C Reduced Sensitivity This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with V299L, 1/2 had a CHR and 0/2 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 4538 1231 4 9 133747588 133747588 G C ENST00000318560.5 75 GRCh37 Somatic 2018-12-21 19:33:42 UTC https://civicdb.org/links/evidence_items/4538 https://civicdb.org/links/variants/1231 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL V299L Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports C Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response, major cytogenetic response, complete cytogenetic response (CCyR), and major molecular response. There was 1 patient with a V299L mutation who did not achieved CCyR with dasatinib monotherapy. Analyses by variant included patients with multiple kinase domain mutations. Of the 63 variants considered, the authors associate T315I, F317L, and V299L with resistance to dasatinib or lower levels of response due to clinical resistance and low in vitro sensitivity. They suggest considering alternative treatment options for patients with these variants. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 1 accepted 4540 1231 4 9 133747588 133747588 G C ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:45:03 UTC https://civicdb.org/links/evidence_items/4540 https://civicdb.org/links/variants/1231 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E279K Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 8 patients with E279K mutations, 5, 5, and 8 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 4543 1526 4 9 133747528 133747528 G A ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:52:30 UTC https://civicdb.org/links/evidence_items/4543 https://civicdb.org/links/variants/1526 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Q300R Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with Q300R, 1/1 had a CHR and 1/1 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 4545 1527 4 9 133747592 133747592 A G ENST00000318560.5 75 GRCh37 Somatic 2018-12-21 19:34:56 UTC https://civicdb.org/links/evidence_items/4545 https://civicdb.org/links/variants/1527 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F311L Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with F311L evaluated, 1/1 had a complete hematologic response and 1/1 had a major cytogenetic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 2 accepted 4546 1528 4 9 133748270 133748270 T C ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 21:48:16 UTC https://civicdb.org/links/evidence_items/4546 https://civicdb.org/links/variants/1528 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL N331S Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with N331S evaluated, 1/1 had a major cytogenetic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 1 accepted 4549 1529 4 9 133748331 133748331 A G ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 21:50:14 UTC https://civicdb.org/links/evidence_items/4549 https://civicdb.org/links/variants/1529 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L364P Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with L364P evaluated, 1/1 had a major cytogenetic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 1 accepted 4551 1530 4 9 133750260 133750260 T C ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 21:58:07 UTC https://civicdb.org/links/evidence_items/4551 https://civicdb.org/links/variants/1530 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L387F Chronic Myeloid Leukemia 8552 Bosutinib Predictive Supports C Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with L387F, 1/1 had a CHR and 0/1 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 4552 1232 4 9 133750330 133750330 G C ENST00000318560.5 75 GRCh37 Somatic 2018-12-21 19:30:16 UTC https://civicdb.org/links/evidence_items/4552 https://civicdb.org/links/variants/1232 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL H396P Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with H396P evaluated, 1/1 had a complete hematologic response and 2/2 had major cytogenetic responses. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 2 accepted 4554 1531 4 9 133750356 133750356 A C ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 21:59:42 UTC https://civicdb.org/links/evidence_items/4554 https://civicdb.org/links/variants/1531 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL D421G Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with D421G evaluated, 1/1 had a complete hematologic response and 0/1 had a major cytogenetic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 1 accepted 4559 1532 4 9 133750431 133750431 A G ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:10:55 UTC https://civicdb.org/links/evidence_items/4559 https://civicdb.org/links/variants/1532 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G398R Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line stably expressing the G398R mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with sensitivity to dasatinib treatment (IC50: 1.27nM vs. IC50: 1.83nM), comparable to Ba/F3 cells expressing BCR-ABL1 fusion protein. Sensitivity was determined by assessing cell proliferation. 19075254 PubMed Redaelli et al., 2009, J. Clin. Oncol. 2 accepted 4561 1233 4 9 133750361 133750361 G C ENST00000318560.5 75 GRCh37 Somatic 2017-07-25 22:27:19 UTC https://civicdb.org/links/evidence_items/4561 https://civicdb.org/links/variants/1233 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E450V Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with E450V evaluated, 1/1 had a complete hematologic response and 1/1 had a major cytogenetic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 2 accepted 4563 1534 4 9 133753880 133753880 A T ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 22:04:23 UTC https://civicdb.org/links/evidence_items/4563 https://civicdb.org/links/variants/1534 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E453K Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with E453K evaluated, 1/1 had a major cytogenetic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 1 accepted 4565 1535 4 9 133753888 133753888 G A ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 22:05:15 UTC https://civicdb.org/links/evidence_items/4565 https://civicdb.org/links/variants/1535 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E453A Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with E453A, 1/1 had a CHR and 0/0 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 4567 1536 4 9 133753889 133753889 A C ENST00000318560.5 75 GRCh37 Somatic 2018-12-21 19:21:16 UTC https://civicdb.org/links/evidence_items/4567 https://civicdb.org/links/variants/1536 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL P480A Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with P480A evaluated, 1/1 had a major cytogenetic response. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 1 accepted 4568 1537 4 9 133755469 133755469 C G ENST00000318560.5 75 GRCh37 Somatic 2018-07-12 22:08:34 UTC https://civicdb.org/links/evidence_items/4568 https://civicdb.org/links/variants/1537 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F486S Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support B Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 13 patients with F486S mutations, 5, 6, and 12 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 4571 1152 4 9 133755488 133755488 T C ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 22:07:42 UTC https://civicdb.org/links/evidence_items/4571 https://civicdb.org/links/variants/1152 https://civicdb.org/links/genes/4 false KIT 3815 K550_W557del Gastrointestinal Stromal Tumor 9253 Sunitinib,Ponatinib,Regorafenib,Imatinib Substitutes Predictive Supports D Sensitivity/Response In an in vitro study, an IL3 independent Ba/F3 cell line expressing KIT K550_W557del primary activating mutation demonstrated sensitivity to imatinib (IC50: 13nmol/L), sunitinib (IC50: 5nmol/L), regorafenib (IC50: 22nmol/L), and ponatinib (IC50: 3nmol/L) treatments. IC50 was determined by assessing cell viability. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 2 accepted 4583 948 29 4 55593582 55593605 AAACCCATGTATGAAGTACAGTGG ENST00000288135.5 75 GRCh37 Somatic 2021-11-12 19:08:05 UTC https://civicdb.org/links/evidence_items/4583 https://civicdb.org/links/variants/948 https://civicdb.org/links/genes/29 false KIT 3815 D820Y Gastrointestinal Stromal Tumor 9253 Regorafenib Predictive Supports C Sensitivity/Response This retrospective study of a phase 2 clinical trial (NCT01068769) examined regorafenib safety and efficacy in advanced gastrointestinal stromal tumor (GIST) patients refractory to at least imatinib and sunitinib. Three patients whose GIST harbored KIT D820Y experienced clinical benefit (defined as complete response, partial response, stable disease >16 weeks) in response to regorafenib. One patient remained on study without disease progression for >11 months, one patient developed disease progression at 5.7 months, and the other patient underwent surgical removal of all residual disease after 7 months, but continued on regorafenib. Immunoblotting of matched pre- and post- treatment GIST biopsies from these patients demonstrated decreased levels of KIT phosphorylation in response to regorafenib. 22614970 PubMed George et al., 2012, J. Clin. Oncol. 2 accepted 4589 986 29 4 55599332 55599332 G T ENST00000288135.5 75 GRCh37 Somatic 2019-03-21 20:40:03 UTC https://civicdb.org/links/evidence_items/4589 https://civicdb.org/links/variants/986 https://civicdb.org/links/genes/29 false KIT 3815 K558NP Gastrointestinal Stromal Tumor 9253 Imatinib,Sunitinib,Regorafenib,Ponatinib Substitutes Predictive Supports D Sensitivity/Response In an in vitro study, an IL3 independent Ba/F3 cell line expressing KIT K558NP primary activating mutation demonstrated sensitivity to imatinib (IC50: 2nmol/L), sunitinib (IC50: 2nmol/L ), regorafenib (IC50: 4nmol/L), and ponatinib (IC50: 1nmol/L) treatments. IC50 was determined by assessing cell viability. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 3 accepted 4594 1549 29 4 55593608 55593608 G TCCT GRCh37 Somatic 2019-07-09 23:18:55 UTC https://civicdb.org/links/evidence_items/4594 https://civicdb.org/links/variants/1549 https://civicdb.org/links/genes/29 false KIT 3815 N822K Gastrointestinal Stromal Tumor 9253 Regorafenib Predictive Supports C Sensitivity/Response This retrospective study of a phase 2 clinical trial (NCT01068769) examined regorafenib safety and efficacy in advanced gastrointestinal stromal tumor (GIST) patients refractory to at least imatinib and sunitinib. One patient whose GIST harbored KIT N882K did not experienced disease progression for >7 months following treatment by regorafenib. Immunoblotting of matched pre- and post- treatment GIST biopsies from this patient demonstrated decreased levels of KIT phosphorylation in response to regorafenib. 22614970 PubMed George et al., 2012, J. Clin. Oncol. 2 accepted 4595 1263 29 4 55599340 55599340 T A ENST00000288135.5 75 GRCh37 Somatic 2021-05-10 20:50:29 UTC https://civicdb.org/links/evidence_items/4595 https://civicdb.org/links/variants/1263 https://civicdb.org/links/genes/29 false PDGFRA 5156 D842V Gastrointestinal Stromal Tumor 9253 Sunitinib Predictive Supports C Resistance Patients 29 and 66 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) PDGFRA D842V mutation. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. Patients took 50 mg sunitib per day. Patient 29 was on a treatment schedule of two weeks on/two weeks off, and patient 66 was scheduled for four weeks on/two weeks off. Patient 29 experienced stable disease for less than 6 months and patient 66 experienced disease progression. Time to progression was censored at 0.1 weeks for patient 29 and was 10 weeks for patient 66. Overall survival was 99 and censored at 129 weeks for patients 29 and 66. 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 3 accepted 4597 99 38 4 55152093 55152093 A T ENST00000257290.5 75 GRCh37 PDGFRA D842 mutations are characterized broadly as imatinib resistance mutations. This is most well characterized in gastrointestinal stromal tumors, but other cell lines containing these mutations have been shown to be resistant as well. Exogenous expression of the A842V mutation resulted in constitutive tyrosine phosphorylation of PDGFRA in the absence of ligand in 293T cells and cytokine-independent proliferation of the IL-3-dependent Ba/F3 cell line, both evidence that this is an activating mutation. In imatinib resistant cell lines, a number of other therapeutics have demonstrated efficacy. These include; crenolanib, sirolimus, and midostaurin (PKC412). Somatic 2019-05-03 23:38:37 UTC https://civicdb.org/links/evidence_items/4597 https://civicdb.org/links/variants/99 https://civicdb.org/links/genes/38 false KIT 3815 Exon 11 Mutation Gastrointestinal Stromal Tumor 9253 Regorafenib Predictive Supports B Sensitivity/Response This international, placebo controlled prospective phase 3 clinical trial (NCT01271712) examined safety and efficacy of regorafenib in patients with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) who failed previous treatments with at least imatinib or sunitinib. Progression free survival was measured for 199 patients treated with either daily 160mg regorafenib (n=133) or a matching placebo (n= 66). Overall, median PFS was 7.4 months in the regorafenib group and 1.7 months in the placebo group (HR= .22, P <.001). Patients with KIT exon 11 mutations (n=51) treated with regorafenib were associated with similarly favorable progression free survival (HR: 0.212), as compared to patients with treated with placebo. 23177515 PubMed Demetri et al., 2013, Lancet NCT01271712 2 accepted 4599 66 29 4 55593582 55593708 ENST00000288135.5 75 GRCh37 c-KIT mutations in exon 11 lie within the juxtamembrane domain, and are very recurrent in gastrointestinal stromal tumors, often bearing a poorer prognosis than other KIT mutations. Cells harboring exon 11 mutations have shown sensitivity to the tyrosine kinase inhibitor imatinib, offering a better prognosis to patients treated with the drug in the first year. Small cohorts of melanoma patients harboring exon 11 KIT mutations have shown response to imatinib and sunitinib. Somatic 2019-03-06 01:04:44 UTC https://civicdb.org/links/evidence_items/4599 https://civicdb.org/links/variants/66 https://civicdb.org/links/genes/29 false KIT 3815 V569_L576DEL Gastrointestinal Stromal Tumor 9253 Sunitinib Predictive Supports B Sensitivity/Response This study (NCT01459757) is a retrospective analysis of sunitinib efficacy on imatinib resistant or intolerant gastrointestinal stromal tumor (GIST) patients who were treated in an open-label clinical trial (NCT00094029). Tumor tissue for mutational status assessment was obtained from 230 patients on one or more occassions (pre-imatinib, post-imatinib/pre-sunitinib, post-sunitinib). Tissue was assessed for mutations in KIT exons 9, 11, 13, and 17 and in PDGFRA exons 12 and 18. With sunitinib treatment, patients with a primary (pre-imatinib) KIT exon 9 mutation (n=42) displayed significantly better PFS compared with those with a primary KIT exon 11 mutation (n=143; p = .011), significantly longer OS (p =.002), and significantly higher ORR (p=.012). The authors conclude that sunitinib displays higher activity in KIT exon 9 vs KIT 11 mutant GIST patients. 26772734 PubMed Reichardt et al., 2016, BMC Cancer NCT01459757 3 accepted 4603 1551 29 4 55593639 55593662 GRCh37 Somatic 2019-07-21 22:39:53 UTC https://civicdb.org/links/evidence_items/4603 https://civicdb.org/links/variants/1551 https://civicdb.org/links/genes/29 false BRAF 673 Exon 15 Mutation Gastrointestinal Stromal Tumor 9253 Regorafenib Predictive Supports C Resistance This retrospective study of a phase 2 clinical trial (NCT01068769) examined regorafenib safety and efficacy in advanced gastrointestinal stromal tumor (GIST) patients refractory to at least imatinib and sunitinib. One patient whose GIST harbored a BRAF exon 15 mutation and wildtype KIT and PDGFRA experienced rapid disease progression despite regorafenib administration. 22614970 PubMed George et al., 2012, J. Clin. Oncol. 1 accepted 4605 2650 5 Somatic 2019-03-21 20:35:49 UTC https://civicdb.org/links/evidence_items/4605 https://civicdb.org/links/variants/2650 https://civicdb.org/links/genes/5 false BRCA1 672 W1815X Endometrioid Ovary Carcinoma 5828 Olaparib Predictive Supports D Sensitivity/Response In an in vitro study, a SNU-251 cell line expressing BRCA1 W1815X truncating mutation demonstrated increased sensitivity to olaparib treatment with long-term exposure, compared to ovarian cell lines expressing BRCA1 wild-type. Sensitivity was determined by assessing cytotoxicity and doubling time. The authors note that the slow doubling time of SNU-251 cells was compensated for with a 2 week cytotoxicity assay as compared to the 1 week assay used for all other cell lines. 23415752 PubMed Stordal et al., 2013, Mol Oncol 2 accepted 4623 1555 6 17 41199682 41199682 C T GRCh37 Somatic 2021-03-02 19:53:45 UTC https://civicdb.org/links/evidence_items/4623 https://civicdb.org/links/variants/1555 https://civicdb.org/links/genes/6 false KIT 3815 Exon 9 Mutation Gastrointestinal Stromal Tumor 9253 Regorafenib Predictive Supports B Sensitivity/Response This international, placebo controlled prospective phase 3 clinical trial (NCT01271712) examined safety and efficacy of regorafenib in patients with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) who failed previous treatments with at least imatinib or sunitinib. Progression free survival was measured for 199 patients treated with either daily 160mg regorafenib (n=133) or a matching placebo (n= 66). Overall, median PFS was 7.4 months in the regorafenib group and 1.7 months in the placebo group (HR= .22, P <.001). Patients with KIT exon 9 mutations (n=15) treated with regorafenib were associated with a similarly favorable progression free survival (HR: 0.239), as compared to patients with treated with placebo. 23177515 PubMed Demetri et al., 2013, Lancet NCT01271712 2 accepted 4628 509 29 4 55592023 55592216 ENST00000288135.5 75 GRCh37 In patients with gastrointestinal stromal tumors (GIST), imatinib has improved outcomes for patients with KIT mutations. However, acquired resistance to imatinib is common. Patients harboring exon 9 KIT mutations may benefit from higher imatinib doses (800mg/daily). Similarly, imatinib-refractory tumors showed sensitivity to sunitinib treatment. Improved responses to either treatment were not observed in patients with exon 11 mutations. Somatic 2019-03-06 01:05:39 UTC https://civicdb.org/links/evidence_items/4628 https://civicdb.org/links/variants/509 https://civicdb.org/links/genes/29 false KIT 3815 Exon 11 Mutation Gastrointestinal Stromal Tumor 9253 Regorafenib Predictive Supports B Sensitivity/Response This retrospective study of a phase 2 clinical trial (NCT01068769) examined regorafenib safety and efficacy in advanced gastrointestinal stromal tumor (GIST) patients who failed previous treatments with imatinib and sunitinib. Of 30 genotyped patients treated with regorafenib, those with KIT exon 11 mutant GISTs (n=19) experienced significantly increased progression free survival (P=0.01), as compared to patients with KIT exon 9 mutant GISTs (n=3). Median PFS for the entire cohort was 10.0 months. Regorafenib treatment induced clinical benefit (defined as complete response, partial response, stable disease > 16 weeks) in 16/19 patients with KIT exon 11 mutant GISTs. 22614970 PubMed George et al., 2012, J. Clin. Oncol. 2 accepted 4629 66 29 4 55593582 55593708 ENST00000288135.5 75 GRCh37 c-KIT mutations in exon 11 lie within the juxtamembrane domain, and are very recurrent in gastrointestinal stromal tumors, often bearing a poorer prognosis than other KIT mutations. Cells harboring exon 11 mutations have shown sensitivity to the tyrosine kinase inhibitor imatinib, offering a better prognosis to patients treated with the drug in the first year. Small cohorts of melanoma patients harboring exon 11 KIT mutations have shown response to imatinib and sunitinib. Somatic 2019-03-21 20:36:55 UTC https://civicdb.org/links/evidence_items/4629 https://civicdb.org/links/variants/66 https://civicdb.org/links/genes/29 false KIT 3815 A502_Y503insAY Gastrointestinal Stromal Tumor 9253 Regorafenib,Ponatinib,Imatinib Substitutes Predictive Does Not Support D Sensitivity/Response In an in vitro study, an IL3 independent Ba/F3 cell line expressing KIT A502_Y503insAY primary activating mutation demonstrated insensitivity to regorafenib (IC50: 138nmol/L), imatinib (IC50: 143nmol/L), and ponatinib (IC50: 56nmol/L) treatments. In comparison, sensitizing KIT mutation del550-557 showed IC50 22, 13 and 3 nmol/L for these drugs respectively. IC50 was determined by assessing cell viability. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 3 accepted 4630 1558 29 4 55592182 55592183 GCCTAT GRCh37 Somatic 2019-07-09 22:06:35 UTC https://civicdb.org/links/evidence_items/4630 https://civicdb.org/links/variants/1558 https://civicdb.org/links/genes/29 false KIT 3815 D816E Gastrointestinal Stromal Tumor 9253 Sunitinib,Imatinib Substitutes Predictive Supports D Resistance Several preclinical studies were done in order to test the effects of various tyrosine kinase inhibitors (TKIs) on KIT-mutant cell lines derived from Gastrointestinal Stromal Tumor (GIST) patients with primary mutation 560-578 deletion and secondary mutation D816E. The cells were tested for Imatinib and Sunitinib resistances. GIST-T1/816 cells with 560-578 deletion and D816E mutations were resistant towards Imatinib and Sunitinib (Imatinib IC50: 604 nM and Sunitinib IC50: 3111 nM) compared to GIST-T1 cells with the 560-578 deletion mutation alone (Imatinib IC50: 30 nM and Sunitinib IC50: 15 nM). Imatinib inhibited phosphorylation in KIT and ERK at high concentrations. Sunitinib did not inhibit phosphorylation in KIT, ERK, or AKT at all. Additionally, Ba/F3 cells were mutagenized with N-ethyl-N-nitrosourea and incubated with varying concentrations of Sunitinib and Imatinib separately. In Imatinib incubated cells, D816E mutations were seen in less than 5% of resistant Ba/F3 cell clones only in the lowest concentration. In Imatinib incubated cells, D816E mutations were seen in approximately 10% of resistant Ba/F3 cell clones. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 4 accepted 4631 1559 29 4 55599322 55599322 C G ENST00000288135.5 75 GRCh37 Somatic 2019-07-19 22:35:35 UTC https://civicdb.org/links/evidence_items/4631 https://civicdb.org/links/variants/1559 https://civicdb.org/links/genes/29 false EGFR 1956 D770_N771insGT Lung Adenocarcinoma 3910 Erlotinib Predictive Supports C Resistance In a lung adenocarcinoma patient harboring EGFR D770_N771insGT mutation, EGFR D770_N771insGT was associated with lack of response to treatment with erlotinib monotherapy. 23371856 PubMed Arcila et al., 2013, Mol. Cancer Ther. accepted 4643 1566 19 7 55249012 55249013 GGCACA ENST00000275493.2 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/4643 https://civicdb.org/links/variants/1566 https://civicdb.org/links/genes/19 false EGFR 1956 Exon 20 Insertion Lung Adenocarcinoma 3910 Erlotinib Predictive Supports C Resistance In stage IV lung adenocarcinoma patients (n=2) harboring EGFR inframe exon 20 insertion mutation, EGFR exon 20 insertion was associated with progressive disease after 1 and 3 months of erlotinib monotherapy, respectively; both patients were previously treated with standard chemotherapy. 22895145 PubMed Lund-Iversen et al., 2012, J Thorac Oncol accepted 4650 726 19 7 55248991 55249022 ENST00000275493.2 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/4650 https://civicdb.org/links/variants/726 https://civicdb.org/links/genes/19 false SMO 6608 L412F Basal Cell Carcinoma 2513 Vismodegib Predictive Supports D Resistance In an in vitro study, mouse embryonic fibroblasts (MEFs), null for the Smo mouse gene expressing SMO L412F mutation, demonstrated resistance to vismodegib treatment (IC50: >320 nmol/L vs. 8.23 nmol/L) compared to MEFs expressing wild-type SMO. Resistance was determined by assessing GLI1 mRNA expression levels. 25759020 PubMed Atwood et al., 2015, Cancer Cell accepted 4653 1570 5365 7 128846398 128846398 C T ENST00000249373.3 75 GRCh37 Somatic 2017-07-20 16:00:58 UTC https://civicdb.org/links/evidence_items/4653 https://civicdb.org/links/variants/1570 https://civicdb.org/links/genes/5365 false SMO 6608 L412F Basal Cell Carcinoma 2513 Vismodegib Predictive Supports C Resistance An Arab basal cell carcinoma patient harboring SMO L412F mutation was associated with response to vismodegib monotherapy. Prior to the identification of the mutation, the patient was treated with acitretin, but did not achieve any response. 26822128 PubMed Khamaysi et al., 2016, Br. J. Dermatol. accepted 4654 1570 5365 7 128846398 128846398 C T ENST00000249373.3 75 GRCh37 Somatic 2017-07-20 15:22:44 UTC https://civicdb.org/links/evidence_items/4654 https://civicdb.org/links/variants/1570 https://civicdb.org/links/genes/5365 false EGFR 1956 W731L Cancer 162 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study performed after identification of the mutation in a malignant peritoneal mesothelioma patient, COS-7 cells expressing EGFR W731L demonstrated increased EGFR phosphotyrosine after EGF treatment over wildtype EGFR expressing cells. Cells expressing mutant EGFR also showed increased sensitivity to erlotinib treatment compared to cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation. 20942962 PubMed Foster et al., 2010, World J Surg Oncol 3 accepted 4655 1571 19 7 55242422 55242422 G T ENST00000275493.2 75 GRCh37 Somatic 2022-03-23 20:04:51 UTC https://civicdb.org/links/evidence_items/4655 https://civicdb.org/links/variants/1571 https://civicdb.org/links/genes/19 false EGFR 1956 E734Q Malignant Mesothelioma 1790 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a COS-7 cell line expressing EGFR E734Q demonstrated increased sensitivity to erlotinib treatment, compared to COS-7 cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation. 20942962 PubMed Foster et al., 2010, World J Surg Oncol accepted 4656 1572 19 7 55242430 55242430 G C ENST00000 75 GRCh37 Somatic 2018-01-18 23:32:47 UTC https://civicdb.org/links/evidence_items/4656 https://civicdb.org/links/variants/1572 https://civicdb.org/links/genes/19 false EGFR 1956 T785A Malignant Mesothelioma 1790 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a COS-7 cell line expressing EGFR T785A demonstrated increased sensitivity to erlotinib treatment, compared to COS-7 cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation. 20942962 PubMed Foster et al., 2010, World J Surg Oncol accepted 4657 1573 19 7 55249055 55249055 A G ENST00000275493.2 75 GRCh37 Somatic 2018-01-18 23:32:25 UTC https://civicdb.org/links/evidence_items/4657 https://civicdb.org/links/variants/1573 https://civicdb.org/links/genes/19 false EGFR 1956 C797Y Malignant Mesothelioma 1790 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a COS-7 cell line expressing EGFR C797Y demonstrated increased sensitivity to erlotinib treatment, compared to COS-7 cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation. 20942962 PubMed Foster et al., 2010, World J Surg Oncol accepted 4658 1574 19 7 55249092 55249092 G A ENST00000275493.2 75 GRCh37 Somatic 2018-01-18 23:32:06 UTC https://civicdb.org/links/evidence_items/4658 https://civicdb.org/links/variants/1574 https://civicdb.org/links/genes/19 false EGFR 1956 Y801H Cancer 162 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study performed after identification of the mutation in a malignant peritoneal mesothelioma patient, COS-7 cells expressing EGFR Y801H demonstrated increased EGFR phosphotyrosine after EGF treatment over wildtype EGFR expressing cells. Cells expressing mutant EGFR also showed increased sensitivity to erlotinib treatment compared to cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation. 20942962 PubMed Foster et al., 2010, World J Surg Oncol 3 accepted 4659 1575 19 7 55249103 55249103 T C ENST00000275493.2 75 GRCh37 Somatic 2022-03-23 19:09:13 UTC https://civicdb.org/links/evidence_items/4659 https://civicdb.org/links/variants/1575 https://civicdb.org/links/genes/19 false EGFR 1956 A767_V769dupASV Lung Adenocarcinoma 3910 Erlotinib Predictive Supports C Resistance In a study of 19 non-small cell lung carcinoma patients with EGFR exon 20 insertion mutations and treated with erlotinib monotherapy, patients with EGFR A767_V769dupASV mutation (n=3) experienced progressive disease. 24353160 PubMed Yasuda et al., 2013, Sci Transl Med accepted 4665 1579 19 7 55249000 55249001 GCCAGCGTG ENST00000275493.2 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/4665 https://civicdb.org/links/variants/1579 https://civicdb.org/links/genes/19 false EGFR 1956 L747_S752delinsQ Lung Adenocarcinoma 3910 Erlotinib Predictive Supports C Sensitivity/Response EGFR exons 18-24 were analyzed in 7 patients who had shown a partial response to erlotinib in a phase II trial for bronchioloalveolar carcinoma (BAC, or in situ pulmonary adenocarcinoma). One patient (Patient E1) had the del L747-S752 insQ mutation. The patient was a male never smoker and demonstrated response for 8 months. He continued to show response and remain on the drug when the manuscript was written. 15329413 PubMed Pao et al., 2004, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 4667 1580 19 7 55242469 55242486 TTAAGAGAAGCAACATCT CAA GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/4667 https://civicdb.org/links/variants/1580 https://civicdb.org/links/genes/19 false EGFR 1956 L861R Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports C Sensitivity/Response In a study, 1 participant with stage IV lung adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have L861R mutation, and was treated with the 1st generation TKI gefitinib. The patient (M, 83, nonsmoker) had a partial response, progression free survival (PFS) of 37.5 months, overall survival (OS) of 53.3 months and was alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 3 accepted 4669 1477 19 7 55259524 55259524 T G ENST00000 75 GRCh37 Somatic 2017-07-06 22:45:42 UTC https://civicdb.org/links/evidence_items/4669 https://civicdb.org/links/variants/1477 https://civicdb.org/links/genes/19 false ABL1 25 BCR::ABL D363G Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the D363G secondary variant in 2/10 bacterial clones generated using peripheral blood RNA. They had complete best hematologic and complete best cytogenetic responses to dasatinib which were improved compared to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 4692 2900 4 Somatic 2020-02-18 04:33:16 UTC https://civicdb.org/links/evidence_items/4692 https://civicdb.org/links/variants/2900 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL V379I Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in accelerated phase had the BCR-ABL1 fusion with E279K, V379I, and V379I/F317L/M351T variants in 3/11, 5/11, and 1/11 clones, respectively. Clones were generated using peripheral blood RNA. The patient had complete response as best cytogenetic response and no evidence of leukemia as best hematologic response to dasatinib which were improved compared to responses in patients with unmutated BCR-ABL1. An additional patient, in myeloid blast crisis, had V379I in 9/10 bacterial clones generated using peripheral blood RNA. They had complete response as best hematologic response and none as best cytogenetic response to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 4702 1609 4 9 133750304 133750304 G A ENST00000318560.5 75 GRCh37 Somatic 2020-07-31 22:53:09 UTC https://civicdb.org/links/evidence_items/4702 https://civicdb.org/links/variants/1609 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL V379I Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with V379I, 3/4 had MaHRs and 2/4 had MCyRs which were comparable to response rates among wild type patients. 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 4704 1609 4 9 133750304 133750304 G A ENST00000318560.5 75 GRCh37 Somatic 2020-04-26 21:30:30 UTC https://civicdb.org/links/evidence_items/4704 https://civicdb.org/links/variants/1609 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports C Sensitivity/Response Prior to dasatanib treatment, fifteen imatinib-resistant patients with chronic myeloid leukemia in various phases had the BCR-ABL1 fusion with no secondary variants in at least ten clones generated using peripheral blood RNA. They had no evidence of leukemia (n = 3), complete (9), minor (2), and no (1) best hematologic responses to dasatinib and complete (3), partial (3), minor (2), minimal (2), and no (5) best cytogenetic responses to dasatinib. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 4 accepted 4706 1 4 22 23522397 23632600 ENST00000305877.8 9 133729451 133763063 ENST00000318560.5 75 GRCh37 The BCR-ABL fusion protein, commonly referred to as the Philadelphia chromosome, is one of the most studied fusion genes in cancer. It has widely been considered the initiating event in chronic myelogenous leukemia (CML). However, despite its ability to initiate disease in mice, its status as an initiating mutation is in dispute. In what is commonly used as the poster-child for targeted therapeutics, the development and use of imatinib in the clinic has led to profound improvements in the prognosis of the disease. However, imatinib resistance is still seen in patients with mutations in the ABL kinase domain of the fusion, most notably the T315I variant. In patients resistant to imatinib, either acquired or otherwise, second generation BCR-ABL TKI's (dasatinib and nilotinib) have seen some success in delivering a tumor response. Third generation ABL1 inhibitor ponatinib is the only FDA approved drug with activity against T315I . However due to risk of life-threatening blood clots and severe narrowing of blood vessels ponatinib is ONLY approved for T315I-positive CML or T315I-positive Ph+ ALL or in cases of CML, Ph+ ALL with resistance or intolerance to other approved ABL1 inhibitors. Somatic 2020-02-08 03:53:21 UTC https://civicdb.org/links/evidence_items/4706 https://civicdb.org/links/variants/1 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL A397P Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with A397P, 2/2 had MaHRs and 1/2 had MCyRs which were comparable to response rates among wild type patients. 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 4710 1612 4 9 133750358 133750358 G C ENST00000318560.5 75 GRCh37 Somatic 2020-04-26 21:30:51 UTC https://civicdb.org/links/evidence_items/4710 https://civicdb.org/links/variants/1612 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E98G Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the E98G secondary variant in 11/11 bacterial clones generated using peripheral blood RNA. They had complete best hematologic and complete best cytogenetic responses to dasatinib which were improved compared to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 4711 2901 4 Somatic 2020-02-18 05:55:16 UTC https://civicdb.org/links/evidence_items/4711 https://civicdb.org/links/variants/2901 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K Acute Lymphoblastic Leukemia 9952 Dasatinib Predictive Supports C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with acute lymphoblastic leukemia had the BCR-ABL1 fusion with the E255K secondary variant in 3/12 bacterial clones generated using peripheral blood RNA. They had no best hematologic and no best cytogenetic responses to dasatinib which were worse compared to responses in patient with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 4718 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2020-02-18 05:28:28 UTC https://civicdb.org/links/evidence_items/4718 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false BRAF 673 G596R Colorectal Cancer 9256 Vemurafenib Predictive Does Not Support D Sensitivity/Response In an in vitro study, an NCI-H508 cell line expressing BRAF G596R demonstrated insensitivity to vemurafenib treatment compared to HT29 cells expressing BRAF V600E (a known vemurafenib sensitizing mutation; IC50 9.89 uM vs 0.025-0.35uM for BRAF V600E expressing cell lines). Note that NCI-H508 also expresses PIK3CA E545K. 22180495 PubMed Yang et al., 2012, Cancer Res. 1 accepted 4729 1627 5 7 140453149 140453149 C G ENST00000288602.6 75 GRCh37 Somatic 2020-06-18 22:37:29 UTC https://civicdb.org/links/evidence_items/4729 https://civicdb.org/links/variants/1627 https://civicdb.org/links/genes/5 false EGFR 1956 Rare Exon 18-21 Mutation Lung Non-small Cell Carcinoma 3908 Erlotinib,Gefitinib Substitutes Predictive Supports B Sensitivity/Response In a cohort of NSCLC patients treated with tyrosine kinase inhibitors erlotinib or gefitinib, 61 patients with uncommon mutations of unknown clinical significance (UMUCS) in EGFR exons 18-21 responded at a rate of 47.5% (primarily G719 and L861, N=30/61). This was significantly greater (p<0.001) than a response rate of 16.5% in EGFR wild type patients but significantly smaller (p<0.001) than a 74.1% response in EGFR mutant patients with canonical exon 19 deletion or L858R mutation. Uncommon mutations also had greater median PFS (5.0 vs. 2.0 months, P < 0.001) and median overall survival (15.0 vs. 10.4 months, P = 0.030) than in patients with the wild-type EGFR. 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 4 accepted 4755 1863 19 7 55241614 5525967 EGFR_ENST00000275493.2 75 GRCh37 Rare exon 18-21 mutations in EGFR consist of all EGFR mutations excluding sensitizing L858R substitutions and exon 19 deletions, as well as resistance mutation T790M. Somatic 2017-07-20 15:35:36 UTC https://civicdb.org/links/evidence_items/4755 https://civicdb.org/links/variants/1863 https://civicdb.org/links/genes/19 false EGFR 1956 Ex19 del L858R Lung Non-small Cell Carcinoma 3908 Gefitinib,Erlotinib Substitutes Predictive Supports B Sensitivity/Response In a study of 1261 non-small cell lung cancer patients, 49.8% of the analyzed tumors had EGFR mutations including deletions in exon 19 (n=258), L858R (n=260), T790M (n=6) and insertions or duplications in exon 20 (n=25). Patients with EGFR deletions in exon 19 or L858R mutations were associated with an improved response to erlotinib or gefitinib with partial or complete response (74.1% vs. 16.5%, P<0.001) when compared to wildtype EGFR patients. Additionally, tumors with EGFR mutations in L858R or deletions in exon 19 were associated with increased overall survival (19.6mo vs. 10.4mo) compared to wildtype (all patients were treated with either erlotinib or gefitinib). From 61 patients with uncommon EGFR mutations of unknown clinical significance, 47.5% were responders in contrast to the 74.1% responders in the exon 19 deletion/L858R group. 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 4 accepted 4759 1854 19 Somatic 2017-07-06 20:26:47 UTC https://civicdb.org/links/evidence_items/4759 https://civicdb.org/links/variants/1854 https://civicdb.org/links/genes/19 false EGFR 1956 Rare Exon 18-21 Mutation Lung Non-small Cell Carcinoma 3908 Erlotinib,Gefitinib Substitutes Predictive Does Not Support B Sensitivity/Response In a cohort of NSCLC patients tested for mutation in EGFR exons 18-21 a subset had uncommon mutations of unknown clinical significance (UMUCS). The most commonly occurring UMUCS were G719 and L861 mutations. Among patients that had UMUCS but not G719 or L861, the response rate to tyrosine kinase inhibitors erlotinib or gefitinib, progression free survival, and overall survival were 20%, 1.6 month and 11.1 months, which was similar for wild type EGFR (16.5%, 2.0 months and 10.4 months), which contrasted to higher response for more commonly occurring G719 and L861 mutations (53.3% and 60.0%, respectively). 21531810 PubMed Wu et al., 2011, Clin. Cancer Res. 2 accepted 4762 1863 19 7 55241614 5525967 EGFR_ENST00000275493.2 75 GRCh37 Rare exon 18-21 mutations in EGFR consist of all EGFR mutations excluding sensitizing L858R substitutions and exon 19 deletions, as well as resistance mutation T790M. Somatic 2017-07-20 15:35:46 UTC https://civicdb.org/links/evidence_items/4762 https://civicdb.org/links/variants/1863 https://civicdb.org/links/genes/19 false EGFR 1956 Exon 19 Deletion Lung Adenocarcinoma 3910 Erlotinib Predictive Supports C Sensitivity/Response In a stage IV lung adenocarcinoma patient harboring EGFR exon 19 deletion, EGFR exon 19 deletion was associated with sensitivity to erlotinib monotherapy. Prior to identification of the EGFR exon 19 deletion, the patient was underwent complex treatments with standard chemotherapy and experienced disease progression; upon identification of EGFR exon 19 deletion and treatment with erlotinib, the patient achieved a clinical response. 27566387 PubMed Kanemaru et al., 2016, Respir Investig accepted 4766 133 19 7 55242415 55242513 ENST00000275493.2 75 GRCh37 Deletions within exon 19 of EGFR are most common in lung cancer. These deletions, in non-small cell lung cancer, have been shown to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib, afatinib, and erlotinib. There is also data to suggest that this event is a good prognostic marker in lung adenocarcinoma. Examples of exon 19 deletions include: p.746_A750delELREA, p.747_753delinsS, p.747_752delLREATS, and p.747_751delLREAT. Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/4766 https://civicdb.org/links/variants/133 https://civicdb.org/links/genes/19 false ABL1 25 C475V Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with C475V, 1/1 had a CHR and 1/1 had a MCyR. 9 patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 4768 1639 4 9 ENST00000318560.5 GRCh37 Somatic 2018-11-16 21:33:44 UTC https://civicdb.org/links/evidence_items/4768 https://civicdb.org/links/variants/1639 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL N336S Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support C Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with N336S, 1/1 had a CHR and 0/1 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 4769 1640 4 9 133748346 133748346 A G ENST00000318560.5 75 GRCh37 Somatic 2018-12-21 19:19:53 UTC https://civicdb.org/links/evidence_items/4769 https://civicdb.org/links/variants/1640 https://civicdb.org/links/genes/4 false POLD1 5424 C284Y Lung Adenocarcinoma 3910 Pembrolizumab Predictive Supports C Sensitivity/Response In a retrospective study of 34 non-small cell lung cancer patients, a lung adenocarcinoma patient with POLD1 deleterious (as determined by Polyphen or SIFT) C284Y mutation and a high nonsynonymous mutation burden, treated with pembrolizumab monotherapy, was associated with a durable clinical benefit; POLD1 deleterious mutation was not identified in any patients who did not experience a durable clinical benefit. 25765070 PubMed Rizvi et al., 2015, Science accepted 4776 1647 4384 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/4776 https://civicdb.org/links/variants/1647 https://civicdb.org/links/genes/4384 false POLD1 5424 E374K Lung Non-small Cell Carcinoma 3908 Pembrolizumab Predictive Supports C Sensitivity/Response In a retrospective study of 34 non-small cell lung cancer patients, a patient, who never smoked, with POLD1 deleterious E374K mutation (as determined by Polyphen or SIFT) and a high nonsynonymous mutation burden, treated with pembrolizumab monotherapy, was associated with a durable clinical benefit; POLD1 deleterious mutation was not identified in patients who did not experience a durable clinical benefit. 25765070 PubMed Rizvi et al., 2015, Science accepted 4777 1648 4384 GRCh37 Somatic 2018-04-16 14:12:40 UTC https://civicdb.org/links/evidence_items/4777 https://civicdb.org/links/variants/1648 https://civicdb.org/links/genes/4384 false PIK3R2 5296 N561D Melanoma 1909 Vemurafenib Predictive Supports D Resistance An in vitro study of WM2664 (a human melanoma cell line) endogenously expressing wildtype PIK3R2 and BRAF V600D (a known BRAF inhibitor sensitizing mutation) found that cells virally induced to stably over-express PIK3R2 N561D were significantly more resistant to vemurafenib (a BRAF inhibitor) than cells transduced with an empty vector (40% vs 0% survival at the highest concentration, p < .0001). 24265155 PubMed Shi et al., 2014, Cancer Discov 3 accepted 4783 1652 4290 GRCh37 Somatic 2018-07-19 20:31:18 UTC https://civicdb.org/links/evidence_items/4783 https://civicdb.org/links/variants/1652 https://civicdb.org/links/genes/4290 false PIK3CA 5290 D350G Melanoma 1909 Vemurafenib Predictive Supports D Resistance An in vitro study of M229 (a human melanoma cell line) endogenously expressing wildtype PIK3CA and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that cells virally induced to stably over-express PIK3CA D350G were significantly more resistant to BRAF inhibition by vemurafenib than cells transduced with empty vectors (40% vs 20% survival at the highest concentration, p=.0148). Though statistics were not provided, D350G appears to confer less resistance to vemurafenib than the positive control variant, PIK3CA E545K. 24265155 PubMed Shi et al., 2014, Cancer Discov 2 accepted 4784 1653 37 3 178921567 178921567 A G ENST00000263967.3 75 GRCh37 Somatic 2018-07-19 20:22:57 UTC https://civicdb.org/links/evidence_items/4784 https://civicdb.org/links/variants/1653 https://civicdb.org/links/genes/37 false NRAS 4893 Q179X Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance In a retrospective study of 148 treatment naive metastatic colorectal cancer patients, patients with RAS mutations (n=10), including KRAS A146T, KRAS G13D, NRAS G12D and NRAS Q179*, treated with FOLFOX4 plus cetuximab were associated with decreased overall survival (16.3mo vs. 28.5mo, HR:0.43, 95% CI:0.20-0.89, P=0.020) and decreased progression free survival (7.2mo vs. 9.7mo, HR:0.56, 95% CI:0.27-1.16, P=0.11), as compared to patients with wild-type KRAS and NRAS. 25666295 PubMed Kaczirek et al., 2015, Clin Colorectal Cancer accepted 4785 1654 36 GRCh37 Somatic 2017-07-20 15:58:23 UTC https://civicdb.org/links/evidence_items/4785 https://civicdb.org/links/variants/1654 https://civicdb.org/links/genes/36 false MET 4233 EXON 14 SKIPPING MUTATION Lung Adenocarcinoma 3910 Crizotinib Predictive Supports C Sensitivity/Response In a never-smoking metastatic lung adenocarcinoma patient harboring a MET splice site mutation (c.2887-18_2887-7del12) treated with crizotinib monotherapy, was associated with a response as evident by the reduced size of tumors. Prior to identification of the MET splice site mutation, the patient was treated with stereotactic radiotherapy, palliative radiation, and a single cycle of pemetrexed; subsequently, the patient was treated with crizotinib, but progressed at 8 weeks of treatment. 25769807 PubMed Jenkins et al., 2015, Clin Lung Cancer 1 accepted 4786 324 52 7 116411903 116412043 ENST00000318493.6 75 GRCh37 Exon 14 mutations have been observed in ~3% of patients with NSCLC (28/933 reported by Awad et al J Clin Onc 2016), confirmed to cause exon skipping when available, and associated with concurrent MET amplification. Responses to the c-MET inhibitor crizotinib have been reported in preclinical models and in individual case reports as well as a small-scale clinical trial (17 patients treated, Drilon et al., 2016 (suppl; abstr 108; ASCO ID 167889-176)). Larger studies are needed but enrollment of patients with MET exon 14 skipping mutation in trials with MET inhibitors or off-label treatment is encouraged (Paik et al., 2015 (suppl; abstr 8021)). Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/4786 https://civicdb.org/links/variants/324 https://civicdb.org/links/genes/52 false ABL1 25 R351W Lung Non-small Cell Carcinoma 3908 Dasatinib Predictive Supports D Sensitivity/Response In this in vitro study, the H1915 non-small cell lung cancer cell line (homozygous for a R351W mutation) was shown to be susceptible to dasatinib. This line showed a significant reduction in colony formation (P < 0.001) and MTT assay, which tests for NADH activity (P = 1.09 x 10^5), with dasatinib vs vehicle treatment. There was no significant difference in a lung cancer cell line without a known driver (H2126) nor in an immortalized bronchial epithelial line (Beas-2B) with either drug treatment in colony forming and MTT assays. Additionally, reduction in cell viability upon kinase inhibitor treatment could be rescued with tetracycline-induced overexpression of resistant ABL1-T315I (P < 0.001) confirming the genetic dependency of this cell line on ABL1. Moreover, a significant increased in cytotoxicity was noted with siRNA facilitated depletion of ABL1 (P < 0.005) with no significant change in H2126 or Beas-2B lines supporting ABL1 as the primary drug target. 26758680 PubMed Testoni et al., 2016, EMBO Mol Med 4 accepted 4787 1656 4 9 133748333 133748333 C T ENST00000372348.2 75 GRCh37 Somatic 2018-11-05 23:08:35 UTC https://civicdb.org/links/evidence_items/4787 https://civicdb.org/links/variants/1656 https://civicdb.org/links/genes/4 false ABL1 25 G340L Lung Non-small Cell Carcinoma 3908 Imatinib Mesylate,Dasatinib Substitutes Predictive Supports D Sensitivity/Response In this in vitro study, the H2110 non-small cell lung cancer cell line (heterozygous for a G340L mutation) was shown to be susceptible to imatinib and dasatinib monotherapies. This line showed a significant reduction in colony formation (P = 0.0001) and MTT assay, which tests for NADH activity (P < 0.001), with imatinib vs vehicle treatment. A significant reduction in colony formation (P < 0.001) with dasatinib treatment vs vehicle was also observed. There was no significant difference in a lung cancer cell line without a known driver (H2126) nor in an immortalized bronchial epithelial line (Beas-2B) with either drug treatment in colony forming and MTT assays. Moreover, a significant increase in cytotoxicity was noted with siRNA facilitated depletion of ABL1 (P < 0.001) with no significant change in H2126 or Beas-2B lines supporting ABL1 as the primary drug target. 26758680 PubMed Testoni et al., 2016, EMBO Mol Med 3 accepted 4788 1657 4 9 133748300 133748301 GG CT ENST00000372348.2 75 GRCh37 Somatic 2018-07-23 21:38:00 UTC https://civicdb.org/links/evidence_items/4788 https://civicdb.org/links/variants/1657 https://civicdb.org/links/genes/4 false KIT 3815 S628N Cancer 162 Imatinib,Dasatinib Substitutes Predictive Supports D Sensitivity/Response In an in vitro study, COS-7 cells expressing KIT S628N activating mutation demonstrated sensitivity to imatinib and dasatinib treatments when compared to the KIT L576P, which was used as an imatinib-sensitive control. Sensitivity was determined by assessing reduced mutant KIT auto-phosphorylation via western blotting with addition of inhibitors. 25317746 PubMed Vita et al., 2014, JAMA Dermatol 2 accepted 4791 1659 29 4 55594180 55594180 G A GRCh37 Somatic 2019-08-05 23:11:46 UTC https://civicdb.org/links/evidence_items/4791 https://civicdb.org/links/variants/1659 https://civicdb.org/links/genes/29 false EGFR 1956 M766_A767insAI Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line expressing EGFR M766_A767insAI demonstrated reduced sensitivity to erlotinib treatment (IC50=3.403�M), comparable to Ba/F3 cells expressing EGFR L858R and T790M co-mutation (T790M is a known resistant mutation to 1st and 2nd generation EGFR tyrosine kinase inhibitors; IC50=4.155�M). Resistance was determined by assessing cell proliferation, EGFR, AKT and ERK phosphorylation. 24353160 PubMed Yasuda et al., 2013, Sci Transl Med accepted 4799 1664 19 7 55249000 55249001 GCCATA ENST00000275493.2 75 GRCh37 Somatic 2018-02-11 10:43:49 UTC https://civicdb.org/links/evidence_items/4799 https://civicdb.org/links/variants/1664 https://civicdb.org/links/genes/19 false EGFR 1956 Y764_V765insHH Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line expressing EGFR Y764_V765insHH demonstrated reduced sensitivity to erlotinib treatment (IC50=3.845�M), comparable to Ba/F3 cells expressing EGFR L858R and T790M co-mutation (T790M is a known resistant mutation to 1st and 2nd generations EGFR tyrosine kinase inhibitors; IC50=4.155�M). Resistance was determined by assessing cell proliferation, EGFR, AKT and ERK phosphorylation. 24353160 PubMed Yasuda et al., 2013, Sci Transl Med accepted 4800 1665 19 7 55248994 55248995 CACCAC ENST00000275493.2 75 GRCh37 Somatic 2018-02-11 10:35:51 UTC https://civicdb.org/links/evidence_items/4800 https://civicdb.org/links/variants/1665 https://civicdb.org/links/genes/19 false EGFR 1956 D770delinsGY Lung Adenocarcinoma 3910 Erlotinib Predictive Supports C Resistance In a study of 19 non-small cell lung carcinoma patients with EGFR exon 20 insertion mutation and treated with erlotinib monotherapy, patients with EGFR D770delinsGY mutation (n=2) experienced progressive disease. Both patients were white females, had adenocarcinoma, and were treated with erlotinib as first line therapy. One was 76 years old with 6 former pack years, 38.1% increase in target lesion, 1 month PFS and 12 month OS. The other was 67 years old with 2 former pack years, 6.0% increase in target lesion, 1 month PFS and 1.5 month OS. 24353160 PubMed Yasuda et al., 2013, Sci Transl Med 4 accepted 4801 2214 19 ENST00000275493.2 75 Somatic 2021-06-10 18:13:22 UTC https://civicdb.org/links/evidence_items/4801 https://civicdb.org/links/variants/2214 https://civicdb.org/links/genes/19 false EGFR 1956 P772_H773insYNP Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports C Resistance A 79 year old Asian male never smoker with not otherwise specified NSCLC harboring EGFR P772_H773insYNP mutation was given erlotinib as first line treatment, and had progressive disease as best response with +2.3% change to target lesions, progression free survival of 2.1 months and overall survival of 16.5 months. 24353160 PubMed Yasuda et al., 2013, Sci Transl Med 3 accepted 4802 1667 19 7 55249018 55249019 TATAATCCC GRCh37 Somatic 2021-06-10 18:59:53 UTC https://civicdb.org/links/evidence_items/4802 https://civicdb.org/links/variants/1667 https://civicdb.org/links/genes/19 false EGFR 1956 P772_V774insPHV Lung Adenocarcinoma 3910 Erlotinib Predictive Does Not Support C Sensitivity/Response A 57 year old male 10 packyear former smoker with lung adenocarcinoma with EGFR P772_V774insPHV mutation was given erlotinib as first line treatment, and had progressive disease as best response with progression free survival of 2 months and overall survival of 16 months. 24353160 PubMed Yasuda et al., 2013, Sci Transl Med 3 accepted 4803 1668 19 GRCh37 Somatic 2021-05-27 22:59:40 UTC https://civicdb.org/links/evidence_items/4803 https://civicdb.org/links/variants/1668 https://civicdb.org/links/genes/19 false ESR1 2099 D538G Breast Cancer 1612 Letrozole,Palbociclib Combination Predictive Does Not Support B Sensitivity/Response In a study of 16 patients with metastatic breast cancer (NCT02142868) treated with palbociclib in combination with letrozole, patients with ESR1 mutations (5/16), including ESR1 D538G (n=2), detected at any time or at initial blood draw, were associated with reduced progression free survival (HR=0.31, 95% CI: 0.05-0.95, P=0.047), as compared with patients with wildtype ESR1 (n=11). There was no significant difference in overall survival (median; 14.1 versus 12.8 months, HR=0.40; 95% CI: 0.06-2.0, P-value=0.24). 27556863 PubMed Gyanchandani et al., 2016, Oncotarget 2 accepted 4814 47 21 6 152419926 152419926 A G ENST00000206249.3 75 GRCh37 ESR1 biology has become a central focus in breast cancer therapy. In ER+ tumors, mutations in the ESR1 ligand binding domain have been shown to confer resistance to hormone therapy. This evidence has led to an increased use of targeted sequencing of the estrogen receptor in breast and ovarian cancer. D538G is one of these ligand binding domain mutations, and is commonly implicated in this hormone resistance. Preliminary data suggests ER-degrading agents, such as fulvestrant, may be beneficial in treating ESR1 mutant, hormone resistant breast cancers. Somatic 2017-07-25 22:25:40 UTC https://civicdb.org/links/evidence_items/4814 https://civicdb.org/links/variants/47 https://civicdb.org/links/genes/21 false JAK2 3717 Splice Site (c.1641+2T>G) Melanoma 1909 Pembrolizumab Predictive Supports C Resistance In a retrospective study of four relapsed, malignant melanoma patients, JAK2 (c.1641+2T>G) F547 splice site mutation was associated with acquired resistance to pembrolizumab monotherapy in one patient. 27433843 PubMed Zaretsky et al., 2016, N. Engl. J. Med. 3 accepted 4825 1681 28 9 5070054 5070054 T G GRCh37 Somatic 2021-03-12 17:12:08 UTC https://civicdb.org/links/evidence_items/4825 https://civicdb.org/links/variants/1681 https://civicdb.org/links/genes/28 false ARID1A 8289 P1175FS*5 Ovarian Clear Cell Carcinoma 0050934 Dasatinib Predictive Supports D Sensitivity/Response In an in vitro study, a HCH1 cell line expressing ARID1A P1172fs mutation demonstrated increased sensitivity to dasatinib treatment, compared to ES2, KK and RMG-1 cells expressing wild-type ARID1A. Sensitivity was determined by assessing cell survival. Authors also observed a modest increase in dasatinib-induced G1 arrest in HCH1 compared to ARID1A wt models (p<0.05) 27364904 PubMed Miller et al., 2016, Mol. Cancer Ther. 2 accepted 4826 1682 6559 GRCh37 Somatic 2021-02-05 01:18:58 UTC https://civicdb.org/links/evidence_items/4826 https://civicdb.org/links/variants/1682 https://civicdb.org/links/genes/6559 false VHL 7428 Mutation Renal Cell Carcinoma 4450 Anti-VEGF Monoclonal Antibody Predictive Does Not Support B Sensitivity/Response A meta-analysis to evaluate the association between the VHL alteration and clinical outcomes in patients with RCC. There were six studies including a total of 633 patients: 244 patients who received anti-VEGF therapy in the predictive value analysis and 419 in the prognostic value analysis. 410 (61.8%) had VHL alteration. The meta-analysis showed no association between the VHL gene alteration and ORR or PFS, as well as no correlation to OS. VEGFR inhibition included: Sunitinib, Sorafenib, Axitinib, Pazopanib, Bevacizumab. 28103578 PubMed Kim et al., 2017, Oncotarget 4 accepted 4832 160 58 3 10182692 10193904 ENST00000256474.2 75 GRCh37 Somatic 2022-04-08 02:12:50 UTC https://civicdb.org/links/evidence_items/4832 https://civicdb.org/links/variants/160 https://civicdb.org/links/genes/58 false IDH2 3418 Mutation Acute Myeloid Leukemia 9119 Enasidenib Predictive Supports D Sensitivity/Response Mutations in IDH1 or IDH2 are identified in approximately 20% of patients with AML.This study report the discovery and characterization of AG-221, orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed oncometobolite 2HG production and induced cellular differentiation in primary human IDH2 mutated AML cells in vivo and in xenograft mouse models, providing a statistically significant benefit in an aggressive IDH2 R140Q-mutant AML xenograft mouse model. Clinical trials are ongoing. 28193778 PubMed Yen et al., 2017, Cancer Discov 4 accepted 4833 570 27 15 90626277 90645736 ENST00000330062.3 75 GRCh37 Somatic 2017-07-25 21:22:09 UTC https://civicdb.org/links/evidence_items/4833 https://civicdb.org/links/variants/570 https://civicdb.org/links/genes/27 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Brigatinib Predictive Supports B Sensitivity/Response In a phase II randomized trial we evaluated two regimens of Brigatinib in Crizotinib-refractory ALK-pos. NSCLC. They were randomly assigned (1:1) to oral Brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg. Of 222 patients enrolled (arm A: n = 112, arm B: n = 110), 154 (69%) had baseline brain metastases and 164 of 222 (74%) had received prior chemotherapy. ORR was 45 (arm A) and 54% (B). Investigator-assessed median PFS was 9.2 months (A) and 12.9 months (B). Independent review committee-assessed intracranial ORR in patients with measurable brain metastases at baseline was 42% (11/26, A) and 67% (12/18, B). Brigatinib yielded substantial whole-body and intracranial responses as well as robust PFS; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety. 28475456 PubMed Kim et al., 2017, J. Clin. Oncol. 4 accepted 4835 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2019-11-28 20:25:42 UTC https://civicdb.org/links/evidence_items/4835 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false BRCA1 672 Loss-of-function Breast Cancer 1612 Talazoparib Predictive Supports B Sensitivity/Response In part 2 of a two-part dose-escalation phase I trial (NCT01286987), 71 patients with Ewings sarcoma, breast, ovarian, small cell lung, or pancreatic cancers received 1.0 mg/day talazoparib treatment. Of patients with BRCA mutation-associated breast and ovarian cancers, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients, respectively. 28242752 PubMed de Bono et al., 2017, Cancer Discov 4 accepted 4838 131 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 BRCA1 loss of function mutations have been shown to increase risk of breast and ovarian cancer in those carrying the allele in their germline. Treating BRCA mutant patients with PARP inhibitors such as Olaparib has led to significant response. Rare Germline 2017-06-15 16:35:11 UTC https://civicdb.org/links/evidence_items/4838 https://civicdb.org/links/variants/131 https://civicdb.org/links/genes/6 false BRCA2 675 Loss-of-function Breast Cancer 1612 Talazoparib Predictive Supports B Sensitivity/Response In part 2 of a two-part dose-escalation phase I trial (NCT01286987), 71 patients with Ewings sarcoma, breast, ovarian, small cell lung, or pancreatic cancers received 1.0 mg/day talazoparib treatment. Of patients with BRCA mutation-associated breast and ovarian cancers, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients, respectively. 28242752 PubMed de Bono et al., 2017, Cancer Discov 4 accepted 4839 132 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 BRCA2 loss of function mutations have been shown to increase risk of breast and ovarian cancer in those carrying the allele in their germline. Treating BRCA mutant patients with PARP inhibitors such as Olaparib has led to significant response. Rare Germline 2017-06-15 16:35:34 UTC https://civicdb.org/links/evidence_items/4839 https://civicdb.org/links/variants/132 https://civicdb.org/links/genes/7 false ERBB2 2064 Overexpression Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Emtansine Predictive Supports B Sensitivity/Response Trastuzumab emtansine has its indication for patients with HER2-positive metastatic breast cancer after therapy with Trastuzumab and Taxane, approval based on PFS and preliminary OS data. EMILIA was a randomised open-label, phase III study for patients with HER2-positive, unresectable, locally advanced, or metastatic breast cancer previously treated with Trastuzumab and a Taxane, randomized 1:1 to Trastuzumab-emtansine or Capecitabine plus Lapatinib. 991 patients were enrolled. Median OS was 29.9m vs. 25.9m. Fewer grade 3 or worse AE occurred with trastuzumab emtansine than with capecitabine plus lapatinib control treatment. 28526536 PubMed Diéras et al., 2017, Lancet Oncol. NCT00829166 4 accepted 4840 875 20 N/A 2020-11-24 07:10:49 UTC https://civicdb.org/links/evidence_items/4840 https://civicdb.org/links/variants/875 https://civicdb.org/links/genes/20 false CDK4 1019 Amplification Liposarcoma 3382 Palbociclib Predictive Supports B Sensitivity/Response A total of 59 patients with well-differentiated or dedifferentiated liposarcomas were enrolled in a phase 2 study to evaluate palbociclib efficacy. Half of the patients had received prior treatment and half were treatment naive. Of the 59 patients, at least 34 conferred CDK4 amplification and the remaining were not tested for CDK4 amplification. In the initial cohort (n=28), where all patients had confirmed CDK4 amplification, at least 14 of the patients were progression free at 12 weeks. Overall progression-free survival at 12 weeks was 57.2% and overall median PFS was 17.9 weeks. There was 1 complete response. Toxic effects were primarily hematologic and included neutropenia (grade 3, n = 20 [33%]; grade 4, n = 2 [3%]) but no neutropenic fever. 27124835 PubMed Dickson et al., 2016, JAMA Oncol NCT01209598 3 accepted 4841 553 13 12 58141510 58146304 ENST00000257904.6 75 GRCh37 Somatic 2021-04-08 17:27:22 UTC https://civicdb.org/links/evidence_items/4841 https://civicdb.org/links/variants/553 https://civicdb.org/links/genes/13 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Abemaciclib Predictive Supports B Sensitivity/Response In this multicenter phase I study of abemaciclib, a total of 225 patients were enrolled: 33 in dose escalation and 192 in tumor-specific cohorts. Radiographic responses were achieved in previously treated patients with breast cancer, NSCLC, and melanoma. The disease control rate for the KRAS-mutant population was 55% (16/29) compared to 39% (13/33) in KRAS wildtype cohort. Stable disease lasting ≥24 weeks was achieved for 31% (9/29) with KRAS-mutant disease vs 12% (4/33) with KRAS wild-type disease. Median PFS was 2.8 months and 1.9 months for the KRAS-mutant and KRAS wild-type populations, respectively. 27217383 PubMed Patnaik et al., 2016, Cancer Discov 3 accepted 4842 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2017-09-08 18:07:16 UTC https://civicdb.org/links/evidence_items/4842 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false CD274 29126 Expression Breast Cancer 1612 Prognostic Supports B Poor Outcome A meta-analysis of the role of PD-L1 expression in breast cancer found nine relevant studies with a total 8583 patients. PD-L1 expression was found to be associated with several poor prognostic indicators, such as ductal cancer, high tumor grade, ER negativity, PR negativity, HER2 positivity and aggressive molecular subtypes. PD-L1 overexpression had no significant impact on metastasis-free survival (HR 0.924, 95% CI = 0.747-1.141, p = 0.462), disease-free survival (HR 1.122, 95% CI = 0.878-1.434, p = 0.357) and overall specific survival (HR 0.837, 95% CI = 0.640-1.093, p = 0.191), but significantly correlated with shortened overall survival (HR 1.573, 95% CI = 1.010-2.451, p = 0.045). 28079291 PubMed Wang et al., 2017, Breast J 2 accepted 4844 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2017-06-22 22:27:11 UTC https://civicdb.org/links/evidence_items/4844 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false ACVR1 90 Gain-of-Function Malignant Astrocytoma 3069 Diagnostic Supports B Positive The authors used whole exome sequencing on 39 midline pediatric high-grade astrocytomas (pHGAs) and identified 5 with mutations in ACVR1, with 2 occurring at G328 (G328V and G328E). The authors state that somatic mutations are specific to tumor location -- gain-of-function mutations in ACVR1 (such as G328V) occur in tumors of the pons in conjunction with H3.1 K27M (as compared to thalamic tumors with FGFR1 mutations). 24705250 PubMed Fontebasso et al., 2014, Nat. Genet. 3 accepted 4845 2061 154 Somatic 2017-08-02 22:09:00 UTC https://civicdb.org/links/evidence_items/4845 https://civicdb.org/links/variants/2061 https://civicdb.org/links/genes/154 false ACVR1 90 G328V Diffuse Midline Glioma, H3 K27M-mutant 0080684 Diagnostic Supports B Positive Sequencing of 39 pediatric midline high-grade astrocytomas identified 5 patients with ACVR1 mutations. The authors identified an increase in endogenous phospho-SMAD1/5/8 signal in diffuse intrinsic pontine glioma (DIPG) cells harboring ACVR1 G328V, with corresponding increase in phospho-SMAD1/5/8 staining as well. By PCR, the authors show strong increase in fold change of mRNA expression in downstream proteins of the ACVR1/BMP pathway, ID, ID2, ID3 and SNAI1 in ACVR1-mutant DIPG cell line compared to glioblastoma cells (KNS42 cells). These activating ACVR1 mutations were exclusively in midline high grade astrocytomas (P = 0.0040, Fisher's exact test). 24705250 PubMed Fontebasso et al., 2014, Nat. Genet. 3 accepted 4846 1686 154 2 158622516 158622516 C A ENST00000434821.1 75 GRCh37 Somatic 2018-10-16 16:57:05 UTC https://civicdb.org/links/evidence_items/4846 https://civicdb.org/links/variants/1686 https://civicdb.org/links/genes/154 false RET 5979 Fusion Lung Adenocarcinoma 3910 Cabozantinib Predictive Supports B Sensitivity/Response RET rearrangements are found in 1-2% of non-small-cell lung cancers. Cabozantinib is a multikinase inhibitor with activity against RET that produced a 10% overall response in unselected patients with lung cancers. This was an open-label, two-stage, single-centre, phase 2, single-arm trial in the USA in metastatic/unresectable lung cancer harbouring RET rearrangement. 26 Patients with lung adenocarcinomas were given 60 mg of cabozantinib orally per day. The primary objective was overall response. Confirmed PR was seen in 7/25 (ORR 28% [95% CI 12–49%]) response-evaluable patients, meeting the primary endpoint. KIF5B-RET was the predominant fusion in 16 (62%) patients. 27825636 PubMed Drilon et al., 2016, Lancet Oncol. NCT01639508 3 accepted 4847 1687 42 Somatic 2022-02-23 22:14:19 UTC https://civicdb.org/links/evidence_items/4847 https://civicdb.org/links/variants/1687 https://civicdb.org/links/genes/42 false RET 5979 Fusion Lung Non-small Cell Carcinoma 3908 Vandetanib Predictive Supports B Sensitivity/Response RET rearrangements involving RET are found in about 1% of NSCLC and define a unique molecular subset. This study was a multi-center, open-label, phase II clinical trial to examine the safety and efficacy of Vandetanib (300 mg/d) in RET positive NSCLC patients (confirmed by FISH), Primary endpoint was the objective response rate. 18 patients were enrolled, the majority were a heavily pretreated population. Among the 17 evaluable patients, three had a partial response (ORR = 18%) and eight had a stable disease (DCR = 65%). Among these patients, the PR or SD was durable for more than 6 months in 8 patients. Vandetanib also showed a PFS of 4.5 months, and an OS of 11.6 months during a median follow-up duration of 14 months. 27803005 PubMed Lee et al., 2017, Ann. Oncol. NCT01823068 3 accepted 4848 1687 42 Somatic 2018-10-11 09:14:36 UTC https://civicdb.org/links/evidence_items/4848 https://civicdb.org/links/variants/1687 https://civicdb.org/links/genes/42 false RET 5979 Fusion Lung Non-small Cell Carcinoma 3908 Vandetanib Predictive Supports B Sensitivity/Response We aimed to assess the efficacy and safety of vandetanib in patients with advanced RET-rearranged NSCLC. In this open-label, multicentre, phase 2 trial (LURET), patients with advanced RET-rearranged NSCLC continuously received 300 mg of oral vandetanib daily. 1536 patients with EGFR mutation-negative NSCLC were screened, 34 were RET-positive (2%). 19 were enrolled and 17 patients were eligible for primary analysis. 9 patients (53%) achieved an objective response. At data cutoff, median PFS was 4.7 months. 27825616 PubMed Yoh et al., 2017, Lancet Respir Med 3 accepted 4849 1687 42 Somatic 2021-01-26 22:13:53 UTC https://civicdb.org/links/evidence_items/4849 https://civicdb.org/links/variants/1687 https://civicdb.org/links/genes/42 false RET 5979 Fusion Lung Non-small Cell Carcinoma 3908 Alectinib Predictive Supports C Sensitivity/Response Alectinib is an anaplastic lymphoma kinase tyrosine kinase inhibitor (TKI) that also has anti-RET activity in vitro. 4 patients with metastatic RET-rearranged NSCLC were identified. 3 of 4 had received prior RET TKIs, including cabozantinib and experimental RET inhibitors. We observed two (50%) objective radiographic responses after treatment with alectinib (one confirmed and one unconfirmed), with durations of therapy of 6 months and more than 5 months (treatment ongoing). Notably, one of these two patients had his dose of alectinib escalated to 900 mg twice daily and had clinical improvement in central nervous system metastases. In addition, one patient (25%) experienced a best response of stable disease lasting approximately 6 weeks. A fourth patient who was RET TKI-naive had primary progression while receiving alectinib. 27544060 PubMed Lin et al., 2016, J Thorac Oncol 3 accepted 4850 1687 42 Somatic 2021-01-28 01:55:56 UTC https://civicdb.org/links/evidence_items/4850 https://civicdb.org/links/variants/1687 https://civicdb.org/links/genes/42 false CD274 29126 Expression Breast Cancer 1612 Prognostic Supports B Poor Outcome In this meta-analysis, 5 studies totalling 2,546 cases were combined to assess the prognostic association of PD-L1 expression in breast cancer. The combined hazard ratio (HR) for PD-L1 overexpression was 1.76 (OS). The pooled odds ratios (ORs) indicated that PD-L1 expression was associated with positive lymph node metastasis, higher histological grades, estrogen receptor (ER)-negativity, and triple-negative breast cancer (TNBC). 28430626 PubMed Zhang et al., 2017, Oncotarget 3 accepted 4855 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2017-06-22 22:23:54 UTC https://civicdb.org/links/evidence_items/4855 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false CD274 29126 Expression Cancer 162 Prognostic Supports B Better Outcome PD-L1 is not only expressed in tumor cells (TCs) but also upregulated in tumor-infiltrating immune cells (TIICs). This meta-analysis evaluated the prognostic value of PD-L1 expression in TIICs in different types of cancers. 18 studies involving 3674 patients were included. PD-L1 positivity in TIICs related to a lower risk of death (HR = 0.784, p=0.047), and TIICs indicated a better prognosis especially in breast cancer patients (HR = 0.359, p=0.002). 28453554 PubMed Zhao et al., 2017, PLoS ONE 2 accepted 4856 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2017-06-22 22:26:25 UTC https://civicdb.org/links/evidence_items/4856 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false CD274 29126 Expression Lung Non-small Cell Carcinoma 3908 Nivolumab,Pembrolizumab,Atezolizumab,Avelumab,Durvalumab Substitutes Predictive Supports B Sensitivity/Response In this meta-analysis of 14 studies with 2857 patients, the immunotherapy response rate was higher among PD-L1-positive patients (RR: 2.19, 95% CI: 1.63-2.94). PD-L1 expression was also related to better progression-free survival (HR: 0.69, 95% CI: 0.57-0.85) and better overall survival (HR: 0.77, 95% CI: 0.67-0.89). 28472902 PubMed Aguiar et al., 2017, Immunotherapy 3 accepted 4857 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2021-04-23 19:15:22 UTC https://civicdb.org/links/evidence_items/4857 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Crizotinib,Alectinib Substitutes Predictive Supports B Sensitivity/Response In a randomized, open-label phase 3 trial 303 patients with ALK-positive, previously untreated NSCLC (including asympt. CNS disease) were randomized to reiceive either Alectinib or Crizotinib. During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression/death occurred in 41% (62/152 pt) in the alectinib group and 68% (102/151 patients) in the crizotinib group. 12-month event-free survival rate 68.4% with alectinib vs. 48.7% with crizotinib. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, compared to 68 patients (45%) in the crizotinib group. Response rates were 82.9% (Alectinib) and 75.5% (crizotinib). 28586279 PubMed Peters et al., 2017, N. Engl. J. Med. NCT02075840 5 accepted 4858 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2017-06-13 01:53:00 UTC https://civicdb.org/links/evidence_items/4858 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false EGFR 1956 Exon 19 Deletion Lung Non-small Cell Carcinoma 3908 Dacomitinib,Erlotinib Substitutes Predictive Supports B Sensitivity/Response Non-small cell cancer patients from two studies [The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067)] with exon 19 deletion and L858R EGFR (Exon 21) mutations were pooled to compare the efficacy of dacomitinib to erlotinib. 121 patients with any EGFR mutation were enrolled, 101 had activating mutations in exon 19 or 21. Median progression-free survival and median survival were better following dacomitinib treatment (14.6 and 26.6 months, N=53) than erlotinib (9.6 and 23.2, P = 0.146 and P = 0.265, N=48). In exon 19 mutated patients (N=32 and 36) PFS was better for dacomitinib treated patients (HR of 0.585 [95% CI 0.335–1.024], two-sided log-rank, P = 0.058) but did not reach significance. 26768165 PubMed Ramalingam et al., 2016, Ann. Oncol. NCT00769067,NCT01360554,NCT01774721 3 accepted 4859 133 19 7 55242415 55242513 ENST00000275493.2 75 GRCh37 Deletions within exon 19 of EGFR are most common in lung cancer. These deletions, in non-small cell lung cancer, have been shown to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib, afatinib, and erlotinib. There is also data to suggest that this event is a good prognostic marker in lung adenocarcinoma. Examples of exon 19 deletions include: p.746_A750delELREA, p.747_753delinsS, p.747_752delLREATS, and p.747_751delLREAT. Somatic 2017-07-27 21:58:24 UTC https://civicdb.org/links/evidence_items/4859 https://civicdb.org/links/variants/133 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Non-small Cell Carcinoma 3908 Dacomitinib Predictive Supports B Sensitivity/Response The authors pooled patients with exon 19 deletion and L858R EGFR (Exon 21) mutations from both studies (The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067)) to compare the efficacy of dacomitinib to erlotinib. 121 patients with any EGFR mutation were enrolled, 101 had activating mutations in exon 19 or 21. For those (exon19/21), the median PFS was 14.6 months with dacomitinib and 9.6 months with erlotinib The median survival was 26.6 months with dacomitinib versus 23.2 months with erlotinib. 26768165 PubMed Ramalingam et al., 2016, Ann. Oncol. NCT00769067,NCT01360554,NCT01774721 5 accepted 4860 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2018-05-23 12:46:45 UTC https://civicdb.org/links/evidence_items/4860 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false FGFR3 2261 Fusion Adrenal Carcinoma 3950 Erdafitinib Predictive Supports C Sensitivity/Response Phase 1 study of pan-FGFR inhibitor JNJ-42756493 in patients with solid tumors. No responses were seen 36 patients without FGFR pathway aberrations. Among 23 patients with FGFR pathway aberrations, 4 partial responses as well as 16 with stable disease were seen. Tumor shrinkage was observed in a patient with adrenal carcinoma and FGFR3-TACC3/FGFR2-CCDC6 fusions. 26324363 PubMed Tabernero et al., 2015, J. Clin. Oncol. NCT01703481 3 accepted 4861 1691 23 Somatic 2019-11-28 18:18:42 UTC https://civicdb.org/links/evidence_items/4861 https://civicdb.org/links/variants/1691 https://civicdb.org/links/genes/23 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Trametinib,Pemetrexed,Docetaxel Combination Predictive Supports B Sensitivity/Response This phase I/Ib two-part study evaluated trametinib in combination with anticancer agents docetaxel or pemetrexed in NSCLC with and without KRAS mutations. Confirmed partial response (PR) was observed in 21% (10/47) patients receiving trametinib/docetaxel. The ORR was 18% (4 PR in 22 patients) in KRAS wild-type versus 24% (six PR in 25 patients) in KRAS-mutant NSCLC. Of the 42 patients treated with trametinib/pemetrexed, 14% (6/42) had a PR; the ORR was 17% (4/23) in KRAS-mutated NSCLC versus 11% (2/19) in KRAS wild-type NSCLC. 27876675 PubMed Gandara et al., 2017, J Thorac Oncol NCT01192165 3 accepted 4862 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2017-09-08 18:08:27 UTC https://civicdb.org/links/evidence_items/4862 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Atezolizumab,Nivolumab Substitutes Predictive Supports B Sensitivity/Response A meta-analysis of randomized trials to investigate if KRAS mutation status affects survival benefits of immune checkpoint inhibition (ICI) in patients with advanced NSCLC. Of 3 eligible studies using either nivolumab or atezolizumab, 138 patients with KRAS mutant NSCLC and 371 with KRAS wild-type were included. ICI improved overall survival over that with docetaxel in KRAS mutant, previously-treated advanced NSCLC (hazard ratio=0.64 [95% confidence interval, 0.43-0.96], P = 0.03) but not in those with KRAS wild-type tumor (HR = 0.88 [95% CI, 0.68-1.13], P = 0.30). These results suggest that KRAS mutation status may be a potential biomarker for survival benefits to ICIs. 28525386 PubMed Kim et al., 2017, Oncotarget 3 accepted 4863 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2017-06-15 18:58:42 UTC https://civicdb.org/links/evidence_items/4863 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Immune Checkpoint Inhibitor Predictive Supports E Sensitivity/Response This meta-analysis of 5 studies with 752 non-small cell lung cancer patients examined the association between PD-L1 expression and KRAS mutation status. KRAS-mutant tumors were marginally more likely to be PD-L1 positive than KRAS-wild type tumors (51% vs 36%; odds ratio: 1.69; 95% CI 1.01-2.84; p = 0.045). Authors concluded that this result contributes to a theoretical basis for including PD-L1 inhibitors in combination with other molecularly targeted drugs in the treatment of patients with KRAS mutations. 28259530 PubMed Li et al., 2017, Eur J Surg Oncol 2 accepted 4864 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2020-09-10 23:47:22 UTC https://civicdb.org/links/evidence_items/4864 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Colorectal Cancer 9256 Cetuximab,Selumetinib Combination Predictive Does Not Support B Sensitivity/Response A phase I study to determine the tolerability and pharmacokinetics of Selumetinib and Cetuximab with an expanded cohort in KRAS-mutant CRC. In the KRAS-mutant CRC dose expansion cohort 14 patients were evaluable for response. Five patients experienced stable disease, nine had progressive disease. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. 26666244 PubMed Deming et al., 2016, Invest New Drugs NCT01287130 3 accepted 4866 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2017-09-08 18:08:41 UTC https://civicdb.org/links/evidence_items/4866 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Trametinib Predictive Does Not Support B Sensitivity/Response In this phase II trial, trametinib or docetaxel was given to patients with advanced KRAS-mutant NSCLC. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (HR 1.14; p = 0.5197). Median OS, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). These data suggest that trametinib is associated with similar PFS and response rates as docetaxel. 25722381 PubMed Blumenschein et al., 2015, Ann. Oncol. NCT01362296 4 accepted 4867 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2017-06-26 13:32:56 UTC https://civicdb.org/links/evidence_items/4867 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Selumetinib,Erlotinib Combination Predictive Does Not Support B Sensitivity/Response 38 KRAS wild-type patients were randomized to erlotinib or combination of selumetinib with erlotinib. 41 KRAS mutant patients were randomized to selumetinib or the combination. The primary end points were progression-free survival (PFS) for the KRAS wild-type cohort and objective response rate (ORR) for the KRAS mutant cohort. Median PFS in the KRAS wild-type arm was 2.4 months for erlotinib alone and 2.1 months for the combination. The ORR in the KRAS mutant group was 0% for selumetinib alone and 10% for the combination. These data suggest no difference in ORR or PFS with combination therapy of over monotherapy in KRAS mutant and KRAS wild-type advanced NSCLC. 26802155 PubMed Carter et al., 2016, Ann. Oncol. NCT01229150 4 accepted 4868 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2017-06-29 18:47:03 UTC https://civicdb.org/links/evidence_items/4868 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Colorectal Cancer 9256 Palbociclib,Binimetinib Combination Predictive Supports D Sensitivity/Response A preclinical study to investigate the efficacy of Binimetinib, Palbociclib and the combination on KRAS mutant colorectal cancer cell lines, cell line-derived and patient-derived xenografts. The combination of MEK and CDK4/6 inhibition inhibited cancer cell growth and caused cell regression in a synergistic manner Combination therapy markedly decreased levels of phosphorylated ribosomal protein S6 both in vitro and in vivo and decreased Ki67 staining in vivo. 27167191 PubMed Lee et al., 2016, Oncotarget 4 accepted 4869 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2017-09-08 18:12:29 UTC https://civicdb.org/links/evidence_items/4869 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false CDK4 1019 EXPRESSION Sarcoma 1115 Palbociclib Predictive Supports D Sensitivity/Response A preclinical study to explore the efficacy of CDK4/6 inhibition with palbociclib, in a panel of sarcoma cell lines and sarcoma tumor xenografts (PDXs). The responsiveness of these cell lines correlated with their levels of CDK4 mRNA as well as in vivo PDX, but not against sarcomas displaying low levels of CDK4 and high levels of p16ink4a (CDKN2A). 26528855 PubMed Perez et al., 2015, Oncotarget 4 accepted 4872 25 13 12 58141510 58146304 ENST00000257904.6 75 GRCh37 CDK4, along with its partner CDK6, are key players in cell cycle progression. The complex has been implicated in a number of cancer types, and is the focus of therapeutic research and development. One targeted therapy for CDK inhibition is palbociclib, which may slow the growth of advanced stage breast cancers. It has also been shown, in mouse, that CDK inhibition may sensitize mutant PIK3CA tumors to PI3K inhibitors. N/A 2017-07-27 14:50:56 UTC https://civicdb.org/links/evidence_items/4872 https://civicdb.org/links/variants/25 https://civicdb.org/links/genes/13 false CHEK1 1111 Overexpression Lung Small Cell Carcinoma 5409 Olaparib,Cisplatin,Prexasertib Combination Predictive Supports D Sensitivity/Response A preclinical study to evaluate the efficacy of targeting the overexpressed CHEK1 cell cycle chekpoint kinase, including both miRNA and Prexasertib-induced inhibition. Both in vitro and in vivo, Prexasertib had strong single agent efficacy and augmented the effect of Olaparib or Cisplatin in either combination, including platinum-resistant models. CHEK1 and MYC overexpression were predictors of response. 28490518 PubMed Sen et al., 2017, Cancer Res. 4 accepted 4874 1693 981 N/A 2017-12-18 20:29:46 UTC https://civicdb.org/links/evidence_items/4874 https://civicdb.org/links/variants/1693 https://civicdb.org/links/genes/981 false BRCA2 675 Loss-of-function Ovarian Cancer 2394 Talazoparib Predictive Supports B Sensitivity/Response In part 2 of a two-part dose-escalation phase I trial (NCT01286987), 71 patients with Ewings sarcoma, breast, ovarian, small cell lung, or pancreatic cancers received 1.0 mg/day talazoparib treatment. Of patients with BRCA mutation-associated breast and ovarian cancers, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients, respectively. 28242752 PubMed de Bono et al., 2017, Cancer Discov 3 accepted 4875 132 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 BRCA2 loss of function mutations have been shown to increase risk of breast and ovarian cancer in those carrying the allele in their germline. Treating BRCA mutant patients with PARP inhibitors such as Olaparib has led to significant response. Rare Germline 2017-06-15 16:39:43 UTC https://civicdb.org/links/evidence_items/4875 https://civicdb.org/links/variants/132 https://civicdb.org/links/genes/7 false BRCA1 672 Loss-of-function Ovarian Cancer 2394 Talazoparib Predictive Supports B Sensitivity/Response In part 2 of a two-part dose-escalation phase I trial (NCT01286987), 71 patients with Ewings sarcoma, breast, ovarian, small cell lung, or pancreatic cancers received 1.0 mg/day talazoparib treatment. Of patients with BRCA mutation-associated breast and ovarian cancers, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients, respectively. 28242752 PubMed de Bono et al., 2017, Cancer Discov 3 accepted 4876 131 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 BRCA1 loss of function mutations have been shown to increase risk of breast and ovarian cancer in those carrying the allele in their germline. Treating BRCA mutant patients with PARP inhibitors such as Olaparib has led to significant response. Rare Germline 2017-06-15 16:39:12 UTC https://civicdb.org/links/evidence_items/4876 https://civicdb.org/links/variants/131 https://civicdb.org/links/genes/6 false EGFR 1956 Expression Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports B Sensitivity/Response Double blind Phase II clinical trial evaluated 208 patients for efficacy of gefitinib against non-small cell lung cancer. For individuals taking 250mg/day, they observed an objective response rate of 18.4%, a PFS of 2.7 months and a median overall survival of 7.6 months. For individuals taking 500mg/day objective response rate was 19%, PFS was 2.8 months, and median overall survival was 8.0 months. For those who responded, median duration of the response was 3 months (ranges=1-5.5 months). The disease control rate was found to be 54.4% and 51.4% for the two groups. 12748244 PubMed Fukuoka et al., 2003, J. Clin. Oncol. 3 accepted 4877 354 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 N/A 2020-10-16 23:34:45 UTC https://civicdb.org/links/evidence_items/4877 https://civicdb.org/links/variants/354 https://civicdb.org/links/genes/19 false TP53 7157 R248W Cancer 162 MDM2 Inhibitor AMGMDS3 Predictive Supports D Resistance Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R248W loss of function mutation is present in 4 cell lines and all are insensitive to MDM2 Inhibitor AMGMDS3. 25730903 PubMed Saiki et al., 2015, Oncotarget 4 accepted 4879 118 45 17 7577539 7577539 G A ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R248 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, R248 mutations have been shown to confer worse overall survival. Somatic 2018-04-30 23:49:40 UTC https://civicdb.org/links/evidence_items/4879 https://civicdb.org/links/variants/118 https://civicdb.org/links/genes/45 false TP53 7157 R175H Cancer 162 MDM2 Inhibitor AMGMDS3 Predictive Supports D Resistance Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R175H loss of function mutation is present in 4 cell lines and all are insensitive to MDM2 Inhibitor AMGMDS3. 25730903 PubMed Saiki et al., 2015, Oncotarget 4 accepted 4880 116 45 17 7578406 7578406 C T ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R175H variant seems not only to result in loss of tumor-suppression, but also acts as a gain-of-function mutation that promotes tumorigenesis in mouse models. Cell lines harboring this mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been shown that the R175H mutation is correlated with worse overall survival than wild-type TP53, but is not as detrimental as the R248W variant. This variant is rare in population databases (ACMG code: PM2; 0.000003980 total exome AF gnomAD v2.1.1). Somatic 2018-04-30 23:46:48 UTC https://civicdb.org/links/evidence_items/4880 https://civicdb.org/links/variants/116 https://civicdb.org/links/genes/45 false TP53 7157 R273C Cancer 162 MDM2 Inhibitor AMGMDS3 Predictive Supports D Resistance Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R273C loss of function mutation is present in 2 cell lines and all are insensitive to MDM2 Inhibitor AMGMDS3. 25730903 PubMed Saiki et al., 2015, Oncotarget 4 accepted 4881 121 45 17 7577121 7577121 G A ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R273 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been suggested that the R273 mutants have been correlated with worse overall survival in breast cancer patients when compared to wild-type. Somatic 2018-04-30 23:44:04 UTC https://civicdb.org/links/evidence_items/4881 https://civicdb.org/links/variants/121 https://civicdb.org/links/genes/45 false TP53 7157 R273H Cancer 162 MDM2 Inhibitor AMGMDS3 Predictive Supports D Resistance Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R273H loss of function mutation is present in 7 cell lines and all are insensitive to MDM2 Inhibitor AMGMDS3. 25730903 PubMed Saiki et al., 2015, Oncotarget 4 accepted 4882 122 45 17 7577120 7577120 C T ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R273 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been suggested that the R273 mutants have been correlated with worse overall survival in breast cancer patients when compared to wild-type. Somatic 2018-04-30 23:43:26 UTC https://civicdb.org/links/evidence_items/4882 https://civicdb.org/links/variants/122 https://civicdb.org/links/genes/45 false TP53 7157 G245S Cancer 162 MDM2 Inhibitor AMGMDS3 Predictive Supports D Resistance Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 G245S loss of function mutation is present in 3 cell lines and all are insensitive to MDM2 Inhibitor AMGMDS3. 25730903 PubMed Saiki et al., 2015, Oncotarget 4 accepted 4883 879 45 17 7577548 7577548 C T ENST00000269305.4 75 GRCh37 Somatic 2018-04-30 23:41:38 UTC https://civicdb.org/links/evidence_items/4883 https://civicdb.org/links/variants/879 https://civicdb.org/links/genes/45 false TP53 7157 Y220C Cancer 162 MDM2 Inhibitor AMGMDS3 Predictive Supports D Resistance Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 Y220C loss of function mutation is present in 1 cell line and it is insensitive to MDM2 Inhibitor AMGMDS3. 25730903 PubMed Saiki et al., 2015, Oncotarget 4 accepted 4884 922 45 17 7578190 7578190 T C ENST00000269305.4 75 GRCh37 Somatic 2018-04-30 23:41:00 UTC https://civicdb.org/links/evidence_items/4884 https://civicdb.org/links/variants/922 https://civicdb.org/links/genes/45 false TP53 7157 M237I Glioblastoma 3068 MDM2 Inhibitor AMGMDS3 Predictive Supports D Resistance Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 M237I loss of function mutation is present in 1 cell line (T98G, glioblastoma) and it is insensitive to MDM2 Inhibitor AMGMDS3 (IC50: 49.97uM). 25730903 PubMed Saiki et al., 2015, Oncotarget 3 accepted 4885 1066 45 17 7577570 7577570 C A ENST00000269305.4 75 GRCh37 Somatic 2020-10-09 18:13:39 UTC https://civicdb.org/links/evidence_items/4885 https://civicdb.org/links/variants/1066 https://civicdb.org/links/genes/45 false TP53 7157 R158H Vulva Squamous Cell Carcinoma 2101 MDM2 Inhibitor AMGMDS3 Predictive Supports D Resistance Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R158H loss of function mutation is present in 1 cell line (SW954) and it is insensitive to MDM2 Inhibitor AMGMDS3. 25730903 PubMed Saiki et al., 2015, Oncotarget 3 accepted 4886 1695 45 17 7578457 7578457 C T ENST00000269305.4 75 GRCh37 Somatic 2022-04-06 09:28:56 UTC https://civicdb.org/links/evidence_items/4886 https://civicdb.org/links/variants/1695 https://civicdb.org/links/genes/45 false TP53 7157 V157F Cancer 162 MDM2 Inhibitor AMGMDS3 Predictive Supports D Resistance Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 V157F loss of function mutation is present in 1 cell line and it is insensitive to MDM2 Inhibitor AMGMDS3. 25730903 PubMed Saiki et al., 2015, Oncotarget 4 accepted 4887 1092 45 17 7578461 7578461 C A ENST00000269305.4 75 GRCh37 Somatic 2018-04-30 23:56:09 UTC https://civicdb.org/links/evidence_items/4887 https://civicdb.org/links/variants/1092 https://civicdb.org/links/genes/45 false TP53 7157 R249S Cancer 162 MDM2 Inhibitor AMGMDS3 Predictive Supports D Resistance Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R249S loss of function mutation is present in 1 cell line and it is insensitive to MDM2 Inhibitor AMGMDS3. 25730903 PubMed Saiki et al., 2015, Oncotarget 4 accepted 4888 1696 45 Somatic 2018-04-30 23:28:59 UTC https://civicdb.org/links/evidence_items/4888 https://civicdb.org/links/variants/1696 https://civicdb.org/links/genes/45 false TP53 7157 R280K Cancer 162 MDM2 Inhibitor AMGMDS3 Predictive Supports D Resistance Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R280K loss of function mutation is present in 1 cell line and it is insensitive to MDM2 Inhibitor AMGMDS3. 25730903 PubMed Saiki et al., 2015, Oncotarget 4 accepted 4889 1697 45 Somatic 2018-04-30 23:28:26 UTC https://civicdb.org/links/evidence_items/4889 https://civicdb.org/links/variants/1697 https://civicdb.org/links/genes/45 false TP53 7157 R280T Cancer 162 MDM2 Inhibitor AMGMDS3 Predictive Supports D Resistance Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R280T loss of function mutation is present in 1 cell line and it is insensitive to MDM2 Inhibitor AMGMDS3. 25730903 PubMed Saiki et al., 2015, Oncotarget 4 accepted 4890 1698 45 Somatic 2018-04-30 23:23:25 UTC https://civicdb.org/links/evidence_items/4890 https://civicdb.org/links/variants/1698 https://civicdb.org/links/genes/45 false TP53 7157 R158L Cancer 162 MDM2 Inhibitor AMGMDS3 Predictive Supports D Resistance Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R158L loss of function mutation is present in 2 cell lines and all are insensitive to MDM2 Inhibitor AMGMDS3. 25730903 PubMed Saiki et al., 2015, Oncotarget 4 accepted 4891 1699 45 17 7578457 7578457 C A ENST00000269305.4 75 GRCh37 Somatic 2018-04-30 23:16:00 UTC https://civicdb.org/links/evidence_items/4891 https://civicdb.org/links/variants/1699 https://civicdb.org/links/genes/45 false VHL 7428 E46* (c.136G>T) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma Predisposing Supports C Likely Pathogenic Study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Frameshift truncation mutation found in a single patient with VHL retinal manifestation, which coincides with mutations confirmed to be associated with VHL type 1 in this study. Only moderate evidence of pathogenicity since the protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants (AMCG code: PM4). 12202531 PubMed Dollfus et al., 2002, Invest. Ophthalmol. Vis. Sci. 4 accepted 4895 1733 58 3 10183667 10183667 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4895 https://civicdb.org/links/variants/1733 https://civicdb.org/links/genes/58 false VHL 7428 E55* (c.163G>T) Von Hippel-Lindau Disease 14175 Retinal detachment,Retinal capillary hemangioma,Renal cell carcinoma Predisposing Supports C Likely Pathogenic Genetic analysis of 7 Hungarian individuals from 5 unrelated families affected with type von Hippel-Lindau disease revealed 5 different mutations, 3 of which were novel. The mutations could not be found within 100 healthy controls. One germline truncation mutation was found in a 15-year-old male patient with bilateral renal cell carcinoma and retinal hemangioblastoma with serious retinal detachment. Neither of his parents displayed any mutations in the VHL gene indicating a de novo mutation. ACMG evidence codes: 'PS2' because they observe a de novo mutation (maternity and paternity confirmed), 'PP4' because the patient's phenotypes or family history are highly specific for a disease with single genetic etiology, 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease. Relevant HPO terms: Renal cell carcinoma, Retinal hemangioblastoma 23298237 PubMed Losonczy et al., 2013, BMC Med. Genet. 3 accepted 4898 1736 58 3 10183694 10183694 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4898 https://civicdb.org/links/variants/1736 https://civicdb.org/links/genes/58 false BRAF 673 L597Q Skin Melanoma 8923 Trametinib Predictive Supports C Sensitivity/Response Case study report including one patient with L597Q mutation-positive metastatic melanoma (M1b disease) treated with the MEK inhibitor trametinib. The L597Q patient achieved a RECIST partial response and showed maximum tumor shrinkage of 33% with trametinib as the first-line treatment and had a partial response for 6.2 months. 24933606 PubMed Bowyer et al., 2014, Melanoma Res. 3 accepted 4905 583 5 7 140453145 140453145 A T ENST00000288602.6 75 GRCh37 Somatic 2018-03-20 15:48:06 UTC https://civicdb.org/links/evidence_items/4905 https://civicdb.org/links/variants/583 https://civicdb.org/links/genes/5 false VHL 7428 Y98H (c.292T>C) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Retinal capillary hemangioma,Pheochromocytoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. Missense mutation found in two VHL type 2A families of 55 individuals altogether (family IDs 3476, 3127). 26 of 55 individuals were identified with retinal hemangioblastomas, 5 with cerebellar hemangioblastomas, and 30 with pheochromocytomas. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 3 accepted 4906 1741 58 3 10183823 10183823 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/4906 https://civicdb.org/links/variants/1741 https://civicdb.org/links/genes/58 false VHL 7428 H115Q (c.345C>A) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Renal cell carcinoma,Pheochromocytoma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in a VHL type 2B family of 12 individuals (Family ID 4486 in publication). All 12 family members identified with cerebellar hemangioblastomas, 2 of 12 family members with retinal hemangioblastomas, one with renal cell carcinoma and one with pheochromocytoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma, Pheochromocytoma. 7728151 PubMed Chen et al., 1995, Hum. Mutat. 2 accepted 4907 1742 58 3 10188202 10188202 C A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4907 https://civicdb.org/links/variants/1742 https://civicdb.org/links/genes/58 false VHL 7428 F119L (c.357C>G) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Pheochromocytoma,Cerebellar hemangioblastoma,Renal cell carcinoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in a VHL type 2B family of 7 individuals (Family ID 4414 in publication). Two of seven individuals were identified with retinal hemangioblastomas, 3 with cerebellar hemangioblastomas, one with renal cell carcinoma, and one with pheochromocytomas. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 2 accepted 4908 1743 58 3 10188214 10188214 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/4908 https://civicdb.org/links/variants/1743 https://civicdb.org/links/genes/58 false VHL 7428 A149T (c.445G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 2 family members with VHL (Family ID 3969 in publication). One carried pheochromocytoma, while both carried angiomas. 7728151 PubMed Chen et al., 1995, Hum. Mutat. 2 accepted 4909 1744 58 3 10188302 10188302 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4909 https://civicdb.org/links/variants/1744 https://civicdb.org/links/genes/58 false VHL 7428 T157I (c.470C>T) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Pheochromocytoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This mutation was found in 2 family members with VHL disease (family ID 4402). One carried pheochromocytoma and both carried retinal hemangioblastoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4910 1745 58 3 10191477 10191477 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4910 https://civicdb.org/links/variants/1745 https://civicdb.org/links/genes/58 false VHL 7428 R161Q (c.482G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma,Retinal capillary hemangioma,Renal cell carcinoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was detected in a VHL type 2B patient with retinal hemangioblastoma, renal cell carcinoma, and pheochromocytoma (family ID 4422). Only supporting evidence for pathogenicity because patient's phenotyoe is highly specific for a disease with a single genetic etiology (ACMG code: PP4). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4911 1746 58 3 10191489 10191489 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/4911 https://civicdb.org/links/variants/1746 https://civicdb.org/links/genes/58 false VHL 7428 R167W (c.499C>T) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma,Cerebellar hemangioblastoma,Pheochromocytoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in four VHL type 2 families of 51 individuals altogether (family IDs 2338, 3490, 4477, 4405). 36 of 51 individuals had retinal hemangioblastomas, 17 had cerebellar hemangioblastomas, 16 with renal cell carcinoma, and 36 with pheochromocytomas. This mutation was also detected in a VHL type 1 patient with angiomas (family ID 3699). Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 3 accepted 4912 1747 58 3 10191506 10191506 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/4912 https://civicdb.org/links/variants/1747 https://civicdb.org/links/genes/58 false VHL 7428 R167Q (c.500G>A) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma,Cerebellar hemangioblastoma,Pheochromocytoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in six VHL type 2 families (including one family with 9 affected individuals) and one VHL type 1 family totaling 23 individuals altogether (family IDs 4421, 3718, 3767, 3493, 3731, 3517, 3739). Twelve of 23 individuals had retinal hemangioblastomas, 12 carried cerebellar hemangioblastomas, 8 carried renal cell carcinoma and 12 carried pheochromocytomas. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 3 accepted 4913 1739 58 3 10191507 10191507 G A ENST00000256474.2 75 GRCh37 R167Q is the most common point mutation in hereditary Von Hippel-Lindau (VHL) disease and disrupts the VHL genes binding to elongin C reducing the levels of the VHL-elongin B-elongin C (VBC) E3 ligase complex and inhibiting the ability of VHL to regulate HIF2α. This partial function in turn leads to an increased risk of tumorgenesis. VHL derived clear cell renal cell carcinoma models however have shown the proteasome inhibitors bortezomib and carfilzomib can act to stabilize mutant VHL-R167Q leading to downregulation of HIF2α and suprressed tumorgenesis. Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/4913 https://civicdb.org/links/variants/1739 https://civicdb.org/links/genes/58 false VHL 7428 L178P (c.533T>C) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Renal cell carcinoma,Pheochromocytoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 2 family members with VHL disease type 2A, who both had retinal hemangioblastomas and cerebellar hemangioblastomas (family ID 3786). One of 2 individuals carried pheochromocytomas as well. Mutation also found in 8 individuals with VHL type 1 phenotype (family IDs 3314, 4419, 4403, 3708). Three of 8 individuals were identified with retinal hemangioblastomas, 5 with cerebellar hemangioblastomas, and 2 with renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4914 1748 58 3 10191540 10191540 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4914 https://civicdb.org/links/variants/1748 https://civicdb.org/links/genes/58 false VHL 7428 V62fs (c.180del) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This frameshift mutation was found in a VHL type 1 family of 8 individuals (family ID 3563). Two of 8 individuals were identified with retinal hemangioblastomas, 3 with cerebellar hemangioblastomas and 3 with renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4916 1750 58 3 10183711 10183711 G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4916 https://civicdb.org/links/variants/1750 https://civicdb.org/links/genes/58 false VHL 7428 S65W (c.194C>G) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in a VHL type 1 family of four individuals (family ID 4325). Three of 4 individuals were identified with retinal hemangioblastomas and one with cerebellar hemangioblastomas. Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma. 7728151 PubMed Chen et al., 1995, Hum. Mutat. 2 accepted 4917 1787 58 3 10183725 10183725 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/4917 https://civicdb.org/links/variants/1787 https://civicdb.org/links/genes/58 false VHL 7428 Q73* (c.217C>T) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Retinal capillary hemangioma,Renal cell carcinoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This nonsense mutation was found in a VHL type 1 family of 7 individuals (family ID 2753). Six of 7 individuals were identified with retinal hemangioblastomas, 3 with cerebellar hemangioblastomas and one with renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4918 1752 58 3 10183748 10183748 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4918 https://civicdb.org/links/variants/1752 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance This deletion mutation was found in two VHL type 1 families of 15 individuals altogether (Family IDs 2693 and 2956 in publication). Five of 7 individuals were identified with retinal hemangioblastomas, 8 with cerebellar hemangioblastomas, and 7 with renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4919 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:42 UTC https://civicdb.org/links/evidence_items/4919 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false VHL 7428 N78H (c.232A>C) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Cerebellar hemangioblastoma,Renal cell carcinoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was detected in a type 1 VHL patient (family ID 4389) with retinal hemangioblastomas, cerebellar hemangioblastomas, and renal cell carcinoma. Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4920 1754 58 3 10183763 10183763 A C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4920 https://civicdb.org/links/variants/1754 https://civicdb.org/links/genes/58 false VHL 7428 N78S (c.233A>G) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Renal cell carcinoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 3 family members with VHL type 1 phenotype (family ID 4327). All 3 individuals carried cerebellar hemangioblastomas and one also carried renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 2 accepted 4921 1755 58 3 10183764 10183764 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/4921 https://civicdb.org/links/variants/1755 https://civicdb.org/links/genes/58 false VHL 7428 N78T (c.233A>C) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 3 family members with VHL type 1 phenotype (family ID 3101). One of 3 members carried retinal hemangioblastomas and 2 carried cerebellar hemangioblastomas. 7728151 PubMed Chen et al., 1995, Hum. Mutat. 2 accepted 4922 1756 58 3 10183764 10183764 A C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4922 https://civicdb.org/links/variants/1756 https://civicdb.org/links/genes/58 false VHL 7428 S80I (c.239G>T) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was detected in a type 1 VHL patient with retinal hemangioblastomas and cerebellar hemangioblastomas (family ID 3630). Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4923 1757 58 3 10183770 10183770 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/4923 https://civicdb.org/links/variants/1757 https://civicdb.org/links/genes/58 false VHL 7428 P86fs (c.254_255insC) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Renal cell carcinoma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This frameshift mutation was found in 3 family members with VHL type 1 phenotype (family ID 3312). All 3 individuals carried retinal hemangioblastomas, 2 of 3 carried cerebellar hemangioblastomas and one carried renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4924 1758 58 3 10183785 10183786 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/4924 https://civicdb.org/links/variants/1758 https://civicdb.org/links/genes/58 false VHL 7428 P86L (c.257C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in two VHL type 1 families of 12 individuals altogether (family IDs 2612 and 3568). Nine of 12 individuals were identified with cerebellar hemangioblastomas, 6 with retinal hemangioblastomas, and 6 with renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4926 1760 58 3 10183788 10183788 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4926 https://civicdb.org/links/variants/1760 https://civicdb.org/links/genes/58 false VHL 7428 W88R (c.262T>A) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 3 family members with VHL type 1 phenotype (family ID 1255). All 3 individuals carried cerebellar hemangioblastomas and retinal hemangioblastomas. Two of 3 also carried renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. 7728151 PubMed Chen et al., 1995, Hum. Mutat. 2 accepted 4927 1761 58 3 10183793 10183793 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/4927 https://civicdb.org/links/variants/1761 https://civicdb.org/links/genes/58 false VHL 7428 S111FS (c.331delA) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This frameshift mutation was detected in a VHL type 1 patient with cerebellar hemangioblastomas (family ID 3669). Only supporting evidence for pathogenicity because the patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). Relevant HPO terms: Cerebellar hemangioblastoma. 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4928 1762 58 3 10183862 10183862 A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4928 https://civicdb.org/links/variants/1762 https://civicdb.org/links/genes/58 false VHL 7428 S111N (c.332G>A) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in a VHL type 1 family of 4 individuals (family ID 3315). One of the 4 individuals was identified with retinal hemangioblastomas, 2 with cerebellar hemangioblastomas and 2 with renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 2 accepted 4929 1763 58 3 10183863 10183863 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/4929 https://civicdb.org/links/variants/1763 https://civicdb.org/links/genes/58 false VHL 7428 S111R (c.333C>G) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was detected in a VHL type 1 patient with cerebellar hemangioblastomas (family ID 4401). Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4930 1764 58 3 10183864 10183864 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4930 https://civicdb.org/links/variants/1764 https://civicdb.org/links/genes/58 false EGFR 1956 Gain-of-function Lung Non-small Cell Carcinoma 3908 Gefitinib Predictive Supports B Sensitivity/Response Study found somatic EGFR mutations localized to exons 19,21 in 8/9 patients who exhibited a response to Gefitinib treatment. Of these mutations 7/8 were localized near the ATP cleft Gefitinib targets, suggesting a specific gain-of-function mechanism. No EGFR mutations were observed in 7 patients with no response to Gefitinib. An expansion cohort independent of the Gefitinib study showed 2/25 patients harbored EGFR mutations. A second expansion independent of Gefitinib consisting of 95 tumors and 108 cell lines showed no mutations in exons 19,21. 15118073 PubMed Lynch et al., 2004, N. Engl. J. Med. 4 accepted 4931 1765 19 7 GRCh37 Somatic 2019-08-02 15:55:52 UTC https://civicdb.org/links/evidence_items/4931 https://civicdb.org/links/variants/1765 https://civicdb.org/links/genes/19 false VHL 7428 Y112* (c.336C>A) Von Hippel-Lindau Disease 14175 Hemangioma,Cerebellar hemangioblastoma,Renal cell carcinoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This nonsense mutation was found in a VHL type 1 patient and familiy of 4 individuals (family IDs 3759 and 3760). Four of 5 individuals were identified with angiomas, 2 with cerebellar hemangioblastomas, and one with renal cell carcinoma. ACMG codes as follows: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). Patient's phenotype is highly specific for a disease with a single genetic etiology (PP4). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4932 1766 58 3 10183867 10183867 C A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/4932 https://civicdb.org/links/variants/1766 https://civicdb.org/links/genes/58 false VHL 7428 W117C (c.351G>T) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in a VHL type 1 family of 10 individuals (family ID 1239). Seven of 10 individuals were identified with cerebellar hemangioblastomas and renal cell carcinoma. One identified with retinal hemangioblastomas. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4933 1767 58 3 10188208 10188208 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4933 https://civicdb.org/links/variants/1767 https://civicdb.org/links/genes/58 false VHL 7428 L129Q (c.386insAGA) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This insertion mutation was detected in a VHL type 1 patient (family ID 4410 in publication) with retinal hemangioblastomas, cerebellar hemangioblastomas, and renal cell carcinoma. Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4934 1768 58 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4934 https://civicdb.org/links/variants/1768 https://civicdb.org/links/genes/58 false VHL 7428 L135* (c.404T>A) Von Hippel-Lindau Disease 14175 Hemangioma,Cerebellar hemangioblastoma,Renal cell carcinoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This nonsense mutation was found in a VHL type 1 family of 6 individuals (family ID 3720). All 6 individuals were identified with cerebellar hemangioblastomas, 4 with angiomas and 3 with renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4935 1769 58 3 10188261 10188261 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4935 https://civicdb.org/links/variants/1769 https://civicdb.org/links/genes/58 false VHL 7428 N150fs (c.449del) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Cerebellar hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This mutation causes a stop codon at amino acid 158. Mutation also found in 3 family members with VHL type 1 phenotype (family ID 3575). Two of 3 members carried retinal hemangioblastomas, one carried cerebellar hemangioblastomas and one with renal cell carcinoma. Supporting evidence of pathogenicity because of the introduction of an early stop codon in a gene where loss of function is an established mechanism of disease (ACMG code: PVS1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 3 accepted 4936 1770 58 10188305 10188305 A ENST00000256474.2 75 GRCh37 There are no similar variants in ClinVar with this exact genomic location. Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/4936 https://civicdb.org/links/variants/1770 https://civicdb.org/links/genes/58 false VHL 7428 P154fs (c.462delA) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Renal cell carcinoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. Mutation causes a stop codon at amino acid 158. This mutation was also found in 4 family members with VHL type 1 phenotype (family ID 3616). Two of 4 members carried retinal hemangioblastomas and 2 with renal cell carcinoma. Supporting evidence of pathogenicity because of the introduction of an early stop codon in a gene where loss of function is an established mechanism of disease (ACMG code: PVS1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 3 accepted 4937 1771 58 3 10188319 10188319 A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4937 https://civicdb.org/links/variants/1771 https://civicdb.org/links/genes/58 false VHL 7428 C162R (c.484T>C) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Hemangioma,Renal cell carcinoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. Missense mutation detected in a VHL type 1 patient (Family ID 3509 in publication) with angiomas, cerebellar hemangioblastomas, and renal cell carcinoma. Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 2 accepted 4939 1772 58 3 10191491 10191491 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4939 https://civicdb.org/links/variants/1772 https://civicdb.org/links/genes/58 false VHL 7428 C162F (c.485G>T) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 4 family members with VHL type 1 phenotype (Family ID 3820 in publication). All 4 family members carried cerebellar hemangioblastomas, 2 of 4 carried retinal hemangioblastomas and one carried renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4940 1773 58 3 10191492 10191492 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4940 https://civicdb.org/links/variants/1773 https://civicdb.org/links/genes/58 false VHL 7428 C162W (c.486C>G) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was detected in VHL type 1 patient (Family ID 3618 in publication) with cerebellar hemangioblastomas. Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). Relevant HPO terms: Cerebellar hemangioblastoma. 7728151 PubMed Chen et al., 1995, Hum. Mutat. 2 accepted 4941 1774 58 3 10191493 10191493 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4941 https://civicdb.org/links/variants/1774 https://civicdb.org/links/genes/58 false VHL 7428 V166D (c.497T>A) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 2 family members with VHL type 1 phenotype (family ID 4480). Both individuals were identified with cerebellar hemangioblastomas and one with retinal hemangioblastoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 4942 1775 58 3 10191504 10191504 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/4942 https://civicdb.org/links/variants/1775 https://civicdb.org/links/genes/58 false VHL 7428 L184P (c.551T>C) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Hemangioblastoma Predisposing N/A C N/A In a study of 114 unrelated VHL affected families, germline mutations in the VHL gene were identified in 85 of the families. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals, however it seems unaffected family members were not tested genetically for the mutations. Mutations in the VHL gene were detected by SSCP and DNA sequencing. Haplotypes were determined with four microsatellite polymorphic probes. The missense mutation L184P (c.551T>C) (In the paper noted as nucleotide position 764 and codon position 255 due to old reference transcript), was found in 2 individuals in family 3708. Both individuals were identified with renal cell carcinoma and one also presented with a CNS hemangioblastoma. Additional information regarding the family information, including a pedigree, were not provided. ACMG evidence codes: 'flag for PP4' since the patients phenotype and family history is consistent with VHL, 'flag for PP1' because there is co-segregation of variant with the phenotype in two members of the family. 7728151 PubMed Chen et al., 1995, Hum. Mutat. 2 accepted 4943 1776 58 3 10191558 10191558 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/4943 https://civicdb.org/links/variants/1776 https://civicdb.org/links/genes/58 false VHL 7428 E186* (c.556G>T) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals .This nonsense mutation was found in a VHL type 1 family of 6 individuals (Family ID 3770 in publication). All 6 individuals were identified with cerebellar hemangioblastomas, 4 with retinal hemangioblastomas, and 5 with renal cell carcinoma. Supporting evidence of pathogenicity because of the introduction of an early stop codon in a gene where loss of function is an established mechanism of disease (ACMG code: PVS1). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 3 accepted 4944 1777 58 3 10191563 10191563 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4944 https://civicdb.org/links/variants/1777 https://civicdb.org/links/genes/58 false VHL 7428 E186K (c.556G>A) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Renal cell carcinoma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 2 family members with VHL type 1 phenotype (Family ID 3736 in publication). One of 2 individuals were identified with retinal hemangioblastomas, one with cerebellar hemangioblastomas, and one with renal cell carcinoma. Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 2 accepted 4945 1778 58 3 10191563 10191563 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4945 https://civicdb.org/links/variants/1778 https://civicdb.org/links/genes/58 false ERBB2 2064 L755S Colorectal Adenocarcinoma 0050861 Trastuzumab,Fluorouracil,Leucovorin Combination Predictive Does Not Support C Sensitivity/Response Patient was a 35 year old male who was treated with pseudoadjuvant FOLFOX chemotherapy. Patient relapsed and was found to have an ERBB2 L755S kinase domain mutation along with mutations in APC and BRAF. He was then treated with trastuzumab combined with infusional 5-Fu and leucovorin but exhibited no response. 27626067 PubMed Aung et al., 2016, Cold Spring Harb Mol Case Stud 3 accepted 4955 39 20 17 37880220 37880220 T C ENST00000269571.5 75 GRCh37 ERBB2 L755S was one of the first ERBB2 variants to be functionally classified (Bose et al. 2013). This mutation was not shown to be an activating mutation, unlike many of the other variants queried. This mutation was also shown to confer resistance to the tyrosine kinase inhibitor lapatinib in MCF10A cell lines. Somatic 2019-10-11 18:55:50 UTC https://civicdb.org/links/evidence_items/4955 https://civicdb.org/links/variants/39 https://civicdb.org/links/genes/20 false VHL 7428 A56fs (c.166_167insA) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This mutation causes a frameshift and premature stop codon at amino acid 131 and was found in a VHL type 1 patient (kindred no. 110). This variant is likely to cause a dramatic alteration in protein function in a gene where loss-of-function mutations are a known mechanism (ACMG code: PVS1). Relevant HPO terms: Pheochromocytoma. 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 2 accepted 4956 1785 58 3 10183697 10183698 A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/4956 https://civicdb.org/links/variants/1785 https://civicdb.org/links/genes/58 false VHL 7428 S65W (c.194C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in a VHL type 1 patient (kindred no. 25). Supporting evidence for pathogenicity because of a missense mutation in a gene where missense variants are a common mechanism of disease (ACMG code: PP2). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4958 1787 58 3 10183725 10183725 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4958 https://civicdb.org/links/variants/1787 https://civicdb.org/links/genes/58 false VHL 7428 S65L (c.194C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in a VHL type 1 patient (kindred no. 52). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4959 1788 58 3 10183725 10183725 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4959 https://civicdb.org/links/variants/1788 https://civicdb.org/links/genes/58 false VHL 7428 C77fs (c.228dup) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation causes a stop codon at amino acid 131 and was found in a VHL type 2 and a VHL type 1 patient (kindred no. 71, 85). A frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). Relevant HPO terms: Pheochromocytoma. 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4961 2132 58 3 10183758 10183759 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/4961 https://civicdb.org/links/variants/2132 https://civicdb.org/links/genes/58 false VHL 7428 N78H (c.232A>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those in which pheochromocytoma had not occurred (VHL type1). This mutation was found in a VHL type 1 patient (kindred no. 34). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4962 1754 58 3 10183763 10183763 A C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4962 https://civicdb.org/links/variants/1754 https://civicdb.org/links/genes/58 false VHL 7428 R79P (c.236G>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those in which pheochromocytoma had not occurred (VHL type 1). This mutation was found in a VHL patient (kindred no. 150). The presence of pheochromocytoma was not indicated. 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4963 1791 58 3 10183767 10183767 G C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4963 https://civicdb.org/links/variants/1791 https://civicdb.org/links/genes/58 false VHL 7428 S80R (c.240T>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those which pheochromocytoma had not occurred (VHL type 1). This mutation was found in a VHL type 1 patient (kindred no. 103). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4964 1792 58 3 10183771 10183771 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4964 https://civicdb.org/links/variants/1792 https://civicdb.org/links/genes/58 false VHL 7428 L89P (c.266T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those which pheochromocytoma had not occurred (VHL type 1). This mutation was found in VHL type 1 patient (kindred no. 59). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4965 1793 58 3 10183797 10183797 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4965 https://civicdb.org/links/variants/1793 https://civicdb.org/links/genes/58 false VHL 7428 Y98H (c.292T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in a VHL family (kindred no. 22). Incidence of pheochromocytoma was unknown. Supporting evidence for pathogenicity because of a missense mutation in a gene where missense variants are a common mechanism of disease (ACMG code: PP2). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4967 1741 58 3 10183823 10183823 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4967 https://civicdb.org/links/variants/1741 https://civicdb.org/links/genes/58 false VHL 7428 G114C (c.340G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in 2 unrelated VHL families (kindred no. 40, 133). One was identified with pheochromocytoma, the other was unknown. Supporting evidence for pathogenicity because of a missense mutation in a gene where missense variants are a common mechanism of disease (ACMG code: PP2). Relevant HPO term: pheochromocytoma. 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4970 1797 58 3 10183871 10183871 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/4970 https://civicdb.org/links/variants/1797 https://civicdb.org/links/genes/58 false VHL 7428 L118P (c.353T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those which pheochromocytoma had not occurred (VHL type 1). This mutation was found in a VHL type 1 patient (kindred no. 19). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4971 1798 58 3 10188210 10188210 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4971 https://civicdb.org/links/variants/1798 https://civicdb.org/links/genes/58 false VHL 7428 N131fs (c.390_391del) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This mutation causes stop codon at amino acid 133 and was found in VHL type 1 patient (kindred no. 64). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4973 1800 58 3 10188247 10188248 TA ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/4973 https://civicdb.org/links/variants/1800 https://civicdb.org/links/genes/58 false VHL 7428 F136S (c.407T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those which pheochromocytoma had not occurred (VHL type 1). This mutation was found in a VHL patient (kindred no. 27). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4974 1801 58 3 10188264 10188264 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4974 https://civicdb.org/links/variants/1801 https://civicdb.org/links/genes/58 false VHL 7428 L153fs (c.457delC) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This mutation causes stop codon at amino acid 158 and was found in 2 unrelated VHL patients (kindred no. 41, 99). One patient did not have pheochromocytoma. 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4975 1802 58 3 10188317 10188317 C ENST00000256474.2 75 GRCh37 There are two similar variants in ClinVar at this exact genomic location with ClinVar IDs: 526670 and 486714. Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/4975 https://civicdb.org/links/variants/1802 https://civicdb.org/links/genes/58 false VHL 7428 P154L (c.461C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those which pheochromocytoma had not occurred (VHL type 1). This mutation was found in VHL type 2 patient (kindred no. 49). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4976 1782 58 3 10188318 10188318 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4976 https://civicdb.org/links/variants/1782 https://civicdb.org/links/genes/58 false VHL 7428 L158V (c.472C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those which pheochromocytoma had not occurred (VHL type 1). This mutation was found in VHL type 1 patient (kindred no. 91). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4977 1803 58 3 10191479 10191479 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4977 https://civicdb.org/links/variants/1803 https://civicdb.org/links/genes/58 false VHL 7428 V170F (c.508G>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in a VHL type 2 patient (kindred no. 26). Supporting evidence of pathogenicity because of a missense mutation in a gene in which missense variants are a common mechanism of disease. Relevant HPO terms: Pheochomocytoma. 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4982 1806 58 3 10191515 10191515 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4982 https://civicdb.org/links/variants/1806 https://civicdb.org/links/genes/58 false VHL 7428 L178P (c.533T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those which pheochromocytoma had not occurred (VHL type 1). This mutation was found in a VHL type 1 patient (kindred no. 44). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4983 1748 58 3 10191540 10191540 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4983 https://civicdb.org/links/variants/1748 https://civicdb.org/links/genes/58 false VHL 7428 I180V (c.538A>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those which pheochromocytoma had not occurred (VHL type 1). This mutation was found in a VHL type 1 patient (kindred no. 79). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4984 1807 58 3 10191545 10191545 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4984 https://civicdb.org/links/variants/1807 https://civicdb.org/links/genes/58 false VHL 7428 Q195* (c.583C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in a VHL type 1 patient (kindred no. 21). This study contains very strong evidence for pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 4987 1810 58 3 10191590 10191590 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4987 https://civicdb.org/links/variants/1810 https://civicdb.org/links/genes/58 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Docetaxel,Erlotinib Substitutes Predictive Does Not Support B Sensitivity/Response 222 EGFR-wt patients with advanced NSCLC were randomized to receive docetaxel or erlotinib In this study (4 patients not eligible, leaving 109 in each arm). KRAS was mutated in 25 and 26 out of 109 patients in the erlotinib and docetaxel arm, respectively. KRAS was neither prognostic nor predictive of benefit for either docetaxel or erlotinib. 26209642 PubMed Rulli et al., 2015, Ann. Oncol. NCT00637910 4 accepted 4996 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2021-01-06 01:54:06 UTC https://civicdb.org/links/evidence_items/4996 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Mutation Lung Non-small Cell Carcinoma 3908 Docetaxel Predictive Does Not Support B Sensitivity/Response Of the 275 patients assessable for KRAS mutation status, 49 (18%) were positive for KRAS mutation. There were no differences between treatments in OS, PFS, or response rates according to KRAS mutation status, and no evidence that KRAS mutation is a predictive factor for a differential survival effect between gefitinib and docetaxel. 20038723 PubMed Douillard et al., 2010, J. Clin. Oncol. NCT00076388 4 accepted 4997 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2017-06-27 10:24:04 UTC https://civicdb.org/links/evidence_items/4997 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false VHL 7428 S65W (c.194C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance In a study of 138 unrelated VHL families, 109 germline mutations were found. Missense mutations were more frequently found in families with pheochromocytoma. Deletions. Nonsense, and frameshift mutations were more frequently found in families without pheochromocytoma. Large deletions and mutations predicted to cause truncated protein were associated with lower risk pheochromocytoma. This missense mutation was found in one of the VHL families (family ID 39). 8730290 PubMed Maher et al., 1996, J. Med. Genet. 3 accepted 4998 1787 58 3 10183725 10183725 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/4998 https://civicdb.org/links/variants/1787 https://civicdb.org/links/genes/58 false VHL 7428 V170D (c.509T>A) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance In a study of 138 unrelated VHL families, 109 germline mutations were found. Missense mutations were more frequently found in families with pheochromocytoma (PC). Deletions. Nonsense, and frameshift mutations were more frequently found in families without PC. Large deletions and mutations predicted to cause truncated protein were associated with lower risk of PC. This missense mutation was found in a VHL family (family ID 77). No phenotype described. 8730290 PubMed Maher et al., 1996, J. Med. Genet. 3 accepted 5013 1826 58 3 10191516 10191516 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/5013 https://civicdb.org/links/variants/1826 https://civicdb.org/links/genes/58 false POLE 5426 P286R Colorectal Cancer 9256 Prognostic Supports B Better Outcome POLE proofreading domain mutations identify a subset of immunogenic colorectal cancers with excellent prognosis. 28404093 PubMed Domingo et al., 2016, Lancet Gastroenterol Hepatol 3 accepted 5017 1830 4386 Somatic 2017-09-09 23:28:10 UTC https://civicdb.org/links/evidence_items/5017 https://civicdb.org/links/variants/1830 https://civicdb.org/links/genes/4386 false POLE 5426 V411L Colorectal Cancer 9256 Prognostic Supports B Better Outcome POLE proofreading domain mutations identify a subset of immunogenic colorectal cancers with excellent prognosis. 28404093 PubMed Domingo et al., 2016, Lancet Gastroenterol Hepatol 3 accepted 5018 1831 4386 Somatic 2017-09-09 23:28:24 UTC https://civicdb.org/links/evidence_items/5018 https://civicdb.org/links/variants/1831 https://civicdb.org/links/genes/4386 false POLE 5426 S459F Colorectal Cancer 9256 Prognostic Supports B Better Outcome POLE proofreading domain mutations identify a subset of immunogenic colorectal cancers with excellent prognosis. 28404093 PubMed Domingo et al., 2016, Lancet Gastroenterol Hepatol 3 accepted 5019 1832 4386 Somatic 2017-07-06 15:27:14 UTC https://civicdb.org/links/evidence_items/5019 https://civicdb.org/links/variants/1832 https://civicdb.org/links/genes/4386 false VHL 7428 N78S (c.233A>G) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Cerebellar hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of VHL gene product (pVHL). Missense mutation, affecting an amino acid within pVHL protein core, was found in 6 VHL type 1 families with 12 affected individuals altogether. Nine of 12 patients had retinal angioma, 5 had cerebellar hemangioblastoma, and 2 had renal cell carcinoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5020 1755 58 3 10183764 10183764 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/5020 https://civicdb.org/links/variants/1755 https://civicdb.org/links/genes/58 false VHL 7428 L116V (c.346C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue with pVHL protein core, was detected in a VHL type 1 family with 3 affected individuals. All 3 patients had retinal angioma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5022 1820 58 3 10188203 10188203 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/5022 https://civicdb.org/links/variants/1820 https://civicdb.org/links/genes/58 false VHL 7428 V166F (c.496G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting surface residue of pVHL protein core, was found in 2 VHL type 2A families with 5 affected individuals altogether. Two of 5 patients had retinal angioma, 2 had cerebellar hemangioblastoma, and 4 had pheochromocytoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5024 1825 58 3 10191503 10191503 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/5024 https://civicdb.org/links/variants/1825 https://civicdb.org/links/genes/58 false VHL 7428 S65W (c.194C>G) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma,Cerebellar hemangioblastoma,Pancreatic cysts,Multiple renal cysts Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This missense mutation was detected in a VHL type 1 patient with retinal and cerebellar hemangioblastoma, renal cell carcinoma, and renal and pancreatic cysts (family no. 3). ACMG codes: PP4. 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 5026 1787 58 3 10183725 10183725 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/5026 https://civicdb.org/links/variants/1787 https://civicdb.org/links/genes/58 false VHL 7428 N78S (c.233A>G) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Multiple renal cysts,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This missense mutation was detected in a VHL type 1 patient with cerebellar hemangioblastoma, renal cysts and pancreatic cysts (family no. 6). 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 5027 1755 58 3 10183764 10183764 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5027 https://civicdb.org/links/variants/1755 https://civicdb.org/links/genes/58 false VHL 7428 V170D (c.509T>A) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Retinal capillary hemangioma,Cerebellar hemangioblastoma,Renal cell carcinoma,Pheochromocytoma Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This missense mutation was identified in 14 VHL patients (family no. 18). Six had retinal hemangioblastoma, 9 had cerebellar hemangioblastoma, 7 had renal cell carcinoma, 8 had renal cysts, 4 had pheochromocytoma, and 5 had pancreatic cysts. 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 5029 1826 58 3 10191516 10191516 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5029 https://civicdb.org/links/variants/1826 https://civicdb.org/links/genes/58 false VHL 7428 S65* (c.194C>A) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation found in VHL type 1 family (lineage 80). This provides strong evidence of pathogenicity as it is a null variant in a gene where loss of function is a known mechanism of disease (ACMG code: PVS1). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5033 1811 58 3 10183725 10183725 C A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5033 https://civicdb.org/links/variants/1811 https://civicdb.org/links/genes/58 false VHL 7428 S65W (c.194C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 1 family (lineage 53). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5034 1787 58 3 10183725 10183725 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5034 https://civicdb.org/links/variants/1787 https://civicdb.org/links/genes/58 false VHL 7428 E70* (c.208G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation was found in a VHL type 1 family (lineage 179). This provides strong evidence of pathogenicity as it is a null variant in a gene where loss of function is a known mechanism of disease (ACMG code: PVS1). Relevant HPO terms: hemangioblastoma, Renal cell carcinoma, Pheochromocytoma. 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5035 1834 58 3 10183739 10183739 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5035 https://civicdb.org/links/variants/1834 https://civicdb.org/links/genes/58 false VHL 7428 F76S (c.227T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 1 family (lineage 132). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5037 1835 58 3 10183758 10183758 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5037 https://civicdb.org/links/variants/1835 https://civicdb.org/links/genes/58 false VHL 7428 L101G (c.301_302delinsGG) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 1 family (lineage 103). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 2 accepted 5040 1838 58 3 10183832 10183833 CT GG ENST00000256474.2 75 GRCh37 Note that there is a different variant reported at this amino acid position of VHL in ClinVar: NM_000551.3(VHL):c.302T>C (p.Leu101Pro; L101P) (https://www.ncbi.nlm.nih.gov/clinvar/variation/480963/) Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5040 https://civicdb.org/links/variants/1838 https://civicdb.org/links/genes/58 false VHL 7428 T105P (c.313A>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in VHL type 1 family (lineage 208). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 2 accepted 5041 1839 58 3 10183844 10183844 A C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5041 https://civicdb.org/links/variants/1839 https://civicdb.org/links/genes/58 false VHL 7428 R107P (c.320G>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 1 family (lineage 76). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5042 1840 58 3 10183851 10183851 G C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5042 https://civicdb.org/links/variants/1840 https://civicdb.org/links/genes/58 false VHL 7428 R113* (c.337C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation was found in a VHL type 1 family (lineage 81). Only moderate evidence for pathogenicity because protein length changes as a result of stop-loss variant (ACMG code: PM4). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5043 1796 58 3 10183868 10183868 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5043 https://civicdb.org/links/variants/1796 https://civicdb.org/links/genes/58 false VHL 7428 W117C (c.351G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in 2 VHL type 1 families (lineage 83 and 146).Discovered the presence of the same missense mutation in another VHL type 1 family, so I changed evidence statement to include findings from both VHL families. 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5044 1767 58 3 10188208 10188208 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5044 https://civicdb.org/links/variants/1767 https://civicdb.org/links/genes/58 false VHL 7428 L118fs (c.352_353insA) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This mutation causes stop codon at amino acid 131 and was found in a VHL type 1 family (lineage 13). This provides strong evidence of pathogenicity as it is a null variant in a gene where loss of function is a known mechanism of disease (ACMG code: PVS1). Relevant HPO terms: hemangioblastoma, Renal cell carcinoma, Pheochromocytoma. 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5045 1841 58 3 10188209 10188210 A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/5045 https://civicdb.org/links/variants/1841 https://civicdb.org/links/genes/58 false VHL 7428 N131T (c.392A>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 1 family (lineage 86). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5046 2580 58 3 10188249 10188249 A C ENST00000256474.2 75 GRCh37 A similar but distinct variant the same position has been reported in ClinVar (c.392A>G (p.Asn131Ser); https://www.ncbi.nlm.nih.gov/clinvar/variation/496062/). It involves the same base position but a different nucleotide change leading to a different amino acid change. Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5046 https://civicdb.org/links/variants/2580 https://civicdb.org/links/genes/58 false VHL 7428 T133fs (c.397del) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This mutation causes an early stop codon at position 158 and was found in a VHL type 1 family (lineage 64). This provides strong evidence of pathogenicity as it is a null variant in a gene where loss of function is a known mechanism of disease (ACMG code: PVS1). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5047 1843 58 3 10188252 10188252 A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5047 https://civicdb.org/links/variants/1843 https://civicdb.org/links/genes/58 false VHL 7428 D143fs (c.430delG) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This mutation causes an early stop codon at position 158 and was found in a VHL type 1 family (lineage 119). Only moderate evidence for pathogenicity because protein length changes as a result of deletion in a nonrepeat region and stop-loss variant (ACMG code: PM4). Relevant HPO terms: hemangioblastoma, Renal cell carcinoma, Pheochromocytoma. 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5048 1844 58 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/5048 https://civicdb.org/links/variants/1844 https://civicdb.org/links/genes/58 false VHL 7428 R161* (c.481C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation was found in 3 VHL type 1 families and one VHL type 2 family (lineages 184, 93, 22, 92). Only moderate evidence for pathogenicity because protein length changes as a result of stop-loss variant (ACMG code: PM4). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5049 1804 58 3 10191488 10191488 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5049 https://civicdb.org/links/variants/1804 https://civicdb.org/links/genes/58 false VHL 7428 C162F (c.485G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 1 family (lineage 69). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 2 accepted 5050 1773 58 3 10191492 10191492 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5050 https://civicdb.org/links/variants/1773 https://civicdb.org/links/genes/58 false VHL 7428 Q164* (c.490C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation was found in a VHL type 1 family (lineage 141). This provides strong evidence of pathogenicity as it is a null variant in a gene where loss of function is a known mechanism of disease (ACMG code: PVS1). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5051 1845 58 3 10191497 10191497 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5051 https://civicdb.org/links/variants/1845 https://civicdb.org/links/genes/58 false VHL 7428 R167W (c.499C>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in six VHL type 2 families (lineages 202, 47, 102, 106, 153, 109). Two of these families (47 and 109) were previously reported in Chen et al 1995 or Zbar et al 1996. 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 4 accepted 5052 1747 58 3 10191506 10191506 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/5052 https://civicdb.org/links/variants/1747 https://civicdb.org/links/genes/58 false VHL 7428 Y175D (c.523T>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 1 family (lineage 7). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5053 1846 58 3 10191530 10191530 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5053 https://civicdb.org/links/variants/1846 https://civicdb.org/links/genes/58 false VHL 7428 V181fs (c.540_543del) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This mutation causes an early stop codon at amino acid 200 and was found in a VHL type 1 family (lineage 25). Only moderate evidence for pathogenicity because protein length changes as a result of deletions in a nonrepeat region and stop-loss variant (ACMG code: PM4). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5054 1847 58 3 10191547 10191550 CGTC ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5054 https://civicdb.org/links/variants/1847 https://civicdb.org/links/genes/58 false VHL 7428 L184P (c.551T>C) Von Hippel-Lindau Disease 14175 Predisposing N/A C N/A 93 families that fulfilled the clinical criteria of VHL disease were assessed for germline mutations in the VHL gene, and mutations were found in all affected family members. The c.551T>C (p.L184P) mutation was found in a family (Lineage 14) in which members were clinically diagnosed with VHL presenting without pheochromocytoma (VHL type 1), however, no further phenotypic information about specific patients was provided. This mutation was recorded as c.764T>C in the paper, due to the use of an older VHL reference transcript. Genomic DNA was extracted from whole blood for analysis. Polymorphisms in the VHL gene were detected by southern blotting, and were further investigated by PCR and Sanger sequencing. Partial and total deletions of the VHL gene were investigated by southern blot. Relevant ACMG codes include: PP4, because the patient’s phenotype is highly specific for a disease with a single genetic etiology. 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 2 accepted 5055 1776 58 3 10191558 10191558 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/5055 https://civicdb.org/links/variants/1776 https://civicdb.org/links/genes/58 false VHL 7428 Y185* (c.555C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation was found in a VHL type 1 family (lineage 50). Only moderate evidence for pathogenicity because protein length changes as a result of stop-loss variant (ACMG code: PM4). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5056 1809 58 3 10191562 10191562 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5056 https://civicdb.org/links/variants/1809 https://civicdb.org/links/genes/58 false VHL 7428 E186* (c.556G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation was found in a VHL type 1 family (lineage 78). Only moderate evidence for pathogenicity because protein length changes as a result of stop-loss variant (ACMG code: PM4). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5057 1777 58 3 10191563 10191563 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5057 https://civicdb.org/links/variants/1777 https://civicdb.org/links/genes/58 false VHL 7428 Q96* (c.286C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation was found in a VHL type 1 family (lineage 48). Only moderate evidence for pathogenicity because protein length changes as a result of stop-loss variant (ACMG code: PM4). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5058 1848 58 3 10183817 10183817 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5058 https://civicdb.org/links/variants/1848 https://civicdb.org/links/genes/58 false VHL 7428 P86R (c.257C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 1 family (lineage 128). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5059 1849 58 3 10183788 10183788 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5059 https://civicdb.org/links/variants/1849 https://civicdb.org/links/genes/58 false VHL 7428 R161Q (c.482G>A) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 2 family (lineage 3). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5061 1746 58 3 10191489 10191489 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5061 https://civicdb.org/links/variants/1746 https://civicdb.org/links/genes/58 false VHL 7428 R167Q (c.500G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in six VHL type 2 families (lineages 100, 42, 44, 88, 105, 135). Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 4 accepted 5062 1739 58 3 10191507 10191507 G A ENST00000256474.2 75 GRCh37 R167Q is the most common point mutation in hereditary Von Hippel-Lindau (VHL) disease and disrupts the VHL genes binding to elongin C reducing the levels of the VHL-elongin B-elongin C (VBC) E3 ligase complex and inhibiting the ability of VHL to regulate HIF2α. This partial function in turn leads to an increased risk of tumorgenesis. VHL derived clear cell renal cell carcinoma models however have shown the proteasome inhibitors bortezomib and carfilzomib can act to stabilize mutant VHL-R167Q leading to downregulation of HIF2α and suprressed tumorgenesis. Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5062 https://civicdb.org/links/variants/1739 https://civicdb.org/links/genes/58 false VHL 7428 G144* (c.430G>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation was found in a VHL type 2 family (lineage 65). Only moderate evidence for pathogenicity because protein length changes as a result of stop-loss variant (ACMG code: PM4). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5064 1850 58 3 10188287 10188287 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:45 UTC https://civicdb.org/links/evidence_items/5064 https://civicdb.org/links/variants/1850 https://civicdb.org/links/genes/58 false VHL 7428 L188P (c.563T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 2 family (lineage 73). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5066 1852 58 3 10191570 10191570 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5066 https://civicdb.org/links/variants/1852 https://civicdb.org/links/genes/58 false VHL 7428 S111C (c.330_331delinsTT) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 2 family (lineage 174). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5067 1853 58 3 10183861 10183862 CA TT ENST00000256474.2 75 GRCh37 Note that there is a different variant reported at this amino acid position of VHL in ClinVar. Clinvar ID: 565557 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5067 https://civicdb.org/links/variants/1853 https://civicdb.org/links/genes/58 false GNAQ 2776 Mutation Uveal Melanoma 6039 Cabozantinib Predictive Supports B Sensitivity/Response Patients with metastatic melanoma (n=77; 48 cutaneous, 23 uveal, 6 mucosal) were enrolled in a phase II randomised discontinuation trial assessing cabozantinib. Patients received 100 mg cabozantinib daily for 12 weeks. Patients with stable disease (SD; RECIST; n=26) were randomly assigned to cabozantinib (n=13) or placebo (n=13). In the uveal melanoma cohort, 61% of patients (14/23, 61%) had SD at week 12. 9 patients had either a GNAQ (n=5) or GNA11 (n=4) mutation; only 10 patients were analyzed. Patients with GNAQ mutations remained on the study treatment from 1.4-10.3 months. The median PFS for the 23 patients with uveal melanoma was 4.8 months (41% PFS at 6 months) and median OS was 12.6 months. In the entire cohort, median overall PFS was 3.8 months (33% PFS at 6 months). After randomisation, median PFS for cabozantinib patients was 4.1 months and 2.8 months for placebo (HR 0.59, p=0.284). 28103611 PubMed Daud et al., 2017, Br. J. Cancer 2 accepted 5068 505 2317 9 80331003 80646374 ENST00000286548.4 75 GRCh37 Somatic 2017-07-20 15:24:28 UTC https://civicdb.org/links/evidence_items/5068 https://civicdb.org/links/variants/505 https://civicdb.org/links/genes/2317 false IDH2 3418 Mutation Acute Myeloid Leukemia 9119 Enasidenib Predictive Supports A Sensitivity/Response A first-in-human phase 1/2 trial assessing the pharmacology, safety and activity of Enasidenib in IDH2-mutant myeloid hematoblastosis patients. In the AML subgroup (n=176, (n=130 R140; n=45 R172; n=1 Other)) of included patients (n=239) the overall response rate was 40.3%, with median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) with complete response was 19.7 months. 28588020 PubMed Stein et al., 2017, Blood NCT01915498 4 accepted 5069 570 27 15 90626277 90645736 ENST00000330062.3 75 GRCh37 Somatic 2021-04-24 03:33:05 UTC https://civicdb.org/links/evidence_items/5069 https://civicdb.org/links/variants/570 https://civicdb.org/links/genes/27 false CTNNB1 1499 T41A Desmoid Tumor 0080366 Diagnostic Supports B Positive In this study a collection of 254 sporadic desmoid tumors were analysed for presence of mutations in CTNNB1. A mutation in exon 3 of the CTNNB1 gene was identified in 223 (88%) of the 254 cases. The CTNNB1 mutation spectra concerned mainly three point mutations in two codons (41 and 45): T41A was identified in 132 cases (59%); S45F was identified in 49 samples (22%); and S45P was identified in 27 samples (12%). None of the 175 lesions mimicking desmoid tumors analyzed harbored any CTNNB1 mutations. 22766794 PubMed Le Guellec et al., 2012, Mod. Pathol. 4 accepted 5070 1285 1290 3 41266124 41266124 A G ENST00000349496.5 75 GRCh37 Somatic 2020-10-09 16:10:06 UTC https://civicdb.org/links/evidence_items/5070 https://civicdb.org/links/variants/1285 https://civicdb.org/links/genes/1290 false CTNNB1 1499 S45F Desmoid Tumor 0080366 Diagnostic Supports B Positive In this study a collection of 254 sporadic desmoid tumors were analysed for presence of mutations in CTNNB1. A mutation in exon 3 of the CTNNB1 gene was identified in 223 (88%) of the 254 cases. The CTNNB1 mutation spectra concerned mainly three point mutations in two codons (41 and 45): T41A was identified in 132 cases (59%); S45F was identified in 49 samples (22%); and S45P was identified in 27 samples (12%). None of the 175 lesions mimicking desmoid tumors analyzed harbored any CTNNB1 mutations. 22766794 PubMed Le Guellec et al., 2012, Mod. Pathol. 4 accepted 5071 1286 1290 3 41266137 41266137 C T ENST00000349496.5 75 GRCh37 Somatic 2020-10-09 16:10:06 UTC https://civicdb.org/links/evidence_items/5071 https://civicdb.org/links/variants/1286 https://civicdb.org/links/genes/1290 false CTNNB1 1499 S45P Desmoid Tumor 0080366 Diagnostic Supports B Positive In this study a collection of 254 sporadic desmoid tumors were analysed for presence of mutations in CTNNB1. A mutation in exon 3 of the CTNNB1 gene was identified in 223 (88%) of the 254 cases. The CTNNB1 mutation spectra concerned mainly three point mutations in two codons (41 and 45): T41A was identified in 132 cases (59%); S45F was identified in 49 samples (22%); and S45P was identified in 27 samples (12%). None of the 175 lesions mimicking desmoid tumors analyzed harbored any CTNNB1 mutations. 22766794 PubMed Le Guellec et al., 2012, Mod. Pathol. 3 accepted 5072 1287 1290 3 41266136 41266136 T C ENST00000349496.5 75 GRCh37 Somatic 2020-10-09 16:10:06 UTC https://civicdb.org/links/evidence_items/5072 https://civicdb.org/links/variants/1287 https://civicdb.org/links/genes/1290 false VHL 7428 V170D (c.509T>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Germline mutation analysis of 469 VHL families reveled 300 mutations. The most common germline mutations were identified between codons 75-82, between codons 157-189 (Elongin binding domain) and at the splice site between exons 2 and 3. The association between mutations in codon 167 and pheochromocytoma was detected in all nationalities tested. This missense mutation was found in a VHL type 2 family (family ID R-D). 8956040 PubMed Zbar et al., 1996, Hum. Mutat. 3 accepted 5092 1826 58 3 10191516 10191516 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5092 https://civicdb.org/links/variants/1826 https://civicdb.org/links/genes/58 false VHL 7428 R64P (c.191G>C) Von Hippel-Lindau Disease 14175 Paraganglioma,Pheochromocytoma,Renal cell carcinoma Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This missense mutation was found in a VHL type 2B family of 6 patients with the mutation, but incomplete penetrance (family no. 1; pedigree in Figure 2). A 59 yo carrier had no VHL manifestations but 2 unaffected children without the mutation and 2 children with the mutation, 1 with pheochromocytoma aged 32 and a 40 yo with no clinical manifestations. The 59 year old also had an affected family with the mutation - a parent (renal cell carcinoma) and a affected sibling (pheochromocytoma) and their child (paraganglioma) - and 4 unaffected siblings without the mutation. Only supporting evidence for pathogenicity because of cosegregation of the disease with multiple affected family in a gene definitively known to cause the disease (ACMG code: PP1). 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 5094 1867 58 3 10183722 10183722 G C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5094 https://civicdb.org/links/variants/1867 https://civicdb.org/links/genes/58 false VHL 7428 Q164* (c.490C>T) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Epididymal cyst,Renal cell carcinoma Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was found in a VHL type 1 patient with cerebellar hemangioblastomas, epididymal cyst, and renal cell carcinoma (family no. 21). 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 5096 1845 58 3 10191497 10191497 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/5096 https://civicdb.org/links/variants/1845 https://civicdb.org/links/genes/58 false VHL 7428 Q195* (c.583C>T) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Retinal capillary hemangioma,Pheochromocytoma Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was found in 2 VHL type 2A family members (family no. 23). Both had retinal hemangioblastomas, one had cerebellar hemangioblastomas, and one had pheochromocytoma. Only supportive evidence for pathogenicity because patient’s phenotype or family history is highly specific for a disease with a single genetic etiology (ACMG code: PP4). 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 5097 1810 58 3 10191590 10191590 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5097 https://civicdb.org/links/variants/1810 https://civicdb.org/links/genes/58 false VHL 7428 E189fs (c.565del) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Multiple renal cysts Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation causes an early stop codon at amino acid 201 and was found in a VHL type 1 patient with cerebellar hemangioblastomas and renal cysts (family no. 27). 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 5098 1869 58 3 10191572 10191572 G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5098 https://civicdb.org/links/variants/1869 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.340+1G>A) Von Hippel-Lindau Disease 14175 Renal cell carcinoma Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was detected in a VHL patient with renal cell carcinoma (family no. 31). 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 5099 2114 58 3 10183872 10183872 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/5099 https://civicdb.org/links/variants/2114 https://civicdb.org/links/genes/58 false VHL 7428 G93S (c.277G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was found in 2 VHL type 2C family members (family no. 9), both with pheochromocytoma. 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 5100 1859 58 3 10183808 10183808 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/5100 https://civicdb.org/links/variants/1859 https://civicdb.org/links/genes/58 false VHL 7428 I151T (c.452T>C) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Renal cell carcinoma Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was detected in a VHL patient with cerebellar hemangioblastomas and renal cell carcinoma (family no. 11). Only supporting evidence for pathogenicity because Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology (ACMG code: PP4). Relevant HPO terms: Cerebellar hemangioblastoma, Renal cell carcinoma. 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 5101 1871 58 3 10188309 10188309 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5101 https://civicdb.org/links/variants/1871 https://civicdb.org/links/genes/58 false VHL 7428 L158P (c.473T>C) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was found in 2 VHL family members with retinal hemangioblastomas (family no.13). 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 5103 1738 58 3 10191480 10191480 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5103 https://civicdb.org/links/variants/1738 https://civicdb.org/links/genes/58 false VHL 7428 S65L (c.194C>T) Von Hippel-Lindau Disease 14175 Epididymal cyst,Cerebellar hemangioblastoma,Renal cell carcinoma,Multiple renal cysts,Pancreatic cysts Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was found in a VHL type 1 patient with cerebellar hemangioblastomas, renal cell carcinoma, renal cysts, epididymal cyst, and pancreatic cysts (family no. 2). 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 5104 1788 58 3 10183725 10183725 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5104 https://civicdb.org/links/variants/1788 https://civicdb.org/links/genes/58 false VHL 7428 S68P (c.202T>C) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was detected in a VHL family with 2 individuals with retinal hemangioblastomas (family no. 4). 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 5105 1873 58 3 10183733 10183733 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5105 https://civicdb.org/links/variants/1873 https://civicdb.org/links/genes/58 false VHL 7428 R161Q (c.482G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting a residue on surface of pVHL protein core, was found in 2 VHL type 2C families with 4 patients altogether. All 4 patients had pheochromocytoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5125 1746 58 3 10191489 10191489 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5125 https://civicdb.org/links/variants/1746 https://civicdb.org/links/genes/58 false VHL 7428 N131fs (c.390_391del) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This frameshift mutation causes an early stop codon at amino acid 133 and was found in a VHL patient with cerebellar hemangioblastomas. This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). Relevant HPO terms: Cerebellar hemangioblastoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5128 1800 58 3 10188247 10188248 TA ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5128 https://civicdb.org/links/variants/1800 https://civicdb.org/links/genes/58 false VHL 7428 N78H (c.232A>C) Renal Cell Carcinoma 4450 Retinal capillary hemangioma,Renal cell carcinoma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting a residue within the pVHL protein core, was found in 2 VHL family members. Both had retinal angiomas and cerebellar hemangioblastomas. One had renal cell carcinoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5130 1754 58 3 10183763 10183763 A C ENST00000256474.2 75 GRCh37 Rare Germline 2017-10-26 20:23:45 UTC https://civicdb.org/links/evidence_items/5130 https://civicdb.org/links/variants/1754 https://civicdb.org/links/genes/58 false VHL 7428 Q132P (c.395A>C) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Cerebellar hemangioblastoma,Renal cell carcinoma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting a residue on surface of pVHL, was found in a VHL family with retinal angiomas, cerebellar hemangioblastomas, and renal cell carcinoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5131 2125 58 3 10188252 10188252 A C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5131 https://civicdb.org/links/variants/2125 https://civicdb.org/links/genes/58 false VHL 7428 Q164R (c.491A>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). This missense mutation was found in a VHL patient with retinal hemangioblastomas and pheochromocytoma. Relevant HPO terms: Retinal hemangioblastoma, Pheochromocytoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5133 1856 58 3 10191498 10191498 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5133 https://civicdb.org/links/variants/1856 https://civicdb.org/links/genes/58 false VHL 7428 Q195* (c.583C>T) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Cerebellar hemangioblastoma,Pheochromocytoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This nonsense mutation was found in 2 VHL families with 9 patients altogether. Eight had retinal hemangioblastoma, one had cerebellar hemangioblastomas, 3 had renal cell carcinoma, and 5 had pheochromcytoma. This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5134 1810 58 3 10191590 10191590 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5134 https://civicdb.org/links/variants/1810 https://civicdb.org/links/genes/58 false VHL 7428 Q73* (c.217C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangioblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This nonsense mutation was found in 3 VHL families with 9 patients altogether. Seven had retinal hemangioblastomas, 3 had cerebellar hemangioblastomas, and 5 had renal cell carcinoma. Only moderate evidence of pathogenicity since the protein length changes as a result of a stop-loss variants (ACMG code: PM4). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5135 1752 58 3 10183748 10183748 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5135 https://civicdb.org/links/variants/1752 https://civicdb.org/links/genes/58 false VHL 7428 E94* (c.280G>T) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal hemangioblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This nonsense mutation was found in 2 VHL families with 6 patients altogether. All six had retinal hemangioblastomas and 2 had cerebellar hemangioblastomas. This study contains very strong evidence for pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5137 1794 58 3 10183811 10183811 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:49 UTC https://civicdb.org/links/evidence_items/5137 https://civicdb.org/links/variants/1794 https://civicdb.org/links/genes/58 false VHL 7428 P103FS (c.309_310delTG) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal hemangioblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This frameshift mutation causes an early stop codon at amino acid 130 and was found in a VHL type 1 family of 16 patients. Six patients had retinal hemangioblastomas, 10 had cerebellar hemangioblastomas, and 2 had renal cell carcinoma. This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5138 1795 58 3 10183840 10183841 TG ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5138 https://civicdb.org/links/variants/1795 https://civicdb.org/links/genes/58 false VHL 7428 G114C (c.340G>T) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). This missense mutation, affecting residue within the pVHL protein core, was found in a VHL patient with cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 2 accepted 5139 1797 58 3 10183871 10183871 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5139 https://civicdb.org/links/variants/1797 https://civicdb.org/links/genes/58 false VHL 7428 H115P (c.344A>C) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). This missense mutation, affecting residue on the surface of pVHL, was found in a VHL type 1 patient with retinal hemangioblastomas and cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5140 1885 58 3 10188201 10188201 A C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:49 UTC https://civicdb.org/links/evidence_items/5140 https://civicdb.org/links/variants/1885 https://civicdb.org/links/genes/58 false VHL 7428 I151T (c.452T>C) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). A missense mutation, affecting residue within the pVHL protein core, was found in 2 VHL families with 4 patients. Two had retinal hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Retinal hemangioblastoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 2 accepted 5141 1871 58 3 10188309 10188309 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5141 https://civicdb.org/links/variants/1871 https://civicdb.org/links/genes/58 false VHL 7428 L118P (c.353T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue within the pVHL protein core, was found in 3 VHL families of 7 patients altogether. Six had retinal hemangioblastomas, one had renal cell carcinoma, 6 had cerebellar hemangioblastomas, and 4 pheochromocytoma. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Renal cell carcinoma. retinal hemangioblastoma cerebellar hemangioblastoma, pheochromocytoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5143 1798 58 3 10188210 10188210 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5143 https://civicdb.org/links/variants/1798 https://civicdb.org/links/genes/58 false VHL 7428 L128R (c.383T>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue within the pVHL protein core, was found in a VHL type 1 family with retinal hemangioblastomas and cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemanioblastoma and retinal hemangioblastoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5144 1886 58 3 10188240 10188240 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5144 https://civicdb.org/links/variants/1886 https://civicdb.org/links/genes/58 false VHL 7428 L153fs (c.457delC) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This frameshift mutation causes an early stop codon at amino acid 158 and was found in 2 VHL families with 5 patients altogether. Three had retinal angiomas, 5 had cerebellar hemangioblastomas, and 2 had renal cell carcinoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5145 1802 58 3 10188317 10188317 C ENST00000256474.2 75 GRCh37 There are two similar variants in ClinVar at this exact genomic location with ClinVar IDs: 526670 and 486714. Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5145 https://civicdb.org/links/variants/1802 https://civicdb.org/links/genes/58 false VHL 7428 L158V (c.472C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). This mutation was found in a VHL type 1 patient with retinal hemangioblastomas and cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2).Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5146 1803 58 3 10191479 10191479 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5146 https://civicdb.org/links/variants/1803 https://civicdb.org/links/genes/58 false VHL 7428 L169P (c.506T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue on the surface of pVHL, was found in a VHL type 1 family with retinal hemangioblastomas and renal cell carcinoma. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5147 1887 58 3 10191513 10191513 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5147 https://civicdb.org/links/variants/1887 https://civicdb.org/links/genes/58 false VHL 7428 L178R (c.533T>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue on the surface of pVHL protein core, was found in a VHL type 1 patient with retinal hemanioblastomas and cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5148 1888 58 3 10191540 10191540 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5148 https://civicdb.org/links/variants/1888 https://civicdb.org/links/genes/58 false VHL 7428 L178P (c.533T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue on the surface of pVHL, was found in a VHL type 1 family of 3. All family members had retinal hemangioblastomas and cerebellar hemangioblastomas. Two had renal cell carcinoma. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5149 1748 58 3 10191540 10191540 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5149 https://civicdb.org/links/variants/1748 https://civicdb.org/links/genes/58 false VHL 7428 L89P (c.266T>C) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Cerebellar hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue within the pVHL protein core, was found in a VHL type 1 patient with retinal hemangioblastomas, cerebellar hemangioblastomas, and renal cell carcinoma. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 2 accepted 5150 1793 58 3 10183797 10183797 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5150 https://civicdb.org/links/variants/1793 https://civicdb.org/links/genes/58 false VHL 7428 M54fs (c.161dup) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). This mutation was found in 2 VHL type 1 family members with cerebellar hemangioblastomas. ACMG codes as follows: Protein length changes as a result of insertion in a nonrepeat region and stop-loss variant (PM4). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). Relevant HPO terms: Cerebellar hemangioblastoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5151 1889 58 3 10183691 10183692 T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5151 https://civicdb.org/links/variants/1889 https://civicdb.org/links/genes/58 false VHL 7428 F136S (c.407T>C) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue within the pVHL protein core, was found in 2 VHL families of 5 patients altogether. Three had retinal hemangioblastomas, 4 had cerebellar hemangioblastomas, 3 had renal cell carcinoma. ACMG codes as follows: supporting evidence for pathogenicity because of cosegregation of disease with multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5152 1801 58 3 10188264 10188264 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5152 https://civicdb.org/links/variants/1801 https://civicdb.org/links/genes/58 false VHL 7428 F91* (c.272_273delinsAA) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Cerebellar hemangioblastoma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangioblastoma and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. c.272T>A and 273C>A mutations (HGVS nomenclature as c.272_273delinsAA) leads to this this nonsense mutation which was found in a VHL with retinal hemangioblastomas and cerebellar hemangioblastomas. Only moderate evidence of pathogenicity since the protein length changes as a result of a stop-loss variant (ACMG code: PM4). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5153 1893 58 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/5153 https://civicdb.org/links/variants/1893 https://civicdb.org/links/genes/58 false VHL 7428 P154L (c.461C>T) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Pheochromocytoma,Renal cell carcinoma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). This missense mutation is within the protein core and was found in a VHL family with 6 patients. One patient had retinal hemangioblastomas, 2 had cerebellar hemangioblastomas, 3 had renal cell carcinoma, 2 had pheochromocytoma. Only supporting evidence of pathogenicity because of cosegregation of disease with multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 2 accepted 5154 1782 58 3 10188318 10188318 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:49 UTC https://civicdb.org/links/evidence_items/5154 https://civicdb.org/links/variants/1782 https://civicdb.org/links/genes/58 false VHL 7428 P59fs (c.176delC) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangioblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This frameshift mutation, affecting residue within the pVHL protein core, was found in a VHL type 1 family of 5 patients. Three had retinal hemangioblastomas, 4 had cerebellar hemangioblastomas, and 2 had renal cell carcinoma. This mutation also causes an early stop codon at amino acid 66. ACMG codes as follows: Protein length changes as a result of in-frame deletions in a nonrepeat region and stop-loss variant (PM4). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5155 1929 58 3 10183707 10183707 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/5155 https://civicdb.org/links/variants/1929 https://civicdb.org/links/genes/58 false VHL 7428 P86R (c.257C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue within the pVHL protein core, was found in a VHL type 1 family with retinal hemangiolastomas and renal cell carcinoma. Only supporting evidence of pathogenicity because of cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). Relevant HPO terms: retinal hemangioblastoma and renal cell carcinoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5156 1849 58 3 10183788 10183788 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5156 https://civicdb.org/links/variants/1849 https://civicdb.org/links/genes/58 false VHL 7428 P86L (c.257C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue within the pVHL protein core, was found in a VHL patient with retinal hemangioblastomas and cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5157 1760 58 3 10183788 10183788 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5157 https://civicdb.org/links/variants/1760 https://civicdb.org/links/genes/58 false VHL 7428 P86S (c.256C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue within the pVHL protein core, was found in a VHL patient with cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5158 1902 58 3 10183787 10183787 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5158 https://civicdb.org/links/variants/1902 https://civicdb.org/links/genes/58 false VHL 7428 S65L (c.194C>T) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. This missense mutation was found in 4 VHL families of 11 patients altogether. Ten had retinal hemangioblastomas, 4 had cerebellar hemangioblastomas, and 2 had renal cell carcinoma. ACMG codes as follows: supporting evidence for pathogenicity because of cosegregation of disease with multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). Two other amino acid changes at this site were also reported in this publication in association with disease (S65W and S65P). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 2 accepted 5159 1788 58 3 10183725 10183725 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/5159 https://civicdb.org/links/variants/1788 https://civicdb.org/links/genes/58 false VHL 7428 S65P (c.193T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). This missense mutation was found in a VHL patient with retinal hemangioblastomas and cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5160 1903 58 3 10183724 10183724 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5160 https://civicdb.org/links/variants/1903 https://civicdb.org/links/genes/58 false VHL 7428 S65W (c.194C>G) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Renal cell carcinoma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). A missense mutation, affecting residue within the pVHL protein core, was found in a VHL family with 8 affected individuals including 6 with retinal hemangioblastomas, 5 with cerebellar hemangioblastomas, and 1 with renal cell carcinoma. ACMG codes as follows: supporting evidence for pathogenicity because of cosegregation of disease with multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5161 1787 58 3 10183725 10183725 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5161 https://civicdb.org/links/variants/1787 https://civicdb.org/links/genes/58 false VHL 7428 S72P (c.214T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue on the surface of pVHL, was found in two VHL families of 4 patients altogether. One patient had retinal hemagioblastomas and two had cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5162 1904 58 3 10183745 10183745 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5162 https://civicdb.org/links/variants/1904 https://civicdb.org/links/genes/58 false VHL 7428 S72fs (c.214del) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Cerebellar hemangioblastoma,Retinal capillary hemangioma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangioblastoma and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation causes a frameshift, an early stop codon at amino acid 158, and was found in a VHL family with 3 affected members: 2 had retinal hemangioblastoma, 2 had cerebellar hemangioblastomas, and 1 had renal cell carcinoma. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5163 1816 58 3 10183745 10183745 T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/5163 https://civicdb.org/links/variants/1816 https://civicdb.org/links/genes/58 false VHL 7428 L135fs (c.404del) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Cerebellar hemangioblastoma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. VHL L135FS (c.404del) results in a frameshift, an early stop codon at amino acid 158, and was found in a VHL family of 2, both with retinal hemangioblastomas and 1 with cerebellar hemangioblastomas. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5165 1906 58 3 10188260 10188260 T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5165 https://civicdb.org/links/variants/1906 https://civicdb.org/links/genes/58 false VHL 7428 R176fs (c.526del) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma,Cerebellar hemangioblastoma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal hemangioblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. VHL R176fs (c.526del) causes a frameshift, an early stop codon at amino acid 201, and was found in two VHL families of 3 patients. One patient had retinal hemangioblastomas, three had cerebellar hemangioblastomas, and one had renal cell carcinoma. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5166 1780 58 3 10191533 10191533 A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5166 https://civicdb.org/links/variants/1780 https://civicdb.org/links/genes/58 false VHL 7428 R177fs (c.528del) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Renal cell carcinoma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal hemangioblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. VHL R177fs (c.528del) causes a frameshift, a stop codon at amino acid 201, and was found in a VHL family of 7, 3 with cerebellar hemangioblastomas and 3 with renal cell carcinoma. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5167 1907 58 3 10191535 10191535 G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5167 https://civicdb.org/links/variants/1907 https://civicdb.org/links/genes/58 false VHL 7428 W88R (c.262T>A) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Retinal capillary hemangioma,Renal cell carcinoma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. This missense mutation, affecting residue on the surface of pVHL, was found in a VHL type 1 patient with retinal hemangioblastoms, cerebellar hemangioblastomas, and renal cell carcinoma. ACMG codes as follows: Supporting evidence of pathogenicity because of a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 2 accepted 5168 1761 58 3 10183793 10183793 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5168 https://civicdb.org/links/variants/1761 https://civicdb.org/links/genes/58 false VHL 7428 W88* (c.264G>A) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma,Cerebellar hemangioblastoma,Pheochromocytoma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangoblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This nonsense mutation was found in a VHL family with 3 affected members, 1 had retinal hemangioblastomas, 1 had cerebellar hemangioblastomas, 2 had renal cell carcinoma, and 1 had pheochromocytoma. There is very strong evidence for pathogenicity in the form of a nonsense variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5169 1908 58 3 10183795 10183795 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/5169 https://civicdb.org/links/variants/1908 https://civicdb.org/links/genes/58 false VHL 7428 Y185* (c.555C>G) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Cerebellar hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal hemangiobastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in 3 VHL families with 4 patients altogether. All four had retinal hemangioblastomas and cerebellar hemangioblastomas. Two had renal cell carcinoma. There is very strong evidence for pathogenicity in the form of a nonsense variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5170 1809 58 3 10191562 10191562 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5170 https://civicdb.org/links/variants/1809 https://civicdb.org/links/genes/58 false VHL 7428 V155E (c.464T>A) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). This missense mutation was found in a VHL type 2B family with retinal hemangioblastomas, cerebellar hemangioblastomas, and pheochromocytoma. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Pheochromocytoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5171 1909 58 3 10191471 10191471 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5171 https://civicdb.org/links/variants/1909 https://civicdb.org/links/genes/58 false VHL 7428 V170G (c.509T>G) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma,Pheochromocytoma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). A missense mutation, affecting residue on the surface of pVHL, was found in a VHL family of 4, 3 with retinal hemangioblastomas, 1 with renal cell carcinoma, and 1 with pheochromocytoma. ACMG codes as follows: supporting evidence for pathogenicity because of cosegregation of disease with multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). Supporting evidence of pathogenicity because missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 2 accepted 5172 1935 58 3 10191516 10191516 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5172 https://civicdb.org/links/variants/1935 https://civicdb.org/links/genes/58 false VHL 7428 F76fs (c.223_224insT) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Hemangioblastoma Predisposing Supports C Uncertain Significance Germline VHL mutations were found in all Korean patients who fulfilled clinical criteria for VHL disease. No mutation of VHL was detected in other patients who did not meet clinical criteria. In all cases, samples from both parents were not available and evidence of de novo mutations could not further be evaluated. This variant is predicted to cause a frameshift and premature stop codon. This variant was found in a 24 year old Korean female with hemangioblastomas of the central nervous system and retinal hemangioblastomas (patient no. 4). There is very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). 19270817 PubMed Cho et al., 2009, J. Korean Med. Sci. 3 accepted 5174 1912 58 3 10183754 10183755 T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/5174 https://civicdb.org/links/variants/1912 https://civicdb.org/links/genes/58 false VHL 7428 C162R (c.484T>C) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Germline VHL mutations were found in all Korean patients who fulfilled clinical criteria for VHL disease. No mutation of VHL was detected in other patients who did not meet clinical criteria. In all cases, samples from both parents were not available and evidence of de novo mutations could not further be evaluated. This missense mutation (p.C162R) was found in a 30 year old Korean female with hemangioblastomas of the central nervous system, retinal hemangioblastomas, and renal cell carcinoma (patient no. 7). This patient's phenotype is highly specific for a disease with a single etiology (ACMG code: PP4). Relevant HPO terms: hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. 19270817 PubMed Cho et al., 2009, J. Korean Med. Sci. 2 accepted 5175 1772 58 3 10191491 10191491 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5175 https://civicdb.org/links/variants/1772 https://civicdb.org/links/genes/58 false VHL 7428 K196* (c.586A>T) Von Hippel-Lindau Disease 14175 Hemangioblastoma Predisposing Supports C Uncertain Significance Germline VHL mutations were found in all Korean patients who fulfilled clinical criteria for VHL disease. No mutation of VHL was detected in other patients who did not meet clinical criteria. In all cases, samples from both parents were not available and evidence of de novo mutations could not further be evaluated. This nonsense mutation was found in a 22 year old Korean female with hemangioblastomas of the central nervous system (patient no. 3). There is very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). 19270817 PubMed Cho et al., 2009, J. Korean Med. Sci. 2 accepted 5176 1913 58 3 10191593 10191593 A T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5176 https://civicdb.org/links/variants/1913 https://civicdb.org/links/genes/58 false VHL 7428 R113* (c.337C>T) Von Hippel-Lindau Disease 14175 Hemangioblastoma Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This nonsense mutation was found in a 23 year old VHL patient with no family history and hemangioblastomas of the central nervous system (index case 77). There is very strong evidence for pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 3 accepted 5177 1796 58 3 10183868 10183868 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5177 https://civicdb.org/links/variants/1796 https://civicdb.org/links/genes/58 false VHL 7428 R120G (c.358A>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 24 year old VHL patient with hemangioblastomas of the central nervous system, retinal hemangioblastomas, pancreatic cysts, clear cell renal cell carcinoma, and multiple renal cysts (index case 100). ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology (PP4)Relevant HPO terms: Renal cell carcinoma, hemangioblastoma, retinal hemangioblastoma, pheochromocytoma, multiple pancreatic cysts and multiple renal cysts. 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 3 accepted 5178 1914 58 3 10188215 10188215 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/5178 https://civicdb.org/links/variants/1914 https://civicdb.org/links/genes/58 false VHL 7428 R161Q (c.482G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 8 year old VHL patient with pheochromocytoma (index case 244). ACMG codes as follows: Supporting evidence of pathogenicity because this is a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 3 accepted 5179 1746 58 3 10191489 10191489 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5179 https://civicdb.org/links/variants/1746 https://civicdb.org/links/genes/58 false VHL 7428 R167L (c.500G>T) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Hemangioblastoma,Pheochromocytoma Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. A novel, missense mutation, was found in 57 year old and 31 year old patients with hemangioblastomas of the central nervous system, retinal hemangioblastomas and pheochromocytoma (index cases 24, 232). This mutation was predicted to alter the linker region between beta and alpha domains of VHL protein. ACMG codes as follows: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (PM5). Patient's phenotype is highly specific for a disease with a single genetic etiology (PP4). 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 2 accepted 5183 1916 58 3 10191507 10191507 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5183 https://civicdb.org/links/variants/1916 https://civicdb.org/links/genes/58 false VHL 7428 R167W (c.499C>T) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Renal cyst,Hemangioblastoma,Pheochromocytoma Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in five VHL patients. The 13 yr old patient had pheochromocytoma (PH) (index case 164). The 25 yr old patient had pheochromocytoma and multiple renal cysts (index case 260). The 27 yr old patient had pheochromocytoma, hemangioblastomas of the central nervous system (CNS) and retinal hemangioblastoma (index case 6). The 30 yr old patient had CNS hemangioblastomas and pheochromocytoma (index case 217). The 33 yr old patient had retinal hemangioblastomas and multiple renal cysts (index case 44). Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 2 accepted 5184 1747 58 3 10191506 10191506 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5184 https://civicdb.org/links/variants/1747 https://civicdb.org/links/genes/58 false VHL 7428 D126FS (c.375_376insC) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Pathogenic In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This de novo frameshift mutation was found in a 24 yr old VHL patient with no family history and central nervous system and retinal hemangioblastomas (index case 107). This variant also potentially alters the beta domain of the VHL protein. ACMG codes as follows: Frameshift variant in a gene where loss-of-function is a known mechanism of disease (PVS1). De novo in a patient with the disease and no family history (PS2). 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 2 accepted 5188 1918 58 3 10188232 10188233 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5188 https://civicdb.org/links/variants/1918 https://civicdb.org/links/genes/58 false VHL 7428 C162F (c.485G>T) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Hemangioblastoma,Retinal capillary hemangioma,Multiple renal cysts,Pheochromocytoma Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 34 yr old VHL patient with multiple pancreatic cysts, pheochromocytoma, multiple renal cysts, and central nervous system and retinal hemangioblastomas (index case 74). There is supporting evidence for pathogenicity because the patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). Relevant HPO terms: Hemangioblastoma, retinal hemangioblastoma, multiple renal cysts, multiple pancreatic cysts, pheochromocytoma. 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 2 accepted 5189 1773 58 3 10191492 10191492 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5189 https://civicdb.org/links/variants/1773 https://civicdb.org/links/genes/58 false VHL 7428 E160FS (c.479_480delAG) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Clear cell renal cell carcinoma Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This frameshift mutation introduces a premature stop codon at amino acid 172 and was found in a 35 yr old VHL patient with hemangioblastomas of the central nervous system and clear cell renal cell carcinoma (index case 182). There is very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code : PVS1). Relevant HPO terms: hemangioblastoma, clear cell renal cell carcinoma. 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 2 accepted 5191 1919 58 3 10191486 10191487 AG ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5191 https://civicdb.org/links/variants/1919 https://civicdb.org/links/genes/58 false VHL 7428 H115Y (c.343C>T) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Pancreatic cysts,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 36 yr old VHL patient with multiple pancreatic cysts as well as central nervous system and retinal hemangioblastomas (index case 118). ACMG codes as follows: Supporting evidence of pathogenicity because this is a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 2 accepted 5193 1921 58 3 10188200 10188200 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5193 https://civicdb.org/links/variants/1921 https://civicdb.org/links/genes/58 false VHL 7428 L153P (c.458T>C) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Renal cyst,Multiple renal cysts,Hemangioblastoma Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 36 yr old VHL patient with multiple renal cysts as well as central nervous system and retinal hemangioblastoma (index case 191). ACMG codes as follows: Supporting evidence of pathogenicity because this is a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: hemangioblastoma, retinal hemangioblastoma, multiple renal cysts 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 2 accepted 5196 1923 58 3 10188315 10188315 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5196 https://civicdb.org/links/variants/1923 https://civicdb.org/links/genes/58 false VHL 7428 L169P (c.506T>C) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 21 yr old VHL patient with retinal hemangioblastomas (index case 344). ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 2 accepted 5197 1887 58 3 10191513 10191513 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5197 https://civicdb.org/links/variants/1887 https://civicdb.org/links/genes/58 false VHL 7428 L178P (c.533T>C) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Renal cyst,Pheochromocytoma,Multiple renal cysts,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 14 yr old VHL patient with retinal hemangioblastomas, multiple pancreatic cysts, pheochromocytoma, and multiple renal cysts (index case 160). This patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 2 accepted 5198 1748 58 3 10191540 10191540 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5198 https://civicdb.org/links/variants/1748 https://civicdb.org/links/genes/58 false VHL 7428 L184R (c.551T>G) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Hemangioblastoma,Clear cell renal cell carcinoma Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 44 yr old VHL patient with clear cell renal cell carcinoma as well as central nervous system and retinal hemangioblastomas (index case 363). ACMG codes as follows: Supporting evidence of pathogenicity because this is a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 2 accepted 5199 1808 58 3 10191558 10191558 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5199 https://civicdb.org/links/variants/1808 https://civicdb.org/links/genes/58 false VHL 7428 L188R (c.563T>G) Von Hippel-Lindau Disease 14175 Multiple renal cysts,Hemangioblastoma,Renal cyst Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This novel, missense mutation was found in a 48 yr old VHL patient with multiple renal cysts and hemangioblastomas of the central nervous system (index case 109). This variant potentially alters the alpha domain core of the VHL protein. ACMG codes as follows: Supporting evidence of pathogenicity because this is a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 2 accepted 5200 1924 58 3 10191570 10191570 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5200 https://civicdb.org/links/variants/1924 https://civicdb.org/links/genes/58 false VHL 7428 F136S (c.407T>C) Von Hippel-Lindau Disease 14175 Hemangioblastoma Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 30 yr old VHL patient with hemangioblastomas of the central nervous system (index case 207). ACMG codes as follows: Supporting evidence of pathogenicity because this is a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 2 accepted 5202 1801 58 3 10188264 10188264 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5202 https://civicdb.org/links/variants/1801 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Hemangioblastoma Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This deletion mutation was found in a 25 yr old VHL patient with multiple pancreatic cysts and hemangioblastomas of the central nervous system (index case 280). This study contains moderate support for pathogenicity because the protein length changes as a result changes as a result of in-frame deletions in a nonrepeat region (ACMG code: PM4). 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 2 accepted 5203 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:42 UTC https://civicdb.org/links/evidence_items/5203 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false VHL 7428 P138T (c.412C>A) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Pheochromocytoma Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This novel, missense mutation was found in a 21 yr old VHL patient with retinal hemangioblastomas and pheochromocytoma (index case 115). This variant potentially alters the beta domain core of the VHL protein. ACMG codes as follows: Supporting evidence of pathogenicity because this is a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 2 accepted 5205 1928 58 3 10188269 10188269 C A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5205 https://civicdb.org/links/variants/1928 https://civicdb.org/links/genes/58 false VHL 7428 S65W (c.194C>G) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Hemangioblastoma,Renal cyst Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, and none were present in 200 unaffected control individuals. This missense variant was found in a 33 yr old VHL patient with pancreatic cyst or tumour, renal cystic lesion and CNS hemangioblastoma (index case 214). ACMG codes as follows: supporting evidence of pathogenicity because Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology (PP4). 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 2 accepted 5212 1787 58 3 10183725 10183725 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5212 https://civicdb.org/links/variants/1787 https://civicdb.org/links/genes/58 false ATM 472 Underexpression Stomach Cancer 10534 Olaparib,Paclitaxel Combination Predictive Supports B Sensitivity/Response A randomized phase 2 trial investigating the efficiency of Olaparib plus Paclitaxel vs. Placebo plus Paclitaxel in recurrent or metastatic gastric cancer patients. 123 patients received treatment. Combination treatment did not significantly improve ORR (26,4% vs 19,1%) or PFS (3,91m vs 3,55 m) but OS (13,8 m vs. 8,3 m) in the overall cohort. A subcohort of ATM low expressing tumours (14%) experienced a greater improvement of OS (not reached vs. 8,2 m) and a trend towards improved PFS (5,29 m vs 3,68 m). 26282658 PubMed Bang et al., 2015, J. Clin. Oncol. 1 accepted 5215 179 69 11 108093559 108239826 ENST00000278616.4 75 GRCh37 N/A 2020-07-02 17:39:18 UTC https://civicdb.org/links/evidence_items/5215 https://civicdb.org/links/variants/179 https://civicdb.org/links/genes/69 false VHL 7428 Y98C (c.293A>G) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Pheochromocytoma Predisposing Supports C Uncertain Significance In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 30 yr old VHL patient with retinal hemangioblastomas and pheochromocytoma (index case 183). ACMG codes as follows: Supporting evidence of pathogenicity because Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology (PP4). 21463266 PubMed Leonardi et al., 2011, Ann. Hum. Genet. 2 accepted 5217 1933 58 3 10183824 10183824 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5217 https://civicdb.org/links/variants/1933 https://civicdb.org/links/genes/58 false VHL 7428 R69fs (c.204insG) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Germline mutation analysis of seven east-Chinese families revealed 6 mutations. This mutation was found in a VHL type 1 male patient with hemangioblastomas of the central nervous system, retinal angiomas, and renal cell carcinomas (family G). 21972040 PubMed Huang et al., 2012, Int. J. Mol. Med. 2 accepted 5245 1948 58 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5245 https://civicdb.org/links/variants/1948 https://civicdb.org/links/genes/58 false VHL 7428 Splice Region (c.340+5G>C) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Pheochromocytoma Predisposing Supports C Uncertain Significance Germline mutation analysis of seven east-Chinese families revealed 6 mutations. This splice-site alteration was found in two VHL type 2A female family members with hemangioblastomas of the central nervous system. Mutation was also found in a male VHL type 2A family member with hemangioblastomas of the central nervous system and pheochromocytomas (family C). This study contains very strong evidence for pathogenicity in the form of a splice-site variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 21972040 PubMed Huang et al., 2012, Int. J. Mol. Med. 2 accepted 5246 2104 58 3 10183876 10183876 G C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5246 https://civicdb.org/links/variants/2104 https://civicdb.org/links/genes/58 false VHL 7428 G144fs (c.432insG) Von Hippel-Lindau Disease 14175 Hemangioblastoma Predisposing Supports C Uncertain Significance Germline mutation analysis of seven east-Chinese families revealed 6 mutations. This novel mutation was found in 2 male VHL type 1 family members with hemangioblastomas of the central nervous system (family B). Family also contained 5 asymptomatic individuals. This study contains very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 21972040 PubMed Huang et al., 2012, Int. J. Mol. Med. 2 accepted 5247 1949 58 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5247 https://civicdb.org/links/variants/1949 https://civicdb.org/links/genes/58 false VHL 7428 Q145* (c.433C>T) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Pancreatic cysts Predisposing Supports C Uncertain Significance Germline mutation analysis of seven east-Chinese families revealed 6 mutations. This nonsense mutation was found in two separate families. One female VHL type 1 patient with hemangioblastomas of the central nervous system and an asymptomatic son (family D). Two male VHL type 1 family members with hemangioblastomas of the central nervous system and pancreatic cysts (family F). This study contains very strong evidence for pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 21972040 PubMed Huang et al., 2012, Int. J. Mol. Med. 2 accepted 5248 1883 58 3 10188290 10188290 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5248 https://civicdb.org/links/variants/1883 https://civicdb.org/links/genes/58 false VHL 7428 Exon 1 Deletion Von Hippel-Lindau Disease 14175 Hemangioblastoma Predisposing Supports C Uncertain Significance Germline mutation analysis of seven east-Chinese families revealed 6 mutations. This mutation was found two separate VHL families. One family contained a male VHL type 1 patient with hemangioblastomas of the central nervous system and a male asymptomatic patient (family A). The other family contained two male VHL type patients with hemangioblastomas of the central nervous system and 4 asymptomatic family members (family E). This study contains very strong evidence for pathogenicity in the form of a single exon deletion variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 21972040 PubMed Huang et al., 2012, Int. J. Mol. Med. 2 accepted 5249 844 58 3 10183532 10183871 ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/5249 https://civicdb.org/links/variants/844 https://civicdb.org/links/genes/58 false VHL 7428 N78S (c.233A>G) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Hemangioblastoma,Pancreatic cysts Predisposing Supports C Uncertain Significance 43 Italian patients were molecularly analyzed for Von Hippel-Lindau disease based on clinical suspicion. 2 of the 43 patients were found to have the above mutation. Clinical manifestations associated with this mutation include: CNS hemangioblastomas, pancreatic cysts, and retinal hemangioblastomas. ACMG evidence codes: 'PP2' because they observe a missense variant in gene where missense variants are common mechanism of disease. 19464396 PubMed Ciotti et al., Eur J Med Genet 3 accepted 5250 1755 58 3 10183764 10183764 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/5250 https://civicdb.org/links/variants/1755 https://civicdb.org/links/genes/58 false VHL 7428 R113* (c.337C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in a VHL type 1 patient (patient V59). This study contains very strong evidence for pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5260 1796 58 3 10183868 10183868 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5260 https://civicdb.org/links/variants/1796 https://civicdb.org/links/genes/58 false FLT3 2322 Mutation Acute Myeloid Leukemia 9119 Midostaurin Predictive Supports A Sensitivity/Response Midostaurin is FDA-approved for the treatment of newly-diagnosed acute myeloid leukemia patients harboring FLT3 mutations. 28546144 PubMed Levis, 2017, Blood 3 accepted 5261 519 24 13 28577411 28674729 ENST00000241453.7 75 GRCh37 Somatic 2017-07-25 20:08:04 UTC https://civicdb.org/links/evidence_items/5261 https://civicdb.org/links/variants/519 https://civicdb.org/links/genes/24 false VHL 7428 R161Q (c.482G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in 3 unrelated VHL type 2A patients (patients V32, V60, V97). This study contains strong evidence of pathogenicity for this variant because the prevalence of the variant in affected individuals is significantly increased compared with the prevalence In controls (ACMG code: PS4). An additional 0, 4 or 1 unaffected family members, respectively, were negative for the R161Q mutation across the 3 families described. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5262 1746 58 3 10191489 10191489 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/5262 https://civicdb.org/links/variants/1746 https://civicdb.org/links/genes/58 false VHL 7428 R161* (c.481C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Pathogenic Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in 2 unrelated VHL type 1 patients (patient V3, V46). ACMG codes as follows: A null, nonsense mutation in a gene where loss-of-function is a known mechanism of disease (PVS1). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5263 1804 58 3 10191488 10191488 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5263 https://civicdb.org/links/variants/1804 https://civicdb.org/links/genes/58 false VHL 7428 R167Q (c.500G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient and two VHL type 2B patients (patient no. V322, V36, V262). This study contains strong evidence of pathogenicity for this variant because the prevalence of the variant in affected individuals is significantly increased compared with the prevalence In controls (ACMG code: PS4). No additional family members were screened in all 3 cases. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5264 1739 58 3 10191507 10191507 G A ENST00000256474.2 75 GRCh37 R167Q is the most common point mutation in hereditary Von Hippel-Lindau (VHL) disease and disrupts the VHL genes binding to elongin C reducing the levels of the VHL-elongin B-elongin C (VBC) E3 ligase complex and inhibiting the ability of VHL to regulate HIF2α. This partial function in turn leads to an increased risk of tumorgenesis. VHL derived clear cell renal cell carcinoma models however have shown the proteasome inhibitors bortezomib and carfilzomib can act to stabilize mutant VHL-R167Q leading to downregulation of HIF2α and suprressed tumorgenesis. Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5264 https://civicdb.org/links/variants/1739 https://civicdb.org/links/genes/58 false VHL 7428 R167W (c.499C>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 2A patient, a VHL type 2B patient and a family with 5 VHL type 2B patients (patient no. V30, V23, V1). This study contains strong evidence of pathogenicity for this variant because the prevalence of the variant in affected individuals is significantly increased compared with the prevalence In controls (ACMG code: PS4). The first two individuals had no family screened but 14 unaffected family members showed no evidence of this mutation in the family with 5 mutation-positive affected members. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 4 accepted 5265 1747 58 3 10191506 10191506 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/5265 https://civicdb.org/links/variants/1747 https://civicdb.org/links/genes/58 false VHL 7428 N131K (c.393C>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 2A patient (patient no. V233). A single unaffected family member available for screening did not have the N131K mutation. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 2 accepted 5266 1953 58 3 10188250 10188250 C A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/5266 https://civicdb.org/links/variants/1953 https://civicdb.org/links/genes/58 false VHL 7428 C162W (c.486C>G) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 2B patient (patient no. V345). No additional family was screened for this mutation. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 2 accepted 5267 1774 58 3 10191493 10191493 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/5267 https://civicdb.org/links/variants/1774 https://civicdb.org/links/genes/58 false VHL 7428 P71fs (c.211insT) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in a VHL type 1 patient (patient no. V96). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5269 1955 58 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5269 https://civicdb.org/links/variants/1955 https://civicdb.org/links/genes/58 false VHL 7428 Q73* (c.217C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in a VHL type 1 patient (patient no. V64). This study contains very strong evidence for pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5270 1752 58 3 10183748 10183748 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5270 https://civicdb.org/links/variants/1752 https://civicdb.org/links/genes/58 false VHL 7428 Q96* (c.286C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in a VHL type 1 patient (patient no. V77). This study contains very strong evidence for pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5271 1848 58 3 10183817 10183817 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5271 https://civicdb.org/links/variants/1848 https://civicdb.org/links/genes/58 false VHL 7428 E52K (c.154G>A) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V285). No additional family members were screened. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 2 accepted 5272 1734 58 3 10183685 10183685 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5272 https://civicdb.org/links/variants/1734 https://civicdb.org/links/genes/58 false VHL 7428 E70K (c.208G>A) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V374). This patient was further described in Hes et al 2007 (family no. 5) to have bilateral, retinal hemangioblastoma. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 2 accepted 5273 1956 58 3 10183739 10183739 G A ENST00000256474.2 75 GRCh37 The VHL gene has a low rate of benign missense variation and is known to be definitively associated with VHL disease. The E70K missense mutation, located in the Beta-domain of VHL, is rare in open-source genome databases (0.00001489 allele frequency in ExAC, 4.365e-6 allele frequency in gnomAD) and was identified in several individuals with VHL disease symptoms (see evidence statements). Thus, this variant could be assigned ACMG code 'PP2' - Missense mutation in a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. Although this variant is registered once in ExAC and gnomAD, 'PM2' could be applied (Absent from controls in ESP, 1000 Genomes or ExAC) because VHL manifestations sometimes emerge later in adulthood. Thus, the allele may have been detected in a proband who was not yet affected by symptoms. Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/5273 https://civicdb.org/links/variants/1956 https://civicdb.org/links/genes/58 false VHL 7428 H115Q (c.345C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V48). No unaffected family members were screened. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 2 accepted 5274 1957 58 3 10188202 10188202 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/5274 https://civicdb.org/links/variants/1957 https://civicdb.org/links/genes/58 false VHL 7428 H191FS (c.571delC) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation causes a premature stop codon at amino acid 201 and was found in a VHL type 2B patient (patient no. V51). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1) 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5275 1958 58 3 10191578 10191578 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5275 https://civicdb.org/links/variants/1958 https://civicdb.org/links/genes/58 false VHL 7428 L118P (c.353T>C) Von Hippel-Lindau Disease 14175 Predisposing N/A C N/A Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in 3 VHL type 1 family members (patient no. V27). Ten unaffected family members were screened with no evidence of the L188P variant. This study contains strong evidence of pathogenicity for this variant because the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (ACMG code: PS4). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5276 1798 58 3 10188210 10188210 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5276 https://civicdb.org/links/variants/1798 https://civicdb.org/links/genes/58 false VHL 7428 L140fs (c.417_418delTC) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Pathogenic Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. ACMG codes as follows. This mutation causes a premature stop codon at amino acid 142 and was found in a VHL type 1 patient and a VHL type 2B patient (patient no. V73, V80). A frameshift mutation in a gene where loss-of-function is a known mechanism of disease is strong evidence for pathogenicity (PVS1). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5279 1960 58 Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/5279 https://civicdb.org/links/variants/1960 https://civicdb.org/links/genes/58 false VHL 7428 K159fs (c.473dup) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation causes a premature stop codon at amino acid 173 and was found in a VHL type 1 patient (patient no. V235). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5280 1872 58 3 10191480 10191480 T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:33 UTC https://civicdb.org/links/evidence_items/5280 https://civicdb.org/links/variants/1872 https://civicdb.org/links/genes/58 false VHL 7428 L158P (c.473T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in two VHL type 1 family members (patient no. V252). One unaffected individual family member did not have the L158P mutation. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5281 1738 58 3 10191480 10191480 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/5281 https://civicdb.org/links/variants/1738 https://civicdb.org/links/genes/58 false VHL 7428 L188P (c.563T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V269). Five unaffected family members were negative for the L188P variant. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5282 1852 58 3 10191570 10191570 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5282 https://civicdb.org/links/variants/1852 https://civicdb.org/links/genes/58 false VHL 7428 M54fs (c.161dup) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation causes a premature stop codon at amino acid 131 and was found in a VHL type 2A patient (patient no. V69). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5283 1889 58 3 10183691 10183692 T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/5283 https://civicdb.org/links/variants/1889 https://civicdb.org/links/genes/58 false VHL 7428 F136S (c.407T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in two unrelated VHL type 1 patients (patient no. V53, V94). No unaffected individuals from either family were tested for this mutation. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5284 1801 58 3 10188264 10188264 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5284 https://civicdb.org/links/variants/1801 https://civicdb.org/links/genes/58 false VHL 7428 P154= (c.462A>C) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This silent mutation was found in two VHL type 2A family members (patient no. V78). Two unaffected family members did not harbor this synonymous mutation. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 2 accepted 5285 1962 58 3 10188319 10188319 A C ENST00000256474.2 75 GRCh37 Note that there is a different variant reported at this amino acid position of VHL in ClinVar: NM_000551.3(VHL):c.462A>G (p.Pro154=).(https://www.ncbi.nlm.nih.gov/clinvar/variation/411977/) Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5285 https://civicdb.org/links/variants/1962 https://civicdb.org/links/genes/58 false VHL 7428 P86S (c.256C>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in 3 VHL type 2B family members (patient no. V11). One unaffected family member was negative for the P86S mutation. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5286 1902 58 3 10183787 10183787 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5286 https://civicdb.org/links/variants/1902 https://civicdb.org/links/genes/58 false VHL 7428 S65L (c.194C>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 2 patient (patient no. V209). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 2 accepted 5287 1788 58 3 10183725 10183725 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/5287 https://civicdb.org/links/variants/1788 https://civicdb.org/links/genes/58 false VHL 7428 S80R (c.238A>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V259). This S80R variant was not detected in 2 unaffected family members. An additional 2 unrelated, affected individuals had the similar S80N missense mutation in this study. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5288 1963 58 3 10183769 10183769 A C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/5288 https://civicdb.org/links/variants/1963 https://civicdb.org/links/genes/58 false VHL 7428 S80N (c.239G>A) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in two VHL type 1 family members (patient no. V19). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5289 1874 58 3 10183770 10183770 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/5289 https://civicdb.org/links/variants/1874 https://civicdb.org/links/genes/58 false VHL 7428 R60FS (c.179delG) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation causes a premature stop codon at amino acid 66 and was found in a VHL type 1 patient (patient no. V9). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5290 1964 58 3 10183710 10183710 G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5290 https://civicdb.org/links/variants/1964 https://civicdb.org/links/genes/58 false VHL 7428 T105P (c.313A>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in 14 VHL type 1 family members (patient no. V8). This study contains supporting evidence of pathogenicity due to cosegregation with disease in multiple affected family members (14 affected, 13 unaffected) in a gene definitively known to cause the disease (ACMG code: PP1). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5293 1839 58 3 10183844 10183844 A C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5293 https://civicdb.org/links/variants/1839 https://civicdb.org/links/genes/58 false VHL 7428 T157I (c.470C>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 2A patient (patient no. V240). No unaffected family members were tested. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 2 accepted 5294 1745 58 3 10191477 10191477 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/5294 https://civicdb.org/links/variants/1745 https://civicdb.org/links/genes/58 false VHL 7428 W117C (c.351G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in 4 VHL type 1 family members (patient no. V13). This study contains supporting evidence of pathogenicity for this variant due to cosegregation of disease with multiple family members (4 affected, 4 unaffected) in a gene definitively known to cause disease (ACMG code: PP1). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5295 1767 58 3 10188208 10188208 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/5295 https://civicdb.org/links/variants/1767 https://civicdb.org/links/genes/58 false VHL 7428 W88S (c.263G>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V266). No unaffected family members were evaluated. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 2 accepted 5296 1966 58 3 10183794 10183794 G C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/5296 https://civicdb.org/links/variants/1966 https://civicdb.org/links/genes/58 false VHL 7428 Y156D (c.466T>G) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 2B patient (patient no.V87). No unaffected family members were evaluated. An additional type 1 patient had a similar missense mutation (Y156C, patient no. V265). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5297 1967 58 3 10191473 10191473 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/5297 https://civicdb.org/links/variants/1967 https://civicdb.org/links/genes/58 false VHL 7428 Y156C (c.467A>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V265). One unaffected family member was negative for this mutation. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5298 1946 58 3 10191474 10191474 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/5298 https://civicdb.org/links/variants/1946 https://civicdb.org/links/genes/58 false VHL 7428 Y156* (c.468T>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in a VHL type 1 patient (patient no. V41). This study contains very strong evidence for pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5299 1968 58 3 10191475 10191475 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5299 https://civicdb.org/links/variants/1968 https://civicdb.org/links/genes/58 false VHL 7428 Y175* (c.525C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in a VHL type 1 patient (patient no. V63). This study contains very strong evidence for pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5300 1969 58 3 10191532 10191532 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5300 https://civicdb.org/links/variants/1969 https://civicdb.org/links/genes/58 false VHL 7428 V130L (c.388G>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V91). No unaffected family members were tested. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 2 accepted 5301 1970 58 3 10188245 10188245 G C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/5301 https://civicdb.org/links/variants/1970 https://civicdb.org/links/genes/58 false VHL 7428 V166F (c.496G>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 2A patient (patient no. V49). This variant was not found in 8 unaffected family members and previously reported in patients with VHL. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5302 1825 58 3 10191503 10191503 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5302 https://civicdb.org/links/variants/1825 https://civicdb.org/links/genes/58 false VHL 7428 V170G (c.509T>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V81). No unaffected family members were tested but this mutation was reported in other unrelated patients previously. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5303 1935 58 3 10191516 10191516 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/5303 https://civicdb.org/links/variants/1935 https://civicdb.org/links/genes/58 false VHL 7428 G114R (c.340G>C) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Hemangioblastoma Predisposing Supports C Uncertain Significance 43 Italian patients were molecularly analyzed for Von Hippel-Lindau disease based on clinical suspicion. 2 of the 43 patients (VHL-6 and -16) were found to have the above mutation. Clinical manifestations associated with this mutation include: CNS hemangioblastomas and pancreatic cysts. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 19464396 PubMed Ciotti et al., Eur J Med Genet 3 accepted 5305 1857 58 3 10183871 10183871 G C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5305 https://civicdb.org/links/variants/1857 https://civicdb.org/links/genes/58 false VHL 7428 Mutation Renal Cell Carcinoma 4450 Everolimus Predictive Supports B Sensitivity/Response A randomized, open-label phase 2 study, encompassing 85 patients, to compare the efficacy of dual PIK3/mTOR Inhibitor Apitolisib and mTORC1 inhibitor Everolimus in patients who progressed on or after antiangiogenetic therapy (VEGFR). There was a trend towards association between deleterious VHL alterations and progression-free-survival in the Everolimus arm only. 26951309 PubMed Powles et al., 2016, J. Clin. Oncol. NCT01442090 4 accepted 5323 160 58 3 10182692 10193904 ENST00000256474.2 75 GRCh37 Somatic 2018-07-12 18:42:56 UTC https://civicdb.org/links/evidence_items/5323 https://civicdb.org/links/variants/160 https://civicdb.org/links/genes/58 false VHL 7428 S65W (c.194C>G) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Hemangioblastoma Predisposing Supports C Uncertain Significance 14 Chinese patients from 10 families were diagnosed with Von Hippel-Lindau disease based on clinical criteria. Genetic testing demonstrated 2 members (Patient 1 and 2) of a single family (Family I) harbored the above mutation. Clinical manifestations in this family included: CNS hemangioblastoma and retinal hemangioblastoma. ACMG evidence codes: PP4 - because the patients' phenotypes and family history are highly specific for a disease with single genetic etiology; PP1 - cosegregation with disease in multiple affected family members in a gene definitively known to cause disease. 20518900 PubMed Zhou et al., 2010, Pathol. Int. 3 accepted 5328 1787 58 3 10183725 10183725 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5328 https://civicdb.org/links/variants/1787 https://civicdb.org/links/genes/58 false VHL 7428 R177* (c.529A>T) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor,Retinal capillary hemangioma,Hemangioblastoma Predisposing Supports C Uncertain Significance 14 Chinese patients from 10 VHL Type I families were diagnosed with Von Hippel-Lindau disease based on clinical criteria. Germline mutations were identified in 7/10 families. In all 14 patients, the first manifestation of VHL disease was a central nervous system hemangioblastoma. Their mean age of neurological symptom onset was 24.5 years (range: 12–58 years). Genetic testing demonstrated that Patient 10 (from family VI) and Patient 11 (from family VII) carried this mutation. Patient 10 was reported to have a retinal hemangioblastoma, and patient 11 had a pancreatic tumor. ACMG evidence codes: 'PP4' because the patients' phenotypes and family history are highly specific for a disease with single genetic etiology. 20518900 PubMed Zhou et al., 2010, Pathol. Int. 3 accepted 5331 1827 58 3 10191536 10191536 A T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/5331 https://civicdb.org/links/variants/1827 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.340+1G>A) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 14 Chinese patients from 10 families were diagnosed with Von Hippel-Lindau disease based on clinical criteria. Genetic testing demonstrated 1 member of a single family harbored the above mutation. Clinical manifestations in this family included: CNS hemangioblastoma. ACMG evidence codes: 'PVS1' because they observe a canonical +1 splice site variant in a gene where loss of function is a known mechanism of disease. Relevant HPO terms: Hemangioblastoma. 20518900 PubMed Zhou et al., 2010, Pathol. Int. 3 accepted 5332 2114 58 3 10183872 10183872 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5332 https://civicdb.org/links/variants/2114 https://civicdb.org/links/genes/58 false VHL 7428 *214L (c.641G>T) Von Hippel-Lindau Disease 14175 Neuroendocrine neoplasm,Pheochromocytoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance This paper identified run-on mutations in 5 members of 4 distinct families. More specifically, genetic testing demonstrated the above mutation (X214LextX15) in 3 individuals in 2 separate families. Clinical evidence suggested an additional 1 family member was affected with VHL, but genetic testing was not conducted on this individual. Clinical manifestations associated with this mutation include: pheochromocytoma, retinal hemangioblastoma, and pancreatic neuroendocrine tumor. ACMG evidence codes: 'PP4' because the patients' phenotypes and family history are highly specific for a disease with single genetic etiology, 'PP1' because of segregation results, and 'PS3' because in-vitro studies demonstrated this variant was unable to perform normal cellular functions (downregulate JunB). 20560986 PubMed Sorrell et al., 2011, Clin. Genet. 4 accepted 5334 1986 58 3 10191648 10191648 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5334 https://civicdb.org/links/variants/1986 https://civicdb.org/links/genes/58 false VHL 7428 *214W (c.642A>G) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Pheochromocytoma Predisposing Supports C Uncertain Significance This paper identified run-on mutations in 5 members of 4 distinct families. More specifically, genetic testing demonstrated the above mutation (X214WextX15) in 1 individual in a single family. Clinical manifestations included: pheochromocytoma and pancreatic cysts. 20560986 PubMed Sorrell et al., 2011, Clin. Genet. 2 accepted 5335 1987 58 3 10191649 10191649 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5335 https://civicdb.org/links/variants/1987 https://civicdb.org/links/genes/58 false VHL 7428 *214C (c.642A>T) Von Hippel-Lindau Disease 14175 Clear cell renal cell carcinoma,Neuroendocrine neoplasm,Hemangioblastoma,Retinal capillary hemangioma,Pancreatic endocrine tumor,Pheochromocytoma Predisposing Supports C Uncertain Significance This paper identified run-on mutations in 5 members of 4 distinct families. More specifically, genetic testing demonstrated the above mutation (X214CextX15) in 1 individual in a single family. Clinical manifestations included: pheochromocytoma, CNS hemangioblastoma, retinal hemangioblastoma, clear cell renal cell carcinoma, and pancreatic neuroendocrine tumor. Relevant HPO terms: Pheochromocytoma, Hemangioblastoma, Retinal hemangioblastoma, Clear cell renal cell carcinoma, Neuroendocrine neoplasm. 20560986 PubMed Sorrell et al., 2011, Clin. Genet. 2 accepted 5336 1988 58 3 10191649 10191649 A T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5336 https://civicdb.org/links/variants/1988 https://civicdb.org/links/genes/58 false ERBB2 2064 Mutation Breast Cancer 1612 Neratinib Predictive Supports B Sensitivity/Response 16 patients with HER2-mutated metastatic breast cancer were treated with neratinib monotherapy. Of these 16 patients, 14 had known-activating mutations and 2 had mutations of unknown significance. Five of the 16 patients achieved clinical benefit including 1 complete response (6%), 1 partial response (6%) and 3 with stable disease >24 weeks (19%). Clinical benefit was observed across different HER2 mutations including L755S, V777_G778 insGSP, P780_Y781 insGSP, V842I, S310F, and L869R. 28679771 PubMed Ma et al., 2017, Clin. Cancer Res. 4 accepted 5338 666 20 17 37868196 37881332 ENST00000269571.5 75 GRCh37 Somatic 2018-07-10 18:54:35 UTC https://civicdb.org/links/evidence_items/5338 https://civicdb.org/links/variants/666 https://civicdb.org/links/genes/20 false BAP1 8314 Mutation Renal Cell Carcinoma 4450 Everolimus,Sunitinib Sequential Predictive Supports B Resistance This study evaluated the effects of everolimus and sunitinib on patients with metastatic renal cell carcinoma. A total of 220 patients with RCC were evaluated for 341 genes at 540x coverage. Of all 220 patients, 19% of had BAP1 mutations. Patients with BAP1 mutations treated with first line everolimus followed by sunitinib (N=87 wildtype, 22 mutant) were associated with shorter progression free survival (median [95% CI] 4.9 [2.9 - 8.1] vs 10.5 [7.3 - 12.9] mo; HR 1.84 [1.1-3.2]; P=0.02). For patients treated with sunitinib followed by everolimus (N=91 wildtype, 20 mutant) were associated with a trend towards shorter progression free survival (median [95% CI] 8.1 [3.1-11.3] vs 11.0 [8.3-13.8] mo; HR 1.69 [0.9-3.2]; P=0.06). 27751729 PubMed Hsieh et al., 2017, Eur. Urol. 4 accepted 5339 183 70 3 52435029 52444366 ENST00000460680.1 75 GRCh37 BAP1 is a tumor suppressor gene, mutations in this gene have been observed in a number of cancers including melanoma, and renal cancers. These mutations generally lead to loss-of-function and mutations in the UHC domain of BAP1 have been shown to lead to structural instability and β-amyloid aggregation in models. Germline mutations are associated with an increased risk of tumorgenesis and can lead to the development of "atypical Spitz tumours (ASTs), cutaneous melanoma (CM), epithelioid malignant mesothelioma (MM) and clear cell RCC". Somatic 2017-07-27 18:10:40 UTC https://civicdb.org/links/evidence_items/5339 https://civicdb.org/links/variants/183 https://civicdb.org/links/genes/70 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Blood samples from 5 Japanese families revealed 4 germline mutations. This mutation was found in a family of 3 individuals (Family B). Only one patient in this family developed symtoms, which included a brain stem hemangioblastoma and retinal angioma discovered at age 30. Parents of this individual showed no manifestations of VHL disease and were negative for bands via single-strand conformational polymorphism (SSCP) analysis where the proband showed extra bands. This study contains moderate evidence of pathogenicity because the protein length changes as a result of an in-frame deletion in a nonrepeat region (ACMG code: PM4). 8641976 PubMed Kanno et al., 1996, Jpn. J. Cancer Res. 2 accepted 5340 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:42 UTC https://civicdb.org/links/evidence_items/5340 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false VHL 7428 N78H (c.232A>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Blood samples from 5 Japanese families revealed 4 germline mutations. This missense mutation was found in a family of five individuals. Only one VHL patient was identified with hemangioblastomas of the cerebellum and spinal cord, retinal angiomas, and renal cysts (family A). 8641976 PubMed Kanno et al., 1996, Jpn. J. Cancer Res. 2 accepted 5341 1754 58 3 10183763 10183763 A C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5341 https://civicdb.org/links/variants/1754 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.464-1G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Blood samples from 5 Japanese families revealed 4 germline mutations. This mutation was found in a family of 10 individuals. Three VHL patients were identified with hemangioblastomas of the central nervous system and retinal angiomas (family C). The eldest patient also had renal cell carcinoma (listed as C-1 in publication). This study contains very strong evidence of pathogenicity in the form of a canonical -1 splice site mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 8641976 PubMed Kanno et al., 1996, Jpn. J. Cancer Res. 2 accepted 5343 1990 58 3 10191470 10191470 G T ENST00000256474.2 75 GRCh37 There are three similar variants in ClinVar with this exact genomic position with ClinVar IDs: 223221, 223220, and 43603 of which only 223221 is an exact match (NM_000551.3:c.464-1G>T). Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5343 https://civicdb.org/links/variants/1990 https://civicdb.org/links/genes/58 false NRAS 4893 Mutation Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Supports A Resistance NCCN guidelines indicate colorectal cancer patients with NRAS mutations should not be treated with EGFR inhibitors cetuximab or panitumumab. 28275037 PubMed Benson et al., 2017, J Natl Compr Canc Netw 4 accepted 5344 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2017-09-08 18:14:00 UTC https://civicdb.org/links/evidence_items/5344 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false KRAS 3845 Mutation Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Supports A Resistance NCCN guidelines indicate colorectal cancer patients with KRAS mutations should not be treated with the anti-EGFR therapies cetuximab or panitumumab. 28275037 PubMed Benson et al., 2017, J Natl Compr Canc Netw 5 accepted 5345 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2017-09-08 18:06:30 UTC https://civicdb.org/links/evidence_items/5345 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false PDGFRA 5156 D842V Cancer 162 Imatinib Mesylate Predictive Supports D Resistance In an in vitro study, Chinese hamster ovary cells expressing PDGFRA D842V mutation demonstrated reduced sensitivity to imatinib treatment (IC50=2,500 vs. IC50<100), compared to Chinese hamster ovary cells expressing wild-type PDGFRA. Sensitivity was determined by assessing PDGFRA auto-phosphorylation. 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 2 accepted 5346 99 38 4 55152093 55152093 A T ENST00000257290.5 75 GRCh37 PDGFRA D842 mutations are characterized broadly as imatinib resistance mutations. This is most well characterized in gastrointestinal stromal tumors, but other cell lines containing these mutations have been shown to be resistant as well. Exogenous expression of the A842V mutation resulted in constitutive tyrosine phosphorylation of PDGFRA in the absence of ligand in 293T cells and cytokine-independent proliferation of the IL-3-dependent Ba/F3 cell line, both evidence that this is an activating mutation. In imatinib resistant cell lines, a number of other therapeutics have demonstrated efficacy. These include; crenolanib, sirolimus, and midostaurin (PKC412). Somatic 2019-04-26 19:08:00 UTC https://civicdb.org/links/evidence_items/5346 https://civicdb.org/links/variants/99 https://civicdb.org/links/genes/38 false PDGFRA 5156 V561D Cancer 162 Imatinib Mesylate Predictive Does Not Support D Resistance In an in vitro study, Chinese hamster ovary cells expressing PDGFRA V561D mutation demonstrated sensitivity to imatinib treatment (IC50<100), though this sensitivity was indistinguishable from Chinese hamster ovary cells expressing wild-type PDGFRA. Sensitivity was determined by assessing PDGFRA auto-phosphorylation. 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 2 accepted 5347 941 38 4 55141036 55141036 T A ENST00000257290.5 75 GRCh37 Somatic 2019-04-26 19:09:12 UTC https://civicdb.org/links/evidence_items/5347 https://civicdb.org/links/variants/941 https://civicdb.org/links/genes/38 false KIT 3815 V560D Cancer 162 Imatinib Mesylate Predictive Supports D Sensitivity/Response In an in vitro study, Chinese hamster ovary cells expressing KIT V560D mutation demonstrated sensitivity to imatinib treatment (IC50 = 100 vs IC50 = 1000) when compared to Chinese hamster ovary cells expressing ligand-activated wild-type KIT. Sensitivity was determined by assessing KIT auto-phosphorylation. 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 2 accepted 5348 971 29 4 55593613 55593613 T A ENST00000288135.5 75 GRCh37 Somatic 2019-04-26 19:21:22 UTC https://civicdb.org/links/evidence_items/5348 https://civicdb.org/links/variants/971 https://civicdb.org/links/genes/29 false VHL 7428 C162R (c.484T>C) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Blood samples from 5 Japanese families revealed 4 germline mutations. This missense mutation was found in a family of 7 individuals. Two VHL patients were identified, 1 with brain stem hemangioblastomas and retinal angiomas, the other with renal cell carcinoma (family D). Single-strand conformational polymorphism (SSCP) analysis showed bands for the 2 affected individuals that were absent from 5 normal individuals. Direct sequencing was performed on SSCP positive patients. Supporting evidence for pathogenicity due to cosegregation with disease in multiple affected family members (ACMG code: PP1). 8641976 PubMed Kanno et al., 1996, Jpn. J. Cancer Res. 2 accepted 5349 1772 58 3 10191491 10191491 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/5349 https://civicdb.org/links/variants/1772 https://civicdb.org/links/genes/58 false PIK3CA 5290 Exon 10 and Exon 21 Mutation Colorectal Cancer 9256 Prognostic Supports B Poor Outcome This was a prospective study involving 1,170 colorectal cancer patients confirmed by histology. PIK3CA mutations were found in 16% (189/1170) of cased via pyrosequencing of FFPE samples, of these 58% (109/189) had mutations in exon 10, 39% (73/189) had mutations in exon 21, and 3.7% (7/189) had mutations in both exons. Study found that exon 10 + exon 21 mutants were associated with shorter cancer specific survival and overall survival when compared to WT PIK3CA (P = 0.031, P = 0.0008). These mutants were also associated with higher colorectal cancer-specific mortality and overall mortality (multivariate hazard ratio (HR) = 3.51, multivariate HR 2.68). In contrast, mutations on either exon 10 or exon 21 alone were not statistically significant in terms of overall survival. Note that exons 10 and 21 are listed as exons 9 and 20 in the source, as it was common at the time of its publication to exclude non-coding exon 1. Authors note that they had limited data on cancer treatment data, but assume that treatment regimens did not differ substantially based on PIK3CA mutation status given that patients were diagnosed prior to clinical availability of PIK3CA genotype data. They further note that treatment decisions were typically based on cancer stage, for which their analyses adjusted. 22357840 PubMed Liao et al., 2012, Clin. Cancer Res. 2 accepted 5350 1991 37 PIK3CA exon 10 and exon 21 mutations occasionally co-occur in the same tumor, same cell line, or same clone (if clonality information is available). Note that exons 10 and 21 are sometimes listed as exons 9 and 20 in publications, as it was once common to exclude non-coding exon 1. Somatic 2020-05-28 18:00:03 UTC https://civicdb.org/links/evidence_items/5350 https://civicdb.org/links/variants/1991 https://civicdb.org/links/genes/37 false VHL 7428 Splice Site (c.464-2A>T) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Hemangioblastoma,Pancreatic cysts Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This splice mutation was found in a German, VHL type 1 family. Only one affected patient was identified with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts. (family VHL 57). This study contains very strong evidence of pathogenicity in the form of a canonical -2 splice variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5351 1992 58 3 10191469 10191469 A T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5351 https://civicdb.org/links/variants/1992 https://civicdb.org/links/genes/58 false VHL 7428 R113* (c.337C>T) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Retinal capillary hemangioma Predisposing N/A C N/A Of 65 VHL families from central Europe, 53 were identified with germline mutations using SSCP analysis of PCR products by peripheral blood. The R113* (c.337C>T) mutation was detected in the patient, referred to in the paper by R113* (c.550C>T) due to a difference in transcript sequence. This nonsense mutation was found in a German, VHL type 1 family (family VHL 55). Two patients were identified with retinal angiomas and hemangioblastomas of the central nervous system. This study contains very strong evidence of pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 3 accepted 5352 1796 58 3 10183868 10183868 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:49 UTC https://civicdb.org/links/evidence_items/5352 https://civicdb.org/links/variants/1796 https://civicdb.org/links/genes/58 false VHL 7428 R161G (c.481C>G) Von Hippel-Lindau Disease 14175 Pheochromocytoma,Renal cell carcinoma,Retinal capillary hemangioma,Hemangioblastoma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a German, VHL type 2B family. Only one patient was identified with retinal angiomas, hemangioblastomas of the central nervous system, pheochromocytoma, and renal cell carcinoma. This patient's phenotype is highly specific for a disease with a single etiology (ACMG code: PP4). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5353 1915 58 3 10191488 10191488 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5353 https://civicdb.org/links/variants/1915 https://civicdb.org/links/genes/58 false VHL 7428 R167Q (c.500G>A) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a German, VHL type 2B family with 5 affected individuals (family VHL 43). Each patient had retinal angiomas, 2 had hemangioblastomas of the central nervous system, and 2 had renal cell carcinoma. The patients phenotype and family history are highly specific for a disease with a single gene etiology (ACMG code: PP4). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5354 1739 58 3 10191507 10191507 G A ENST00000256474.2 75 GRCh37 R167Q is the most common point mutation in hereditary Von Hippel-Lindau (VHL) disease and disrupts the VHL genes binding to elongin C reducing the levels of the VHL-elongin B-elongin C (VBC) E3 ligase complex and inhibiting the ability of VHL to regulate HIF2α. This partial function in turn leads to an increased risk of tumorgenesis. VHL derived clear cell renal cell carcinoma models however have shown the proteasome inhibitors bortezomib and carfilzomib can act to stabilize mutant VHL-R167Q leading to downregulation of HIF2α and suprressed tumorgenesis. Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5354 https://civicdb.org/links/variants/1739 https://civicdb.org/links/genes/58 false VHL 7428 C162W (c.486C>G) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Pancreatic cysts,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a German, VHL type 1 patient with retinal angiomas, hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (family VHL 42). HPO terms: retinal hemangioblastoma, hemangioblastoma, renal cell carcinoma, multiple pancreatic cysts. 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5355 1774 58 3 10191493 10191493 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5355 https://civicdb.org/links/variants/1774 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.463+2T>C) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma,Hemangioblastoma,Pancreatic cysts Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This splice mutation was found in a Croatian, VHL type 1 family of 3. Each individual had retinal angiomas, one had hemangioblastomas of the central nervous system, one had renal cell carcinoma, and one had pancreatic cysts (family VHL 7). This study contains very strong evidence of pathogenicity in the form of a canonical +2 splice site variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5356 2075 58 3 10188322 10188322 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/5356 https://civicdb.org/links/variants/2075 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.464-1G>A) Von Hippel-Lindau Disease 14175 Hemangioblastoma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This splice mutation was found in a German, VHL type 1 patient with hemangioblastomas of the central nervous system (family VHL 48). This study contains very strong evidence of pathogenicity in the form of a canonical -1 splice site variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5357 1974 58 3 10191470 10191470 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5357 https://civicdb.org/links/variants/1974 https://civicdb.org/links/genes/58 false VHL 7428 Q132* (c.394C>T) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Pancreatic cysts,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This nonsense mutation was found in a German, VHL type 1 patient with retinal angiomas, hemangioblastomas of the central nervous system, and pancreatic cysts (family VHL 30). This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5358 1994 58 3 10188251 10188251 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5358 https://civicdb.org/links/variants/1994 https://civicdb.org/links/genes/58 false VHL 7428 Q164* (c.490C>T) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma,Hemangioblastoma,Pancreatic endocrine tumor,Pancreatic cysts Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This nonsense mutation was found in an Iranian, VHL type 1 patient with retinal angiomas, hemangioblastomas of the central nervous system, renal cell carcinoma, pancreatic cysts, and pancreatic islet cell tumors (family VHL 65). This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5359 1845 58 3 10191497 10191497 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5359 https://civicdb.org/links/variants/1845 https://civicdb.org/links/genes/58 false VHL 7428 Q195* (c.583C>T) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This nonsense mutation was found in 2 German, VHL type 1 family members with retinal angiomas and hemangioblastomas of the central nervous system (family VHL 56). This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5360 1810 58 3 10191590 10191590 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5360 https://civicdb.org/links/variants/1810 https://civicdb.org/links/genes/58 false VHL 7428 E70* (c.208G>T) Von Hippel-Lindau Disease 14175 Hemangioblastoma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This nonsense mutation was found in a Filipino, VHL type 1 patient with hemangioblastomas of the central nervous system (family VHL 50). This study contains very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5361 1834 58 3 10183739 10183739 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5361 https://civicdb.org/links/variants/1834 https://civicdb.org/links/genes/58 false VHL 7428 H115Y (c.343C>T) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a German, VHL type 1 patient with retinal angiomas (family VHL 59). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5363 1921 58 3 10188200 10188200 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5363 https://civicdb.org/links/variants/1921 https://civicdb.org/links/genes/58 false VHL 7428 C77_N78insL (c.230_231insTCT) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Hemangioblastoma,Renal cell carcinoma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This mutation was found in 2 Croatian, VHL type 1 family members (family VHL 26). Both have hemangioblastomas of the central nervous system, one has renal cell carcinoma, and one with pancreatic cysts. 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5364 3096 58 3 10183761 10183762 TCT ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5364 https://civicdb.org/links/variants/3096 https://civicdb.org/links/genes/58 false VHL 7428 L129fs (c.384delT) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Renal cell carcinoma,Pancreatic cysts Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This mutation was found in 2 German, VHL type 1 family members with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (family VHL 44). This study contains very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 3 accepted 5365 1996 58 3 10188241 10188241 T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/5365 https://civicdb.org/links/variants/1996 https://civicdb.org/links/genes/58 false VHL 7428 L178Q (c.533T>A) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Pheochromocytoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in 2 German, VHL type 2 family members with retinal angiomas, hemangioblastomas of the central nervous system, and pheochromocytomas (family VHL 29). Each patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5366 1997 58 3 10191540 10191540 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5366 https://civicdb.org/links/variants/1997 https://civicdb.org/links/genes/58 false VHL 7428 L89P (c.266T>C) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Hemangioblastoma,Retinal capillary hemangioma,Renal cell carcinoma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a German, VHL type 1 family of 11. Three patients had retinal angiomas, 7 hand hemangioblastomas of the central nervous system, 7 had renal cell carcinoma, and 6 had pancreatic cysts (family VHL 3). This study contains supporting evidence of pathogenicity due to cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5368 1793 58 3 10183797 10183797 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/5368 https://civicdb.org/links/variants/1793 https://civicdb.org/links/genes/58 false VHL 7428 P81S (c.241C>T) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Renal cell carcinoma,Hemangioblastoma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a German, VHL type 1 patient with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (family VHL 23). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5369 1837 58 3 10183772 10183772 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/5369 https://civicdb.org/links/variants/1837 https://civicdb.org/links/genes/58 false VHL 7428 S183* (c.548C>A) Renal Cell Carcinoma 4450 Renal cell carcinoma,Hemangioblastoma,Pancreatic cysts,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This nonsense mutation was found in 3 Italian, VHL type 1 family members. Two had retinal angiomas, 2 had hemangioblastomas of the central nervous system, 2 had renal cell carcinoma, and all three had pancreatic cysts. This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 3 accepted 5370 1784 58 3 10191555 10191555 C A ENST00000256474.2 75 GRCh37 Rare Germline 2020-04-11 04:25:02 UTC https://civicdb.org/links/evidence_items/5370 https://civicdb.org/links/variants/1784 https://civicdb.org/links/genes/58 false VHL 7428 S80N (c.239G>A) Renal Cell Carcinoma 4450 Renal cell carcinoma,Pancreatic endocrine tumor,Pancreatic cysts,Hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a Slovakian, VHL type 1 family of 13 affected individuals. Seven had retinal angiomas, 7 had hemangioblastomas of the central nervous system, 5 had renal cell carcinoma, one had pancreatic cysts, and one had pancreatic islet cell tumors (family VHL 39). This study contains supporting evidence for pathogenicity due to cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5371 1874 58 3 10183770 10183770 G A ENST00000256474.2 75 GRCh37 Rare Germline 2020-04-11 04:30:54 UTC https://civicdb.org/links/evidence_items/5371 https://civicdb.org/links/variants/1874 https://civicdb.org/links/genes/58 false VHL 7428 Y98H (c.292T>C) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Pheochromocytoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found 3 unrelated, German families, 2 of which had been previously described (Neumann et al. 1995). The newly-identified VHL type 2 patient had retinal angiomas and pheochromocytoma (family VHL 54). As previously described, one VHL type 2A family of 52 affected individuals had 26 patients with retinal angiomas, 6 with hemangioblastomas of the central nervous system, and 41 with pheochromocytoma (family VHL*). A VHL type 1 family of 3 had 2 patients with retinal angiomas and one with renal cell carcinoma (family VHL 47). This study contains supporting evidence for pathogenicity due to cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5372 1741 58 3 10183823 10183823 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5372 https://civicdb.org/links/variants/1741 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.463+1G>C) Renal Cell Carcinoma 4450 Pancreatic cysts,Retinal capillary hemangioma,Renal cell carcinoma,Hemangioblastoma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This splice mutation was found in a German, VHL type 1 patient with retinal angiomas, hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (family VHL 45). This study contains very strong evidence of pathogenicity in the form of a canonical +1 splice site variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5373 1998 58 3 10188321 10188321 G C ENST00000256474.2 75 GRCh37 Rare Germline 2020-04-11 04:31:27 UTC https://civicdb.org/links/evidence_items/5373 https://civicdb.org/links/variants/1998 https://civicdb.org/links/genes/58 false VHL 7428 V74G (c.221T>G) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Renal cell carcinoma,Pheochromocytoma,Pancreatic cysts,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in 2 unrelated, German families. The VHL type 1 family of 4 affected individuals had 2 patients with retinal angiomas, 5 with hemangioblastomas of the central nervous system, and one with renal cell carcinoma (family VHL 53). The VHL type 2B family of 3 affected individuals had one patient with retinal angioma, 3 with hemangioblastomas of the central nervous system, one with pheochromocytoma, one with renal cell carcinoma, one with pancreatic cysts, and one with cystadenomas of the epididymis (family VHL 9). This study contains supporting evidence of pathogenicity due to cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). HPO terms: papillary cystadenomas of the broad ligament 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5374 1999 58 3 10183752 10183752 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/5374 https://civicdb.org/links/variants/1999 https://civicdb.org/links/genes/58 false VHL 7428 R161* (c.481C>T) Renal Cell Carcinoma 4450 Hemangioblastoma,Renal cell carcinoma,Pancreatic cysts,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This nonsense mutation was found in 2 unrelated, German families. One VHL type 1 family of 2 affected individuals had one patient with retinal angiomas, 2 with hemangioblastomas of the central nervous system, one with renal cell carcinoma, one with pancreatic cysts, and one with cystadenomas of the epididymis (family VHL 32). Another VHL type 1 family of 3 affected individuals had 3 patients with retinal angiomas, one with hemangioblastomas of the central nervous system, 2 with renal cell carcinoma, one with pancreatic cysts, and one with cystadenomas of the epididymis (family VHL 49). ACMG codes as follows: A nonsense mutation in a gene where loss-of-function is a known mechanism of disease (PVS1). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). HPO terms: papillary cystadenomas of the broad ligament. 8707293 PubMed Glavac et al., 1996, Hum. Genet. 3 accepted 5375 1804 58 3 10191488 10191488 C T ENST00000256474.2 75 GRCh37 Rare Germline 2018-07-27 02:16:03 UTC https://civicdb.org/links/evidence_items/5375 https://civicdb.org/links/variants/1804 https://civicdb.org/links/genes/58 false VHL 7428 N78S (c.233A>G) Von Hippel-Lindau Disease 14175 Hemangioblastoma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a German, VHL type 1 family of 6. Each patient had hemangioblastomas of the central nervous system and 4 had cystadenomas of the epididymis (family VHL 51). This study contains supporting evidence of pathogenicity due to cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). HPO terms: papillary cystadenomas of the broad ligament. 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5376 1755 58 3 10183764 10183764 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/5376 https://civicdb.org/links/variants/1755 https://civicdb.org/links/genes/58 false VHL 7428 H115R (c.344A>G) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Retinal capillary hemangioma,Hemangioblastoma,Renal cell carcinoma Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a German, VHL type 1 family of 2. Both patients had hemangioblastomas of the central nervous system, renal cell carcinoma, pancreatic cysts, and cystadenomas of the epididymis (family VHL 60). One patient also had retinal angiomas. This study contains supporting evidence of pathogenicity due to cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). HPO terms: papillary cystadenomas of the broad ligament. 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5377 2000 58 3 10188201 10188201 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5377 https://civicdb.org/links/variants/2000 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Hemangioblastoma,Renal cell carcinoma Predisposing Supports C Uncertain Significance A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families. Renal cell carcinoma occurred predominantly in non-missense mutations predicted to lead to gross alteration or complete loss of the VHL protein. This mutation was found in a VHL type 1 patient with hemangioblastomas of the central nervous system, pancreatic cyst or tumor, and renal cell carcinoma (family ID 80). 10761708 PubMed Yoshida et al., 2000, Jpn. J. Cancer Res. 3 accepted 5386 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:42 UTC https://civicdb.org/links/evidence_items/5386 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false VHL 7428 R107G (c.319C>G) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5399 2007 58 3 10183850 10183850 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5399 https://civicdb.org/links/variants/2007 https://civicdb.org/links/genes/58 false VHL 7428 R161Q (c.482G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and two patients with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5400 1746 58 3 10191489 10191489 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5400 https://civicdb.org/links/variants/1746 https://civicdb.org/links/genes/58 false VHL 7428 R161P (c.482G>C) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5401 1855 58 3 10191489 10191489 G C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5401 https://civicdb.org/links/variants/1855 https://civicdb.org/links/genes/58 false VHL 7428 R167Q (c.500G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5402 1739 58 3 10191507 10191507 G A ENST00000256474.2 75 GRCh37 R167Q is the most common point mutation in hereditary Von Hippel-Lindau (VHL) disease and disrupts the VHL genes binding to elongin C reducing the levels of the VHL-elongin B-elongin C (VBC) E3 ligase complex and inhibiting the ability of VHL to regulate HIF2α. This partial function in turn leads to an increased risk of tumorgenesis. VHL derived clear cell renal cell carcinoma models however have shown the proteasome inhibitors bortezomib and carfilzomib can act to stabilize mutant VHL-R167Q leading to downregulation of HIF2α and suprressed tumorgenesis. Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/5402 https://civicdb.org/links/variants/1739 https://civicdb.org/links/genes/58 false VHL 7428 Q164* (c.490C>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This nonsense mutation was found in the VHL gene and one patient with pheochromocytoma. This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5403 1845 58 3 10191497 10191497 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/5403 https://civicdb.org/links/variants/1845 https://civicdb.org/links/genes/58 false VHL 7428 Q195* (c.583C>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This nonsense mutation was found in the VHL gene and one patient with pheochromocytoma. This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5404 1810 58 3 10191590 10191590 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5404 https://civicdb.org/links/variants/1810 https://civicdb.org/links/genes/58 false VHL 7428 E94* (c.280G>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This nonsense mutation was found in the VHL gene and one patient with pheochromocytoma. This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5405 1794 58 3 10183811 10183811 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5405 https://civicdb.org/links/variants/1794 https://civicdb.org/links/genes/58 false VHL 7428 G93C (c.277G>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5406 2008 58 3 10183808 10183808 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5406 https://civicdb.org/links/variants/2008 https://civicdb.org/links/genes/58 false VHL 7428 G93S (c.277G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and two patients with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5407 1859 58 3 10183808 10183808 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5407 https://civicdb.org/links/variants/1859 https://civicdb.org/links/genes/58 false VHL 7428 G93V (c.278G>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5408 2009 58 3 10183809 10183809 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5408 https://civicdb.org/links/variants/2009 https://civicdb.org/links/genes/58 false VHL 7428 L188V (c.562C>G) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5409 1836 58 3 10191569 10191569 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5409 https://civicdb.org/links/variants/1836 https://civicdb.org/links/genes/58 false VHL 7428 L198Q (c.593T>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5410 2010 58 3 10191600 10191600 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5410 https://civicdb.org/links/variants/2010 https://civicdb.org/links/genes/58 false VHL 7428 F119L (c.357C>G) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5411 1743 58 3 10188214 10188214 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5411 https://civicdb.org/links/variants/1743 https://civicdb.org/links/genes/58 false VHL 7428 F136C (c.407T>G) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5412 1814 58 3 10188264 10188264 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5412 https://civicdb.org/links/variants/1814 https://civicdb.org/links/genes/58 false VHL 7428 S65A (c.193T>G) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5413 2011 58 3 10183724 10183724 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5413 https://civicdb.org/links/variants/2011 https://civicdb.org/links/genes/58 false VHL 7428 S68W (c.203C>G) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5414 2012 58 3 10183734 10183734 C G ENST00000256474.2 GRCh37 One similar submission at this exact genomic location has been entered into ClinVar (ClinVar ID: 625222 C>T). Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5414 https://civicdb.org/links/variants/2012 https://civicdb.org/links/genes/58 false VHL 7428 S80N (c.239G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5415 1874 58 3 10183770 10183770 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5415 https://civicdb.org/links/variants/1874 https://civicdb.org/links/genes/58 false VHL 7428 Y156N (c.466T>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5416 2013 58 3 10191473 10191473 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5416 https://civicdb.org/links/variants/2013 https://civicdb.org/links/genes/58 false VHL 7428 Y156C (c.467A>G) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and two patients with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5417 1946 58 3 10191474 10191474 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5417 https://civicdb.org/links/variants/1946 https://civicdb.org/links/genes/58 false VHL 7428 Y98H (c.292T>C) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 5418 1741 58 3 10183823 10183823 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/5418 https://civicdb.org/links/variants/1741 https://civicdb.org/links/genes/58 false VHL 7428 P61fs (c.183insC) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This mutation was detected in a previously diagnosed VHL patient by DHPLC (VHL 73). This frameshift mutation provides strong evidence of pathogenicity (PVS1). 11409863 PubMed Klein et al., 2001, Hum. Genet. 3 accepted 5420 2014 58 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5420 https://civicdb.org/links/variants/2014 https://civicdb.org/links/genes/58 false VHL 7428 S65* (c.194C>A) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This nonsense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 83). This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 11409863 PubMed Klein et al., 2001, Hum. Genet. 3 accepted 5422 1811 58 3 10183725 10183725 C A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5422 https://civicdb.org/links/variants/1811 https://civicdb.org/links/genes/58 false VHL 7428 V74G (c.221T>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This missense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 92). This was the same missense mutation as was described in the previously published Glavač et al. (1996) study included in this study (VHL 9 and 53). 11409863 PubMed Klein et al., 2001, Hum. Genet. 2 accepted 5424 1999 58 3 10183752 10183752 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5424 https://civicdb.org/links/variants/1999 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This mutation was found in 2 previously diagnosed VHL patients and a suspect VHL mutation carrier by DHPLC (family VHL 26, VHL 63, VHL 77). This variant results in an in frame deletion providing moderate evidence for pathogenicity (PM4). 11409863 PubMed Klein et al., 2001, Hum. Genet. 2 accepted 5426 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:42 UTC https://civicdb.org/links/evidence_items/5426 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false VHL 7428 S80N (c.239G>A) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This missense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 82). 11409863 PubMed Klein et al., 2001, Hum. Genet. 2 accepted 5427 1874 58 3 10183770 10183770 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5427 https://civicdb.org/links/variants/1874 https://civicdb.org/links/genes/58 false VHL 7428 S80I (c.239G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This missense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 104). 11409863 PubMed Klein et al., 2001, Hum. Genet. 2 accepted 5428 1757 58 3 10183770 10183770 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5428 https://civicdb.org/links/variants/1757 https://civicdb.org/links/genes/58 false VHL 7428 V84L (c.250G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This nonsense mutation was found in a suspect VHL mutation carrier by DHPLC (family VHL 110). 11409863 PubMed Klein et al., 2001, Hum. Genet. 2 accepted 5430 1815 58 3 10183781 10183781 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5430 https://civicdb.org/links/variants/1815 https://civicdb.org/links/genes/58 false VHL 7428 L85P (c.254T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This missense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 66). 11409863 PubMed Klein et al., 2001, Hum. Genet. 2 accepted 5431 2020 58 3 10183785 10183785 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5431 https://civicdb.org/links/variants/2020 https://civicdb.org/links/genes/58 false VHL 7428 G93R (c.277G>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This missense mutation was found in a suspected VHL mutation carrier by DHPLC (family VHL 106). 11409863 PubMed Klein et al., 2001, Hum. Genet. 2 accepted 5432 1920 58 3 10183808 10183808 G C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5432 https://civicdb.org/links/variants/1920 https://civicdb.org/links/genes/58 false VHL 7428 E94* (c.280G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This nonsense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 85). This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 11409863 PubMed Klein et al., 2001, Hum. Genet. 2 accepted 5433 1794 58 3 10183811 10183811 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5433 https://civicdb.org/links/variants/1794 https://civicdb.org/links/genes/58 false VHL 7428 R108dup (c.322_324dup) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 86). Protein length changes as a result of in-frame insertion in a nonrepeat region (ACMG code: PM4). 11409863 PubMed Klein et al., 2001, Hum. Genet. 2 accepted 5434 2021 58 3 10183849 10183850 CGC ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5434 https://civicdb.org/links/variants/2021 https://civicdb.org/links/genes/58 false VHL 7428 L118P (c.353T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This missense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 94). 11409863 PubMed Klein et al., 2001, Hum. Genet. 2 accepted 5435 1798 58 3 10188210 10188210 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/5435 https://civicdb.org/links/variants/1798 https://civicdb.org/links/genes/58 false VHL 7428 F119L (c.357C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This missense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 99). 11409863 PubMed Klein et al., 2001, Hum. Genet. 2 accepted 5436 1743 58 3 10188214 10188214 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5436 https://civicdb.org/links/variants/1743 https://civicdb.org/links/genes/58 false VHL 7428 D121G (c.362A>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This missense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 105). 11409863 PubMed Klein et al., 2001, Hum. Genet. 2 accepted 5437 1813 58 3 10188219 10188219 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5437 https://civicdb.org/links/variants/1813 https://civicdb.org/links/genes/58 false VHL 7428 Y175* (c.525C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This nonsense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 103). This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 11409863 PubMed Klein et al., 2001, Hum. Genet. 3 accepted 5440 1969 58 3 10191532 10191532 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5440 https://civicdb.org/links/variants/1969 https://civicdb.org/links/genes/58 false VHL 7428 V194fs (c.581_582del) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 79). This study contains very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 11409863 PubMed Klein et al., 2001, Hum. Genet. 3 accepted 5441 1977 58 3 10191587 10191588 TG ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5441 https://civicdb.org/links/variants/1977 https://civicdb.org/links/genes/58 false VHL 7428 A149fs (c.449del14-nt) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 75). This study contains very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 11409863 PubMed Klein et al., 2001, Hum. Genet. 2 accepted 5442 2023 58 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5442 https://civicdb.org/links/variants/2023 https://civicdb.org/links/genes/58 false VHL 7428 3'UTR alteration (c.639+10C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 80). 11409863 PubMed Klein et al., 2001, Hum. Genet. 2 accepted 5443 2024 58 3 10191656 10191656 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5443 https://civicdb.org/links/variants/2024 https://civicdb.org/links/genes/58 false VHL 7428 Q164R (c.491A>G) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Renal cyst,Pheochromocytoma,Simple renal cyst,Epididymal cyst Predisposing N/A C N/A A 2.75 year old patient (32 month-old girl) presented with a pheochromocytoma. Genetic sequencing revealed a c.491A>G (p.Gln164Arg) heterozygous germline mutation in exon 3 of the VHL gene. Sequencing of her mother, father, a sibling, and her paternal grandparents revealed that the mutation was present only in her father, and was de-novo in her father. Upon screening, her father (a 31 year old male) presented with a retinal angioma, an adenoma of right adrenal gland, a right-sided renal cyst, an epidydymal cyst, a contrast-enhancing lesion in the pancreas, and bilateral pheochromocytomas. ACMG evidence codes: 'PP1'- Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease, and 'PP4'- patients' phenotypes or family history are highly specific for a disease with a single genetic etiology. 20583150 PubMed Sovinz et al., 2010, Am. J. Med. Genet. A 4 accepted 5444 1856 58 3 10191498 10191498 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/5444 https://civicdb.org/links/variants/1856 https://civicdb.org/links/genes/58 false VHL 7428 E70* (c.208G>T) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease. 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5445 1834 58 3 10183739 10183739 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5445 https://civicdb.org/links/variants/1834 https://civicdb.org/links/genes/58 false VHL 7428 V74G (c.221T>G) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5446 1999 58 3 10183752 10183752 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5446 https://civicdb.org/links/variants/1999 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. More specifically, the mutation causes the following protein change: F76Cfs*83. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a frameshift variant in a gene where loss of function is a known mechanism of disease. 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5447 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:42 UTC https://civicdb.org/links/evidence_items/5447 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false VHL 7428 S80R (c.240T>G) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5448 1792 58 3 10183771 10183771 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5448 https://civicdb.org/links/variants/1792 https://civicdb.org/links/genes/58 false VHL 7428 L89P (c.266T>C) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5449 1793 58 3 10183797 10183797 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5449 https://civicdb.org/links/variants/1793 https://civicdb.org/links/genes/58 false VHL 7428 G93R (c.277G>C) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5450 1920 58 3 10183808 10183808 G C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5450 https://civicdb.org/links/variants/1920 https://civicdb.org/links/genes/58 false VHL 7428 Y98H (c.292T>C) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 2 patients were found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5451 1741 58 3 10183823 10183823 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5451 https://civicdb.org/links/variants/1741 https://civicdb.org/links/genes/58 false VHL 7428 G114S (c.340G>A) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5452 2026 58 3 10183871 10183871 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5452 https://civicdb.org/links/variants/2026 https://civicdb.org/links/genes/58 false VHL 7428 W117fs (c.349dup) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. More specifically, the mutation causes the following protein change W117LfsX1. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a frameshift variant in a gene where loss of function is a known mechanism of disease. 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5453 2027 58 3 10188206 10188207 T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5453 https://civicdb.org/links/variants/2027 https://civicdb.org/links/genes/58 false VHL 7428 F119L (c.357C>G) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 2 patients were found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5454 1743 58 3 10188214 10188214 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5454 https://civicdb.org/links/variants/1743 https://civicdb.org/links/genes/58 false VHL 7428 D121G (c.362A>G) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5455 1813 58 3 10188219 10188219 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5455 https://civicdb.org/links/variants/1813 https://civicdb.org/links/genes/58 false VHL 7428 A122I (c.364_365GC>AT) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the A122I mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5456 2028 58 3 10188221 10188222 GC AT ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5456 https://civicdb.org/links/variants/2028 https://civicdb.org/links/genes/58 false VHL 7428 N131K (c.393C>A) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5457 1953 58 3 10188250 10188250 C A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5457 https://civicdb.org/links/variants/1953 https://civicdb.org/links/genes/58 false VHL 7428 Q132* (c.394C>T) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease. 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5458 1994 58 3 10188251 10188251 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5458 https://civicdb.org/links/variants/1994 https://civicdb.org/links/genes/58 false VHL 7428 N150fs (c.445_458del) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. More specifically, this mutation causes the following protein change: N150SfsX19. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a frameshift variant in a gene where loss of function is a known mechanism of disease. Relevant HPO terms: Neuroendocrine neoplasm. 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5459 2029 58 3 10188302 10188315 GCCAATATCACACT ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5459 https://civicdb.org/links/variants/2029 https://civicdb.org/links/genes/58 false VHL 7428 I151M (c.453C>G) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5460 2030 58 3 10188310 10188310 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5460 https://civicdb.org/links/variants/2030 https://civicdb.org/links/genes/58 false VHL 7428 P154L (c.461C>T) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5461 1782 58 3 10188318 10188318 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5461 https://civicdb.org/links/variants/1782 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.464-2A>G) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 2 patients were found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5462 2078 58 3 10191469 10191469 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5462 https://civicdb.org/links/variants/2078 https://civicdb.org/links/genes/58 false VHL 7428 Y156C (c.467A>G) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5463 1946 58 3 10191474 10191474 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5463 https://civicdb.org/links/variants/1946 https://civicdb.org/links/genes/58 false VHL 7428 L158V (c.472C>G) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5464 1803 58 3 10191479 10191479 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5464 https://civicdb.org/links/variants/1803 https://civicdb.org/links/genes/58 false VHL 7428 E160FS (c.479_480delAG) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 2 patients were found to have the above mutation. More specifically, this mutation causes the following protein change: E160AfsX12. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a frameshift variant in a gene where loss of function is a known mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5465 1919 58 3 10191486 10191487 AG ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5465 https://civicdb.org/links/variants/1919 https://civicdb.org/links/genes/58 false VHL 7428 R161Q (c.482G>A) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 5 patients were found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5466 1746 58 3 10191489 10191489 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5466 https://civicdb.org/links/variants/1746 https://civicdb.org/links/genes/58 false VHL 7428 L163H (c.488T>A) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5467 2033 58 3 10191495 10191495 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5467 https://civicdb.org/links/variants/2033 https://civicdb.org/links/genes/58 false VHL 7428 R167W (c.499C>T) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 7 patients were found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 3 accepted 5468 1747 58 3 10191506 10191506 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/5468 https://civicdb.org/links/variants/1747 https://civicdb.org/links/genes/58 false VHL 7428 R167Q (c.500G>A) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 4 patients were found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5469 1739 58 3 10191507 10191507 G A ENST00000256474.2 75 GRCh37 R167Q is the most common point mutation in hereditary Von Hippel-Lindau (VHL) disease and disrupts the VHL genes binding to elongin C reducing the levels of the VHL-elongin B-elongin C (VBC) E3 ligase complex and inhibiting the ability of VHL to regulate HIF2α. This partial function in turn leads to an increased risk of tumorgenesis. VHL derived clear cell renal cell carcinoma models however have shown the proteasome inhibitors bortezomib and carfilzomib can act to stabilize mutant VHL-R167Q leading to downregulation of HIF2α and suprressed tumorgenesis. Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5469 https://civicdb.org/links/variants/1739 https://civicdb.org/links/genes/58 false VHL 7428 L178P (c.533T>C) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5470 1748 58 3 10191540 10191540 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5470 https://civicdb.org/links/variants/1748 https://civicdb.org/links/genes/58 false VHL 7428 S183* (c.548C>A) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5471 1784 58 3 10191555 10191555 C A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5471 https://civicdb.org/links/variants/1784 https://civicdb.org/links/genes/58 false VHL 7428 Q195* (c.583C>T) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5472 1810 58 3 10191590 10191590 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5472 https://civicdb.org/links/variants/1810 https://civicdb.org/links/genes/58 false VHL 7428 L198Q (c.593T>A) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 2 patients were found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 5473 2010 58 3 10191600 10191600 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5473 https://civicdb.org/links/variants/2010 https://civicdb.org/links/genes/58 false VHL 7428 Y98H (c.292T>C) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 20846682 PubMed Benhammou et al., 2010, J. Urol. 2 accepted 5474 1741 58 3 10183823 10183823 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5474 https://civicdb.org/links/variants/1741 https://civicdb.org/links/genes/58 false VHL 7428 Y112H (c.334T>C) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 20846682 PubMed Benhammou et al., 2010, J. Urol. 2 accepted 5475 1865 58 3 10183865 10183865 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/5475 https://civicdb.org/links/variants/1865 https://civicdb.org/links/genes/58 false VHL 7428 G114R (c.340G>C) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 20846682 PubMed Benhammou et al., 2010, J. Urol. 2 accepted 5476 1857 58 3 10183871 10183871 G C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5476 https://civicdb.org/links/variants/1857 https://civicdb.org/links/genes/58 false VHL 7428 L118P (c.353T>C) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 20846682 PubMed Benhammou et al., 2010, J. Urol. 2 accepted 5477 1798 58 3 10188210 10188210 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5477 https://civicdb.org/links/variants/1798 https://civicdb.org/links/genes/58 false VHL 7428 L128F (c.382C>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 20846682 PubMed Benhammou et al., 2010, J. Urol. 2 accepted 5478 3066 58 3 10188239 10188239 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/5478 https://civicdb.org/links/variants/3066 https://civicdb.org/links/genes/58 false VHL 7428 L129P (c.386T>C) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 20846682 PubMed Benhammou et al., 2010, J. Urol. 2 accepted 5479 2508 58 3 10188243 10188243 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/5479 https://civicdb.org/links/variants/2508 https://civicdb.org/links/genes/58 false VHL 7428 F136C (c.407T>G) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance 26 VHL patients, from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 20846682 PubMed Benhammou et al., 2010, J. Urol. 2 accepted 5480 1814 58 3 10188264 10188264 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5480 https://civicdb.org/links/variants/1814 https://civicdb.org/links/genes/58 false VHL 7428 R161Q (c.482G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance 26 VHL patients, from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 20846682 PubMed Benhammou et al., 2010, J. Urol. 2 accepted 5481 1746 58 3 10191489 10191489 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5481 https://civicdb.org/links/variants/1746 https://civicdb.org/links/genes/58 false VHL 7428 C162fs (c.483del) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance 26 VHL patients, from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. More specifically, this mutation causes the following protein change: C162AfsX8. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a frameshift variant in a gene where loss of function is a known mechanism of disease. Relevant HPO terms: Pheochromocytoma. 20846682 PubMed Benhammou et al., 2010, J. Urol. 2 accepted 5482 2035 58 3 10191490 10191490 A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5482 https://civicdb.org/links/variants/2035 https://civicdb.org/links/genes/58 false VHL 7428 R161* (c.481C>T) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This nonsense mutation was found in a VHL patient with hemangioblastomas of the central nervous system and retina, and renal cell carcinoma (family no. 15). This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 12114495 PubMed Cybulski et al., 2002, J. Med. Genet. 3 accepted 5483 1804 58 3 10191488 10191488 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5483 https://civicdb.org/links/variants/1804 https://civicdb.org/links/genes/58 false VHL 7428 R167W (c.499C>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 2 patients from 2 families were confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. 20846682 PubMed Benhammou et al., 2010, J. Urol. 2 accepted 5484 1747 58 3 10191506 10191506 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5484 https://civicdb.org/links/variants/1747 https://civicdb.org/links/genes/58 false VHL 7428 R167Q (c.500G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 12 patients from 4 families were confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. 20846682 PubMed Benhammou et al., 2010, J. Urol. 2 accepted 5485 1739 58 3 10191507 10191507 G A ENST00000256474.2 75 GRCh37 R167Q is the most common point mutation in hereditary Von Hippel-Lindau (VHL) disease and disrupts the VHL genes binding to elongin C reducing the levels of the VHL-elongin B-elongin C (VBC) E3 ligase complex and inhibiting the ability of VHL to regulate HIF2α. This partial function in turn leads to an increased risk of tumorgenesis. VHL derived clear cell renal cell carcinoma models however have shown the proteasome inhibitors bortezomib and carfilzomib can act to stabilize mutant VHL-R167Q leading to downregulation of HIF2α and suprressed tumorgenesis. Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5485 https://civicdb.org/links/variants/1739 https://civicdb.org/links/genes/58 false VHL 7428 Null (Partial deletion of Exons 2 & 3) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 3 patients from 3 families were confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a multiexon deletion variant in a gene where loss of function is a known mechanism of disease. 20846682 PubMed Benhammou et al., 2010, J. Urol. 3 accepted 5486 2036 58 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/5486 https://civicdb.org/links/variants/2036 https://civicdb.org/links/genes/58 false VHL 7428 R167Q (c.500G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma,Cerebellar hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). Arg167Trp and Arg167Gln mutations conferred a high (62%) risk for pheochromocytoma. Pheochromocytoma was diagnosed in all families with Arg167Gln mutation. This missense mutation was found in a VHL patient with retinal hemangioblastomas and pheochromocytoma (family no. 17). This mutation was also found in a VHL family of 8 affected patients (family no. 18). Seven had retinal hemangioblastomas, six had hemangioblastomas of the central nervous system, and 2 had pheochromocytoma. Cosegregation of the disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 12114495 PubMed Cybulski et al., 2002, J. Med. Genet. 2 accepted 5487 1739 58 3 10191507 10191507 G A ENST00000256474.2 75 GRCh37 R167Q is the most common point mutation in hereditary Von Hippel-Lindau (VHL) disease and disrupts the VHL genes binding to elongin C reducing the levels of the VHL-elongin B-elongin C (VBC) E3 ligase complex and inhibiting the ability of VHL to regulate HIF2α. This partial function in turn leads to an increased risk of tumorgenesis. VHL derived clear cell renal cell carcinoma models however have shown the proteasome inhibitors bortezomib and carfilzomib can act to stabilize mutant VHL-R167Q leading to downregulation of HIF2α and suprressed tumorgenesis. Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5487 https://civicdb.org/links/variants/1739 https://civicdb.org/links/genes/58 false VHL 7428 N78I (c.233A>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This missense mutation was found in a VHLD family of 4 affected patients (family no. 10). All 4 patients had retinal hemangioblastomas, 3 had hemangioblastomas of the central nervous system, and one had renal cell carcinoma. Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). HPO terms: retinal hemangioblastoma, hemangioblastoma, renal cell carcinoma. 12114495 PubMed Cybulski et al., 2002, J. Med. Genet. 2 accepted 5489 2037 58 3 10183764 10183764 A T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5489 https://civicdb.org/links/variants/2037 https://civicdb.org/links/genes/58 false VHL 7428 N78S (c.233A>G) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This missense mutation was found in a VHL patient and 2 VHL family members. The single patient had hemangioblastomas of the central nervous system and retina (family no. 8). One of the family members had retinal hemangioblastomas and the other had renal cell carcinoma (family no. 9). 12114495 PubMed Cybulski et al., 2002, J. Med. Genet. 2 accepted 5491 1755 58 3 10183764 10183764 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/5491 https://civicdb.org/links/variants/1755 https://civicdb.org/links/genes/58 false VHL 7428 C162Y (c.485G>A) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This missense mutation was found in a VHL family of 5 affected patients (family no. 16). Four had retinal hemangioblastomas and 4 had hemangioblastomas of the central nervous system. Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). HPO terms: hemangioblastoma, retinal hemangioblastoma. 12114495 PubMed Cybulski et al., 2002, J. Med. Genet. 2 accepted 5493 1824 58 3 10191492 10191492 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5493 https://civicdb.org/links/variants/1824 https://civicdb.org/links/genes/58 false VHL 7428 W88FS (c.263_265delGGCinsTT) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This mutation was found in a VHL patient with hemangioblastomas of the central nervous system and retina (family no. 11). This study contains very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). HPO terms: hemangioblastoma, retinal hemangioblastoma. 12114495 PubMed Cybulski et al., 2002, J. Med. Genet. 2 accepted 5495 2039 58 3 10183794 10183796 GGC TT ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5495 https://civicdb.org/links/variants/2039 https://civicdb.org/links/genes/58 false VHL 7428 K159fs (c.477_478insCA) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This mutation was found in VHL patient with hemangioblastomas of the retina and central nervous system (family no. 14). This study contains very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). HPO terms: hemangioblastoma, retinal hemangioblastoma. 12114495 PubMed Cybulski et al., 2002, J. Med. Genet. 2 accepted 5496 2040 58 3 10191484 10191485 CA ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5496 https://civicdb.org/links/variants/2040 https://civicdb.org/links/genes/58 false VHL 7428 S111R (c.333C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This missense mutation was found in a VHL patient with hemangioblastomas of the central nervous system and retina (family no. 12). HPO terms: hemangioblastoma, retinal hemangioblastoma. 12114495 PubMed Cybulski et al., 2002, J. Med. Genet. 2 accepted 5498 1764 58 3 10183864 10183864 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5498 https://civicdb.org/links/variants/1764 https://civicdb.org/links/genes/58 false VHL 7428 S65L (c.194C>T) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This missense mutation was found in a single VHL patient and 2 VHL families with multiple affected individuals. The patient had hemangioblastomas of the central nervous system (family no. 1). A VHL family of 4 affected individuals had one patient with retinal hemangioblastomas, 3 with hemangioblastomas of the central nervous system, and one with renal cell carcinoma (family no. 2). A VHL family of 12 individuals had 10 with retinal hemangioblastomas, 3 with renal cell carcinoma, and 12 with hemangioblastomas of the central nervous system (family no. 3). Supporting evidence of pathogenicity since there is cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). HPO terms: hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma. 12114495 PubMed Cybulski et al., 2002, J. Med. Genet. 2 accepted 5499 1788 58 3 10183725 10183725 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5499 https://civicdb.org/links/variants/1788 https://civicdb.org/links/genes/58 false VHL 7428 Q73FS (c.217delC) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This mutation was found in a VHL patient with hemangioblastomas of the central nervous system and retina (family no. 4). This study contains very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). HPO terms: hemangioblastoma, retinal hemangioblastoma. 12114495 PubMed Cybulski et al., 2002, J. Med. Genet. 2 accepted 5500 2041 58 3 10183748 10183748 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5500 https://civicdb.org/links/variants/2041 https://civicdb.org/links/genes/58 false VHL 7428 A149fs (c.445delG) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This mutation was found in a VHL family of 3 individuals. All 3 had retinal hemangioblastomas, 2 had hemangioblastomas of the central nervous system, and one had renal cell carcinoma (family no. 13). ACMG codes as follows: A frameshift variant in a gene where loss-of-function is a known mechanism of disease (PVS1). HPO terms: hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma. 12114495 PubMed Cybulski et al., 2002, J. Med. Genet. 2 accepted 5501 2042 58 3 10188302 10188302 G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5501 https://civicdb.org/links/variants/2042 https://civicdb.org/links/genes/58 false MYC 4609 Overexpression Multiple Myeloma 9538 JQ-1 Predictive Supports D Sensitivity/Response BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. 21889194 PubMed Delmore et al., 2011, Cell 5 accepted 5505 1303 3737 Somatic 2017-12-18 20:39:08 UTC https://civicdb.org/links/evidence_items/5505 https://civicdb.org/links/variants/1303 https://civicdb.org/links/genes/3737 false RRM1 6240 Underexpression Pancreatic Cancer 1793 Gemcitabine Predictive Supports B Sensitivity/Response There were 68 patients enrolled in this study, 28 of which were treated with gemcitabine. Of those 28, 14 patients had a low RRM1 expression and 14 had a high RRM1 expression. Only the patients with low RRM1 expression received a significant benefit from gemcitabine (p=0.0010) whereas the benefit for those with a high RRM1 expression was not significantly better (p=0.3309). The study also tested the role of ERCC1 expression and its correlation to RRM1 expression. It was found that patients with a combined high RRM1 and ERCC1 expression had good prognosis with the highest survival rate (P=0.0127). 19543324 PubMed Akita et al., 2009, Oncogene 3 accepted 5506 1257 5051 11 4116039 4160106 ENST00000300738.5 75 GRCh37 N/A 2017-07-28 18:30:58 UTC https://civicdb.org/links/evidence_items/5506 https://civicdb.org/links/variants/1257 https://civicdb.org/links/genes/5051 false CD274 29126 Expression Cancer 162 Prognostic Supports B Poor Outcome A meta analysis of 60 research studies involving 10,310 solid tumors indicated that CD274 over expression results in poor overall survival (HR = 1.58, P <.001) and poor disease free/progression free survival (DFS/PFS) (HR = 1.72, P =0 .001). When split into sub groups by cancer type overall survival was poor for breast (HR = 1.98, P =0 .014), urothelial (HR = 2.24, P <0.001), renal (HR = 3.30, P <0.001), and gastric cancers (HR = 1.56, P =0 .040). DFS/PFS was poor in patients with hepatocellular carcinoma (HR = 1.72, P = 0.003), melanoma (HR = 3.39, P <0.001), and renal carcinoma, (HR = 5.04, P <0.001). 28471952 PubMed Wang et al., 2017, Medicine (Baltimore) 4 accepted 5507 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2017-08-11 15:54:07 UTC https://civicdb.org/links/evidence_items/5507 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false RRM1 6240 Underexpression Pancreatic Cancer 1793 Gemcitabine Predictive Supports B Sensitivity/Response In this study, human pancreatic carcinoma cell line MiaPaCa2, which is a gemcitabine-sensitive cell line, was used for the establishment of chemoresistant cells MiaPaCa2-RG. Analysis for identifying genetic alterations relating to gemcitabine resistance revealed that RRM1 was the most upregulated gene with a 4.5 fold expression. RRM1-specific RNAi transfection significantly reduced the gemcitabine chemoresistance of MiaPaCa2-RG to the same level as that of gemcitabine sensitive MiaPaCa2. Moreover, gemcitabine response of MiaPaCa2 also became more sensitive. Next, patients with pancreatic cancer were recruited and 18 tissue samples were taken. The patients with a low RRM1 expression had a significantly better outcome after gemcitabine treatment than those patients with high RRM1 expression (P=0.016). 17131328 PubMed Nakahira et al., 2007, Int. J. Cancer 3 accepted 5508 1257 5051 11 4116039 4160106 ENST00000300738.5 75 GRCh37 N/A 2017-09-09 23:01:50 UTC https://civicdb.org/links/evidence_items/5508 https://civicdb.org/links/variants/1257 https://civicdb.org/links/genes/5051 false RRM1 6240 Underexpression Lung Non-small Cell Carcinoma 3908 Gemcitabine Predictive Supports B Sensitivity/Response In this study, 229 tumors were analyzed for RRM1 expression. This resulted in 146 that were negative for RRM1 expression and 83 that were positive. These tumors were studied for a relationship between RRM1 expression and chemotherapy regimens, gemcitabine, docetaxel and carboplatin, and vinorelbine and carboplatin. In the patients receiving gemcitabine treatment, the progression-free survival of RRM1-negative patients was significantly higher than that of RRM1-positive patients (8.8 months vs. 7.6 months, P = 0.01). The patients that were positive for RRM1 expression, had a better response to docetaxel or vinorelbine treatment than gemcitabine (P=0.047 and P=0.047). However, there were no differences of response to docetaxel and vinorelbine in regards to RRM1 expression. 24647522 PubMed Dong et al., 2014, PLoS ONE 4 accepted 5530 1257 5051 11 4116039 4160106 ENST00000300738.5 75 GRCh37 N/A 2022-01-07 01:13:00 UTC https://civicdb.org/links/evidence_items/5530 https://civicdb.org/links/variants/1257 https://civicdb.org/links/genes/5051 false DICER1 23405 E1705K Sertoli-Leydig Cell Tumor 2997 Diagnostic Supports B Positive Sanger sequencing identified DICER1 hotspot mutations in 20 of 32 (63%) ovarian Sertoli–Leydig cell tumors. These mutations were unrelated to tumor differentiation and mostly (16/20, 80%) were E1705K. Additionally, DICER1 E1705K mutations were identified in 5/8 (63%) Sertoli cell tumors and 2/5 (40%) gynandroblastomas. However, no mutations were identified in 15 testicular sex cord-stromal tumors (8 classical Sertoli cell tumors, 3 Sertoli cell tumors-large cell calcifying variant, 4 sex cord-stromal tumors not otherwise specified). 26428316 PubMed Conlon et al., 2015, Mod. Pathol. 4 accepted 5533 2050 9533 14 95560476 95560476 C T ENST00000526495.1 75 GRCh37 Somatic 2021-03-02 19:58:47 UTC https://civicdb.org/links/evidence_items/5533 https://civicdb.org/links/variants/2050 https://civicdb.org/links/genes/9533 false DICER1 23405 D1709N Sertoli-Leydig Cell Tumor 2997 Diagnostic Does Not Support B Positive In this exploratory study of Sertoli-Leydig cell tumors, DICER1 mutations were found in over half of the samples sequenced, but were not found to have any role in tumorigenesis, contrary to what was previously believed. 26428316 PubMed Conlon et al., 2015, Mod. Pathol. 4 accepted 5534 2051 9533 Somatic 2021-03-02 19:58:16 UTC https://civicdb.org/links/evidence_items/5534 https://civicdb.org/links/variants/2051 https://civicdb.org/links/genes/9533 false DICER1 23405 E1813Q Sertoli-Leydig Cell Tumor 2997 Diagnostic Does Not Support B Positive In this exploratory study of Sertoli-Leydig cell tumors, DICER1 mutations were found in over half of the samples sequenced, but were not found to have any role in tumorigenesis, contrary to what was previously believed. 26428316 PubMed Conlon et al., 2015, Mod. Pathol. 4 accepted 5535 2052 9533 14 95557630 95557630 C G ENST00000526495.1 75 GRCh37 Somatic 2021-03-02 19:55:29 UTC https://civicdb.org/links/evidence_items/5535 https://civicdb.org/links/variants/2052 https://civicdb.org/links/genes/9533 false VHL 7428 F136S (c.407T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in 20 Brazilian, VHL probands and their families. This missense mutation was found in a VHL type 1 family of 8 affected individuals (VHL family 12). Seven had hemangioblastomas of the central nervous system, one had retinal angiomas, and 2 had renal carcinoma. Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). HPO terms: hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma. 12624160 PubMed Rocha et al., 2003, J. Med. Genet. 3 accepted 5543 1801 58 3 10188264 10188264 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5543 https://civicdb.org/links/variants/1801 https://civicdb.org/links/genes/58 false VHL 7428 P146fs (c.437del) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in 20 Brazilian, VHL probands and their families. This mutation causes a premature stop codon at amino acid 158 and was found in a VHL type 1 patient with hemangioblastomas of the central nervous system, retinal angiomas, and renal carcinoma (VHL family 13). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). HPO terms: hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma. 12624160 PubMed Rocha et al., 2003, J. Med. Genet. 3 accepted 5544 2055 58 3 10188293 10188293 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5544 https://civicdb.org/links/variants/2055 https://civicdb.org/links/genes/58 false VHL 7428 R167W (c.499C>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma,Hemangioblastoma Predisposing Supports C Uncertain Significance Germline mutations were found in 20 Brazilian, VHL probands and their families. This missense mutation was found in 2 affected family members with pheochromocytoma (VHL family 15). One also had hemangioblastomas of the central nervous system. 12624160 PubMed Rocha et al., 2003, J. Med. Genet. 3 accepted 5545 1747 58 3 10191506 10191506 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/5545 https://civicdb.org/links/variants/1747 https://civicdb.org/links/genes/58 false VHL 7428 R167Q (c.500G>A) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Pheochromocytoma Predisposing Supports C Uncertain Significance Germline mutations were found in 20 Brazilian, VHL probands and their families. This missense mutation was found in a VHL type 2 family of 4 affected individuals (VHL family 16). Two patients had hemangioblastomas of the central nervous system and three had pheochromocytoma. ACMG codes as follows: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). 12624160 PubMed Rocha et al., 2003, J. Med. Genet. 3 accepted 5546 1739 58 3 10191507 10191507 G A ENST00000256474.2 75 GRCh37 R167Q is the most common point mutation in hereditary Von Hippel-Lindau (VHL) disease and disrupts the VHL genes binding to elongin C reducing the levels of the VHL-elongin B-elongin C (VBC) E3 ligase complex and inhibiting the ability of VHL to regulate HIF2α. This partial function in turn leads to an increased risk of tumorgenesis. VHL derived clear cell renal cell carcinoma models however have shown the proteasome inhibitors bortezomib and carfilzomib can act to stabilize mutant VHL-R167Q leading to downregulation of HIF2α and suprressed tumorgenesis. Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5546 https://civicdb.org/links/variants/1739 https://civicdb.org/links/genes/58 false VHL 7428 S80R (c.238A>C) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Renal cell carcinoma,Hemangioblastoma Predisposing Supports C Uncertain Significance Germline mutations were found in 20 Brazilian, VHL probands and their families. This missense mutation was found in a VHL type 1 family of 10 affected individuals (VHL family 2). Seven had hemangioblastomas of the central nervous system, 3 had retinal angiomas, and 3 had renal carcinoma. Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 12624160 PubMed Rocha et al., 2003, J. Med. Genet. 3 accepted 5547 1963 58 3 10183769 10183769 A C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/5547 https://civicdb.org/links/variants/1963 https://civicdb.org/links/genes/58 false VHL 7428 S80R (c.238A>C) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Germline mutations were found in 20 Brazilian, VHL probands and their families. This missense mutation was found in a VHL type 1 family of 10 affected individuals (VHL family 2). Seven had hemangioblastomas of the central nervous system, 3 had retinal angiomas, and 3 had renal carcinoma. Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 12624160 PubMed Rocha et al., 2003, J. Med. Genet. 3 accepted 5548 1963 58 3 10183769 10183769 A C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5548 https://civicdb.org/links/variants/1963 https://civicdb.org/links/genes/58 false VHL 7428 W88R (c.262T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in 20 Brazilian, VHL probands and their families. This missense mutation was found in 2 VHL family members (VHL family 3). One had hemangioblastomas of the central nervous system and the other had retinal angiomas. HPO terms: hemangioblastoma, retinal hemangioblastoma. 12624160 PubMed Rocha et al., 2003, J. Med. Genet. 3 accepted 5549 2056 58 3 10183793 10183793 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5549 https://civicdb.org/links/variants/2056 https://civicdb.org/links/genes/58 false VHL 7428 E94* (c.280G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in 20 Brazilian, VHL probands and their families. This nonsense mutation was found in a VHL type 1 family of 3 affected individuals. All three family members had retinal angiomas and 2 also had hemangioblastomas of the central nervous system (VHL family 4). A nonsense mutation in a gene where loss-of-function is a known mechanism of disease (PVS1). HPO terms: hemangioblastoma, retinal hemangioblastoma. 12624160 PubMed Rocha et al., 2003, J. Med. Genet. 3 accepted 5550 1794 58 3 10183811 10183811 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5550 https://civicdb.org/links/variants/1794 https://civicdb.org/links/genes/58 false VHL 7428 H115fs (c.344del) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in 20 Brazilian, VHL probands and their families. This mutstaion was found in a VHL type 1 family of 3 affected individuals (VHL family 9). One had hemangioblastomas of the central nervous system, one with retinal angiomas, and one with renal carcinoma. ACMG codes as follows: A frameshift mutation in a gene where loss-of-function is a known mechanism of disease (PVS1). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). HPO terms: hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma. 12624160 PubMed Rocha et al., 2003, J. Med. Genet. 3 accepted 5553 2057 58 3 10188201 10188201 A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5553 https://civicdb.org/links/variants/2057 https://civicdb.org/links/genes/58 false VHL 7428 P102fs (c.305delC) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in 20 Brazilian, VHL probands and their families. This mutation causes a premature stop codon at amino acid 142 and was found in a VHL type 1 patient with hemangioblastomas of the central nervous system (VHL family 6). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). HPO terms: hemangioblastoma. 12624160 PubMed Rocha et al., 2003, J. Med. Genet. 3 accepted 5554 2058 58 3 10183836 10183836 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5554 https://civicdb.org/links/variants/2058 https://civicdb.org/links/genes/58 false VHL 7428 E94* (c.280G>T) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Spinal hemangioblastoma Predisposing N/A C N/A Case report of a female VHL patient presenting with spinal hemangioblastoma at the age of 32. Further workup showed the presence of pancreatic cysts and a history of spinal hemangioblastoma in the mother. Genetic testing confirmed the presence of the above mutation in the proband. There was no mention of genetic testing performed on her mother in this paper. ACMG evidence codes: 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease, 'PP4' because the patients' phenotypes or family history are highly specific for a disease with single genetic etiology. Relevant HPO terms: Spinal hemangioblastoma, Multiple pancreatic cysts. 22133049 PubMed Sun et al., 2012, Br J Neurosurg 3 accepted 5561 1794 58 3 10183811 10183811 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5561 https://civicdb.org/links/variants/1794 https://civicdb.org/links/genes/58 false VHL 7428 Y175N (c.523T>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma,Retinal capillary hemangioma Predisposing N/A C N/A Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This missense mutation (Y175N (c.523T>A)) was found in a 32 year old patient with retinal hemangioblastomas and pheochromocytomas (patient no. F11). ACMG evidence code: "flag for PP4" because patients phenotype is highly specific for the disease. 14722919 PubMed Ruiz-Llorente et al., 2004, Hum. Mutat. 3 accepted 5576 2066 58 3 10191530 10191530 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5576 https://civicdb.org/links/variants/2066 https://civicdb.org/links/genes/58 false VHL 7428 Y175C (c.524A>G) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing N/A C N/A Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This missense mutation was found in a 32 year old patient with unilateral pheochromocytoma (patient no. F15). The patient also had a family history of pheochromocytoma. ACMG evidence codes: none 14722919 PubMed Ruiz-Llorente et al., 2004, Hum. Mutat. 3 accepted 5577 2067 58 3 10191531 10191531 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/5577 https://civicdb.org/links/variants/2067 https://civicdb.org/links/genes/58 false VHL 7428 D121G (c.362A>G) Von Hippel-Lindau Disease 14175 Renal cyst,Hemangioblastoma,Pheochromocytoma,Retinal capillary hemangioma Predisposing N/A C N/A Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This missense mutation was found in a 31 year old patient with retinal hemangioblastomas and renal cysts (patient no. F26). Patient had family history of pheochromocytomas and hemangioblastomas of the central nervous system. ACMG evidence code: "flag for PP4" because patients phenotype is highly specific for the disease. 14722919 PubMed Ruiz-Llorente et al., 2004, Hum. Mutat. 3 accepted 5578 1813 58 3 10188219 10188219 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/5578 https://civicdb.org/links/variants/1813 https://civicdb.org/links/genes/58 false VHL 7428 S65L (c.194C>T) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Clear cell renal cell carcinoma Predisposing N/A C N/A Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This germline missense mutation was found in a 25 year old patient with cerebellar hemangioblastomas, and clear cell renal carcinoma (patient no. F62). The patient's family history was negative for VHL features. This evidence supports the following ACMG Code: PP4- Patient's phenotype is specific for a disease with a single genetic etiology. 14722919 PubMed Ruiz-Llorente et al., 2004, Hum. Mutat. 3 accepted 5582 1788 58 3 10183725 10183725 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/5582 https://civicdb.org/links/variants/1788 https://civicdb.org/links/genes/58 false VHL 7428 Q96* (c.286C>T) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma Predisposing N/A C N/A Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This nonsense mutation was found in a patient with retinal hemangioblastoma (patient no. F66). Patient has family history of pancreatic cysts. This study contains very strong evidence for pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 14722919 PubMed Ruiz-Llorente et al., 2004, Hum. Mutat. 3 accepted 5583 1848 58 3 10183817 10183817 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5583 https://civicdb.org/links/variants/1848 https://civicdb.org/links/genes/58 false VHL 7428 S65W (c.194C>G) Von Hippel-Lindau Disease 14175 Renal cell carcinoma Predisposing Supports C Uncertain Significance The study looked to evaluate growth kinetic in VHL-associated renal cell carcinoma. Of the 64 VHL patients with renal involvement, 61 were confirmed to have a germline variant. This variant was identified in one patient (Patient #3 - supplementary table). Clinical manifestations included renal cell carcinoma; other manifestations were not discussed. 22156657 PubMed Jilg et al., 2012, Urol. Int. 2 accepted 5592 1787 58 3 10183725 10183725 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5592 https://civicdb.org/links/variants/1787 https://civicdb.org/links/genes/58 false RRM1 6240 Underexpression Lung Non-small Cell Carcinoma 3908 Paclitaxel,Gemcitabine,Vinorelbine Substitutes Predictive Supports B Sensitivity/Response The study began with a total of 443 patients that were randomly assigned to either regimen A (Paclitaxel and cisplatin with gemcitabine) or regimen B ( cisplatin and vinorelbine). Of those patients, 261 had tissue available for RRM1 evaluation. In regimen B, survival increased significantly in patients with low RRM1 expression as compared to those with a high expression (P=0.046). However, in regimen A, the increase in survival for patients with low RRM1 expression as opposed to those with a high RRM1 expression was not as significant (P=0.366). 23038758 PubMed Vilmar et al., 2013, Ann. Oncol. 3 accepted 5599 1257 5051 11 4116039 4160106 ENST00000300738.5 75 GRCh37 N/A 2021-02-23 18:42:57 UTC https://civicdb.org/links/evidence_items/5599 https://civicdb.org/links/variants/1257 https://civicdb.org/links/genes/5051 false VHL 7428 Splice Site (c.463+2T>C) Von Hippel-Lindau Disease 14175 Renal cell carcinoma Predisposing Supports C Uncertain Significance 64 VHL patients with renal involvement were analyzed. 61 of the 64 patients had a known germline mutation. The above mutation was found in 2 patients. Clinical manifestations included renal cell carcinoma; other manifestations are possible, but not discussed. ACMG evidence codes: 'PSV1' because they observe a canonical +2 splice site variant in a gene where loss of function is a known mechanism of disease. 22156657 PubMed Jilg et al., 2012, Urol. Int. 3 accepted 5610 2075 58 3 10188322 10188322 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5610 https://civicdb.org/links/variants/2075 https://civicdb.org/links/genes/58 false VHL 7428 R82_V84del (c.243_251del) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This mutation was found in a VHL type 1 patient (kindred no. 35). Only moderate support for pathogenicity because protein length changes as a result of in-frame deletions in a nonrepeat region (ACMG code: PM4). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 5637 2089 58 3 10183774 10183782 GCGCGTCGT ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5637 https://civicdb.org/links/variants/2089 https://civicdb.org/links/genes/58 false VHL 7428 P40fs (c.118ins) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This mutation was found in a VHL type 1 patient (kindred no. 46). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 5638 2090 58 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5638 https://civicdb.org/links/variants/2090 https://civicdb.org/links/genes/58 false VHL 7428 T152fs (c.455insA) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in a VHL type 1 patient (kindred no. 151). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 5639 2091 58 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5639 https://civicdb.org/links/variants/2091 https://civicdb.org/links/genes/58 false VHL 7428 T157fs (c.472ins) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in a VHL type 1 patient (kindred no. 76). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). However, the bases inserted were not described. 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 5640 2092 58 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5640 https://civicdb.org/links/variants/2092 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in 2 VHL type 1 patients (kindred no. 48, 75). Only moderate support for pathogenicity because protein length changes as a result of in-frame deletion in a nonrepeat region (ACMG code: PM4). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 5641 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5641 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.464-1G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This splice mutation was found in a VHL type 1 patient (kindred no. 143). This study contains very strong evidence for pathogenicity in the form of a canonical -1 splice site mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 5642 1990 58 3 10191470 10191470 G T ENST00000256474.2 75 GRCh37 There are three similar variants in ClinVar with this exact genomic position with ClinVar IDs: 223221, 223220, and 43603 of which only 223221 is an exact match (NM_000551.3:c.464-1G>T). Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5642 https://civicdb.org/links/variants/1990 https://civicdb.org/links/genes/58 false VHL 7428 R177fs (c.528del) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in a VHL type 1 family (kindred no. 54). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 7987306 PubMed Crossey et al., 1994, Hum. Mol. Genet. 3 accepted 5643 1907 58 3 10191535 10191535 G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:32 UTC https://civicdb.org/links/evidence_items/5643 https://civicdb.org/links/variants/1907 https://civicdb.org/links/genes/58 false VHL 7428 L158fs (c.471dupT) Von Hippel-Lindau Disease 14175 Predisposing N/A C N/A Germline mutation analysis of 469 VHL families reveled 300 mutations. The most common germline mutations were identified between codons 75-82, between codons 157-189 (Elongin binding domain) and at the splice site between exons 2 and 3. The association between mutations in codon 167 and pheochromocytoma was detected in all nationalities tested. This mutation was found in a VHL family (family ID 6BMS). No phenotype described. This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 8956040 PubMed Zbar et al., 1996, Hum. Mutat. 2 accepted 5646 1783 58 3 10191478 10191479 T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/5646 https://civicdb.org/links/variants/1783 https://civicdb.org/links/genes/58 false VHL 7428 G93_Y98del (c.275_292del) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This mutation was found in VHL type 1 family (lineage 11). Only moderate evidence for pathogenicity because protein length changes as a result of in-frame deletion in a nonrepeat region (ACMG code: PM4). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5649 2097 58 3 10183806 10183823 ACGGCGAGCCGCAGCCC ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/5649 https://civicdb.org/links/variants/2097 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This mutation was found in 2 VHL type 1 families (lineages 136, 183). Only moderate evidence for pathogenicity because protein length changes as a result of in-frame deletion in a nonrepeat region (ACMG code: PM4). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5650 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:42 UTC https://civicdb.org/links/evidence_items/5650 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false VHL 7428 E160fs (c.477del) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This mutation causes a premature stop codon at amino acid 170 and was found in a VHL type 1 family (lineage 16). There is very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). 9829911 PubMed Stolle et al., 1998, Hum. Mutat. 3 accepted 5651 2098 58 3 10191482 10191482 A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5651 https://civicdb.org/links/variants/2098 https://civicdb.org/links/genes/58 false VHL 7428 V66del (c.197_220del) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in a VHL type 1 patient (patient no. V287). Only moderate evidence of pathogenicity since the protein length changes as a result of an in-frame deletion in a nonrepeat region (AMCG code: PM4). One unaffected family member was tested and negative for this mutation. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 2 accepted 5653 2099 58 3 10183728 10183742 TGAACTCGCGCGAGC ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5653 https://civicdb.org/links/variants/2099 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in a VHL type 1 patient (patient no. V67). Only moderate evidence of pathogenicity since the protein length changes as a result of an in-frame deletion in a nonrepeat region (AMCG code: PM4). 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 2 accepted 5654 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:42 UTC https://civicdb.org/links/evidence_items/5654 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false VHL 7428 V84M (c.250G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance This study examined 182 patients with non-syndromic pheochromocytoma or paraganglioma for the presence of VHL mutations. VHL mutations were found in 3 of the 182 patients. The above mutation was found in 1 patient with pheochromocytoma. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 22438210 PubMed Eisenhofer et al., 2012, Horm. Metab. Res. 2 accepted 5660 2101 58 3 10183781 10183781 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/5660 https://civicdb.org/links/variants/2101 https://civicdb.org/links/genes/58 false ARID1A 8289 Underexpression Stomach Cancer 10534 Prognostic Supports D Poor Outcome In this study, real-time quantitative RT-PCR assays were used in 66 pairs of cancerous and matched adjacent normal tissues. In 43 of those pairs, the expression level of ARID1A was significantly lower in the cancerous tissue than in the normal tissue (P=0.0029). This was then again tested using Western Blotting. Consistent with the real-time PCR results, there was a lower expression of ARID1A in 13 of the tumor tissue samples compared to the normal tissue samples (P=0.0015). In an immunohistochemical analysis of 224 tissue blocks, 115 of those had a decreased ARID1A expression. The data conveyed that lower ARID1A expression was correlated with depth of tumor infiltration (P=0.001). Lastly, cell proliferation in regards to ARID1A expression was tested in cell lines. The cells with silenced expression of ARID1A had a much greater growth than those with greater expression of the protein. 22808142 PubMed Wang et al., 2012, PLoS ONE 4 accepted 5675 2108 6559 1 27022524 27108595 ENST00000324856.7 75 GRCh37 N/A 2018-07-06 20:40:05 UTC https://civicdb.org/links/evidence_items/5675 https://civicdb.org/links/variants/2108 https://civicdb.org/links/genes/6559 false ARID1A 8289 Underexpression Clear Cell Renal Cell Carcinoma 4467 Prognostic Supports B Poor Outcome This study included 290 patients with Clear Cell Renal Cell Carcinoma whose tumor tissues were sampled and then analyzed. These samples were then divided according to ARID1A expression after immunohistochemical staining. Of the 290 patients, 213 had a low ARID1A expression and 77 patients had a high expression. Low ARID1A expression was associated with higher nuclear grade (P<0.001), advanced pTNM stage (P=0.013), shorter cancer-specific survival (p=0.001) and progression-free survival (P<0.001). After a multivariate analysis using Cox proportional hazards, it was found that ARID1A expression levels are an independent predictor of progression-free survival in patients with CCRCC, although no significant correlation was found between the expression levels and cancer-specific survival. 25628030 PubMed Park et al., 2015, Hum. Pathol. 3 accepted 5676 2108 6559 1 27022524 27108595 ENST00000324856.7 75 GRCh37 N/A 2020-09-29 05:39:09 UTC https://civicdb.org/links/evidence_items/5676 https://civicdb.org/links/variants/2108 https://civicdb.org/links/genes/6559 false VHL 7428 A149S (c.445G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 49 family members from three generations of a Turkish family were examined. A clinical presentation of VHL type 2B was noted. Genetic testing was performed on 17 family members. 11 members with the mutation had manifestations, while 6 members with the mutation were asymptomatic. 1 of the asymptomatic individuals belonged to generation 2, while the remaining 5 belonged to the fourth generation, suggesting they may be too young to present manifestations. From the members that had manifestations: 9 had pheochromocytoma (5 bilateral), 1 had lumbar spine hemangioblastoma, 1 had retinal hemangioblastoma, 4 had renal cell carcinoma (2 bilateral), and 3 had pancreatic neuroendocrine tumours (1 also had a serous cystadenoma in addition to the neuroendocrine tumour). ACMG evidence codes: 'PP1' because of segregation results, 'PP2' because there is a missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease, 'PP4' because the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Relevant HPO terms: Renal cell carcinoma, Spinal hemangioblastoma, Multiple pancreatic cysts, Pheochromocytoma, Neuroendocrine neoplasm, Retinal hemangioblastoma. 23673869 PubMed Mete et al., 2014, Endocrine 3 accepted 5679 820 58 3 10188302 10188302 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/5679 https://civicdb.org/links/variants/820 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Renal cell carcinoma,Multiple renal cysts,Pancreatic cysts,Hemangioblastoma Predisposing Supports C Uncertain Significance This paper reports on 4 Chinese kindreds with VHL. The VHL gene was screened using direct DNA sequencing and MLPA in 44 volunteers among the 4 families. The above mutation was found in 1 kindred; 10 members were tested and 3 were found to harbour the mutation. The 7 members without a mutation were asymptomatic, while the 3 members with a mutation had manifestations. In addition to the 3 members who tested positive, there were 2 additional members who displayed manifestations, but died before testing could be performed. Clinical manifestations in this kindred included: renal cell carcinoma, CNS hemangioblastoma, pancreatic cysts, renal cysts, and retinal hemangioblastoma. ACMG evidence codes: 'PP1' because of segregation results, 'PP4' because the patient's phenotypes or family history are highly specific for a disease with single genetic etiology. 23143947 PubMed Chen et al., 2013, Clin Transl Oncol 4 accepted 5682 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:42 UTC https://civicdb.org/links/evidence_items/5682 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.340+1G>A) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Clear cell renal cell carcinoma,Cerebellar hemangioblastoma,Spinal hemangioblastoma Predisposing Supports C Uncertain Significance Genetic analysis of 7 Hungarian individuals from 5 unrelated families affected with von Hippel-Lindau disease revealed 5 different mutations, 3 of which were novel. The mutations could not be found within 100 healthy controls. The above mutation was found in 2 members (father and daughter) of a single family. The mutation was absent in two healthy family members. The mutation destroys the conserved intronic donor splice site and likely leads to premature protein termination (G114Dfs*6). The 12-year-old daughter had retinal and spinal hemangioblastoma, while the 34-year-old father had retinal, spinal, and cerebellar hemangioblastoma, and bilateral clear cell renal cell carcinoma. ACMG evidence codes: 'PVS1' because they observe a canonical +1 splice site variant in a gene where loss of function is a known mechanism of disease, 'PP4' because the patient's phenotypes or family history are highly specific for a disease with single genetic etiology, 'PP1' because of segregation results. 23298237 PubMed Losonczy et al., 2013, BMC Med. Genet. 4 accepted 5689 2114 58 3 10183872 10183872 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5689 https://civicdb.org/links/variants/2114 https://civicdb.org/links/genes/58 false VHL 7428 Q195* (c.583C>T) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance Genetic analysis of 7 Hungarian individuals from 5 unrelated families affected with von Hippel-Lindau disease revealed 5 different mutations, 3 of which were novel. All 7 patients were found to have Type 1 VHL disease. The mutations could not be found within 100 healthy controls. The above mutation was found in 1 member of a single family. The patient developed retinal and cerebellar hemangioblastoma. ACMG evidence codes: 'PP4' because the patient's phenotypes or family history are highly specific for a disease with single genetic etiology, 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease. 23298237 PubMed Losonczy et al., 2013, BMC Med. Genet. 3 accepted 5691 1810 58 3 10191590 10191590 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5691 https://civicdb.org/links/variants/1810 https://civicdb.org/links/genes/58 false VHL 7428 S65W (c.194C>G) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Multiple renal cysts,Renal cell carcinoma,Renal cyst,Spinal hemangioblastoma Predisposing Supports C Uncertain Significance A case report of a Chinese family with mosaic VHL is described. The proband first came to medical attention with bilateral renal cell carcinoma, renal cysts, and pancreatic cysts. However, she initially tested negative for VHL. Her daughter presented with spinal hemangioblastoma, and upon genetic testing was found to have the above mutation. The probands' DNA was reexamined and was determined to harbour the above mutation in approximately 18% of peripheral leukocytes. ACMG evidence codes: 'PP4' because the patient's phenotypes or family history are highly specific for a disease with single genetic etiology, 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 23384228 PubMed Wu et al., 2013, Clin. Genet. 3 accepted 5693 1787 58 3 10183725 10183725 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5693 https://civicdb.org/links/variants/1787 https://civicdb.org/links/genes/58 false VHL 7428 I151T (c.452T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A cohort of 141 patients with hemangioblastomas of the central nervous system was analyzed. 81 patients had germline mutations in the VHL gene. This missense mutation was found in one patient with hemangioblastomas of the central nervous system. No other phenotype described. HPO terms: hemangioblastoma. 10567493 PubMed Gläsker et al., 1999, J. Neurol. Neurosurg. Psychiatry 2 accepted 5720 1871 58 3 10188309 10188309 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5720 https://civicdb.org/links/variants/1871 https://civicdb.org/links/genes/58 false VHL 7428 E94FS (c.279delC) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Hemangioblastoma,Renal cell carcinoma Predisposing Supports C Uncertain Significance This mutation was found in a 51 year old female with hemangioblastomas of the cerebellum, pancreatic cysts, and bilateral renal adenocarcinomas. Patient's mother died of a brain tumor. Mutation was not found in 55 normal individuals. This study contains very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). 10862095 PubMed Moore et al., 2000, Hum. Mutat. 2 accepted 5722 2127 58 3 10183810 10183810 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:44 UTC https://civicdb.org/links/evidence_items/5722 https://civicdb.org/links/variants/2127 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.464-2A>G) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Cerebellar hemangioblastoma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. This splice mutation was found in a VHL type 1 family of 3 individuals. One family member had retinal angiomas and 2 had hemangioblastomas of the central nervous system. There is very strong evidence for pathogenicity in the form of a splice-site variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). HPO terms: retinal hemangioblastoma, hemangioblastoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 2 accepted 5724 2078 58 3 10191469 10191469 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5724 https://civicdb.org/links/variants/2078 https://civicdb.org/links/genes/58 false VHL 7428 G114dup (c.342dupGGT) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Hemangioblastoma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). This mutation was found in 2 VHL type 1 family members with retinal angiomas and hemangioblastomas of the central nervous system. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 2 accepted 5725 2129 58 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5725 https://civicdb.org/links/variants/2129 https://civicdb.org/links/genes/58 false VHL 7428 R82_V84del (c.243_251del) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). This mutation was found in a VHL type 1 family of 5 individuals. Four family members had retinal angiomas and 3 had hemangioblastomas of the central nervous system. Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). HPO terms: retinal hemangioblastoma, hemangioblastoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5726 2089 58 3 10183774 10183782 GCGCGTCGT ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5726 https://civicdb.org/links/variants/2089 https://civicdb.org/links/genes/58 false VHL 7428 S65FS (c.194delC) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Retinal capillary hemangioma,Renal cell carcinoma,Pheochromocytoma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a VHL type 2 family of 7 individuals. Three family members had retinal angiomas, 2 had hemangioblastomas of the cerebellum, 2 had renal cell carcinoma, and one had pheochromocytoma. ACMG codes as follows: A frameshift variant in a gene where loss-of-function is known mechanism of disease (PSV1). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5727 2130 58 3 10183725 10183725 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/5727 https://civicdb.org/links/variants/2130 https://civicdb.org/links/genes/58 false VHL 7428 Q73fs (c.214insGCCC) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Cerebellar hemangioblastoma,Renal cell carcinoma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This frameshift mutation was found in a VHL type 1 family of 3. All three had retinal angiomas and hemangioblastomas of the cerebellum. One also had renal cell carcinoma. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5728 2131 58 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5728 https://civicdb.org/links/variants/2131 https://civicdb.org/links/genes/58 false VHL 7428 C77fs (c.228dup) Von Hippel-Lindau Disease 14175 Pheochromocytoma,Retinal capillary hemangioma,Renal cell carcinoma,Cerebellar hemangioblastoma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This frameshift mutation was found in 3 VHL type 1 families of 7 individuals total. Five patients had retinal angiomas, 3 had hemangioblastomas of the central nervous system, 3 had renal cell carcinoma and 2 had pheochromocytoma. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5729 2132 58 3 10183758 10183759 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:42 UTC https://civicdb.org/links/evidence_items/5729 https://civicdb.org/links/variants/2132 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.341-2A>C) Renal Cell Carcinoma 4450 Renal cell carcinoma,Pheochromocytoma,Hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. This mutation was found in a VHL type 2 patient with retinal angiomas, hemangioblastomas of the central nervous system, renal cell carcinoma, and pheochromocytoma. There is very strong evidence for pathogenicity in the form of a splice-site variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 2 accepted 5730 2133 58 3 10188196 10188196 A C ENST00000256474.2 75 GRCh37 Rare Germline 2021-06-11 15:25:42 UTC https://civicdb.org/links/evidence_items/5730 https://civicdb.org/links/variants/2133 https://civicdb.org/links/genes/58 false VHL 7428 Intronic deletion (c.341-13delCGTTTCCAACAATTTCTCGGTGT) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. This mutation was found in a VHL type 1 family of 3. All three family members had retinal angiomas. One also had renal cell carcinoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 2 accepted 5731 2134 58 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5731 https://civicdb.org/links/variants/2134 https://civicdb.org/links/genes/58 false VHL 7428 G123fs (c.369_375delGACACAC) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a patient with no clinical manifestations of VHL disease as described in their supplemental table (retinal angioma, cerebellar hemangioblastoma, renal cell carcinoma, pheochromocytoma). There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 1 accepted 5732 2135 58 3 10188226 10188232 GACACAC ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5732 https://civicdb.org/links/variants/2135 https://civicdb.org/links/genes/58 false VHL 7428 H125fs (c.374insA) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma,Hemangioblastoma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a VHL type 1 family of 3. One family member had retinal angiomas, one had hemangioblastomas of the central nervous system, and one had renal cell carcinoma. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5733 2136 58 Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/5733 https://civicdb.org/links/variants/2136 https://civicdb.org/links/genes/58 false VHL 7428 T152fs (c.455insA) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. VHL T152fs (c.455insA) was found in a VHL patient with retinal angiomas. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5734 2091 58 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/5734 https://civicdb.org/links/variants/2091 https://civicdb.org/links/genes/58 false VHL 7428 K159fs (c.474_476delGAAinsC) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Cerebellar hemangioblastoma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. VHL K159fs (c.474_476delGAAinsC) frameshift mutation was found in a VHL type 1 family of 5 individuals. Three had cerebellar hemangioblastomas and one had renal cell carcinoma. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5735 2137 58 3 10191481 10191483 GAA C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5735 https://civicdb.org/links/variants/2137 https://civicdb.org/links/genes/58 false VHL 7428 Y175* (c.525delC) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Hemangioblastoma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in 2 family members. One family member had retinal angiomas and the other had hemangioblastomas of the central nervous system. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5736 2138 58 3 10191532 10191532 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5736 https://civicdb.org/links/variants/2138 https://civicdb.org/links/genes/58 false VHL 7428 L188fs (c.562delC) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in 2 family members with renal cell carcinomas. One relative also had retinal angiomas, while the other had hemangioblastomas of the central nervous system. HPO terms: retinal hemangioblastoma, hemangioblastoma, renal cell carcinoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5737 2139 58 3 10191569 10191569 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5737 https://civicdb.org/links/variants/2139 https://civicdb.org/links/genes/58 false VHL 7428 K196fs (c.584_585delAG) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a VHL type 1 patient with retinal angiomas, hemangioblastomas of the central nervous system, and renal cell carcinoma. HPO terms: hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5738 2140 58 3 10191591 10191592 AG ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5738 https://civicdb.org/links/variants/2140 https://civicdb.org/links/genes/58 false VHL 7428 D197FS (c.589delG) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a VHL type 1 family with 3 individuals, 1 with retinal angiomas and 1 with renal cell carcinoma. Supporting evidence of pathogenicity because of the introduction of a frame shift in a gene where loss of function is an established mechanism of disease (ACMG code: PVS1). HPO terms: retinal hemangioblastoma, renal cell carcinoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5739 2141 58 3 10191596 10191596 G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/5739 https://civicdb.org/links/variants/2141 https://civicdb.org/links/genes/58 false VHL 7428 T202fs (c.606insA) Von Hippel-Lindau Disease 14175 Hemangioblastoma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a patient with hemangioblastomas of the central nervous system. ACMG evidence codes: 'PVS1' because they observe a frameshift variant in a gene where loss-of-function is known mechanism of disease. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5740 2142 58 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5740 https://civicdb.org/links/variants/2142 https://civicdb.org/links/genes/58 false VHL 7428 R113FS (c.337delC) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a patient with retinal hemangioblastomas. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5741 2143 58 3 10183868 10183868 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5741 https://civicdb.org/links/variants/2143 https://civicdb.org/links/genes/58 false VHL 7428 A56fs (c.166dup) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Retinal capillary hemangioma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a VHL patient with retinal angiomas at 24Y old and cerebellar hemangioblastoma at 15Y old. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). HPO terms: retinal hemangioblastoma, hemangioblastoma. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5742 2144 58 3 10183696 10183697 G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/5742 https://civicdb.org/links/variants/2144 https://civicdb.org/links/genes/58 false VHL 7428 P61FS (c.182_185delCCGT) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Retinal capillary hemangioma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a VHL patient with retinal angiomas and hemangioblastomas of the central nervous system. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 4 accepted 5743 2145 58 3 10183713 10183716 CCGT ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/5743 https://civicdb.org/links/variants/2145 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Renal cell carcinoma,Cerebellar hemangioblastoma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in 4 unrelated families of 8 individuals total. 5 individuals had retinal hemangioblastomas, 4 had hemangioblastomas of the cerebellum, and 3 had renal cell carcinoma. ACMG evidence codes: 'PM4' because they observe a protein length change as a result of an in-frame deletion in a nonrepeat region or stop-loss variants, 'PP4' because the patients' phenotypes or family history are highly specific for a disease with single genetic etiology. 17024664 PubMed Ong et al., 2007, Hum. Mutat. 3 accepted 5744 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/5744 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.464-1G>C) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Cerebellar hemangioblastoma,Renal cell carcinoma Predisposing N/A C N/A Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in 2 unrelated VHL families with 4 individuals total. Three had hemangioblastomas of the cerebellum, 4 had retinal angiomas, and 2 had renal cell carcinoma. There is very strong evidence for pathogenicity in the form of a splice-site variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). 17024664 PubMed Ong et al., 2007, Hum. Mutat. 2 accepted 5745 2077 58 3 10191470 10191470 G C ENST00000256474.2 75 GRCh37 There are three variants in ClinVar at this exact position: (ClinVar ID: 223220, ClinVar ID:223221, and ClinVar ID:43603). ClinVar ID: 223220 is an exact match. Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5745 https://civicdb.org/links/variants/2077 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.341-2A>C) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Pancreatic cysts,Renal cell carcinoma,Hemangioblastoma Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This splice mutation was found in VHL patient with hemangioblastomas of the retina and central nervous system, renal cell carcinoma, and pancreatic cysts (family no. 32). ACMG evidence codes: 'PSV1' because they observe a splice-site variant in a gene where loss-of-function is known mechanism of disease, 'PP4' because the patients' phenotypes or family history are highly specific for a disease with single genetic etiology. 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 5748 2133 58 3 10188196 10188196 A C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5748 https://civicdb.org/links/variants/2133 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was found in 2 family members with retinal hemangioblastomas and renal cell carcinoma (family no. 25). One family member also had central nervous system hemangioblastoma. ACMG evidence codes: 'PM4' because they observe a protein length change as a result of an in-frame deletion in a nonrepeat region. 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 5749 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:42 UTC https://civicdb.org/links/evidence_items/5749 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Renal cell carcinoma,Hemangioblastoma Predisposing N/A C N/A This study reports 1,548 germline and somatic mutations from 945 VHL families. Mutation was detected in a VHL kindred with hemangioblastomas of the central nervous system, retinal hemangioblastomas and Grawitz tumor (also known as RCC) (case no. 2034). Protein length changes as a result of an in-frame deletion in a nonrepeat region (ACMG code: PM4). Patient's phenotypes or family history are highly specific for a disease with a single genetic etiology (ACMG code: PP4). 20151405 PubMed Nordstrom-O'Brien et al., 2010, Hum. Mutat. 3 accepted 5750 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:42 UTC https://civicdb.org/links/evidence_items/5750 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false VHL 7428 R161* (c.481C>T) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance This study reports 1,548 germline and somatic mutations from 945 VHL families. This nonsense mutation was found in a VHL patient with retinal angiomas and pancreatic cysts (case no. 306). There is very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). 20151405 PubMed Nordstrom-O'Brien et al., 2010, Hum. Mutat. 4 accepted 5761 1804 58 3 10191488 10191488 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5761 https://civicdb.org/links/variants/1804 https://civicdb.org/links/genes/58 false VHL 7428 S65W (c.194C>G) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Pancreatic cysts,Hemangioblastoma Predisposing Supports C Uncertain Significance Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This missense mutation was found in a 40 year old type 1 VHL patient with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (proband no. 1) but no family history. 22357542 PubMed Wu et al., 2012, J. Hum. Genet. 3 accepted 5765 1787 58 3 10183725 10183725 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/5765 https://civicdb.org/links/variants/1787 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Renal cell carcinoma,Hemangioblastoma Predisposing Supports C Uncertain Significance Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This mutation was found in a 42-year-old VHL patient with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (proband no. 12). ACMG evidence codes: 'PP4' because the patient's phenotypes or family history are highly specific for a disease with single genetic etiology. 22357542 PubMed Wu et al., 2012, J. Hum. Genet. 3 accepted 5766 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:42 UTC https://civicdb.org/links/evidence_items/5766 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false VHL 7428 Exon 3 Deletion Von Hippel-Lindau Disease 14175 Hemangioblastoma,Renal cell carcinoma,Pancreatic cysts,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This mutation was found in 3 family members and an unrelated patient. All three family members had hemangioblastomas of the central nervous system (proband no. 13). The 32-year-old sister and 27-year-old proband had renal cell carcinoma and pancreatic cysts. The proband also had retinal angiomas. The unrelated, 45-year-old VHL patient had hemangioblastomas of the central nervous system and retina, renal cell carcinoma, and pancreatic cysts (proband no. 14). ACMG codes as follows: A single exon deletion variant in a gene where loss-of-function is known mechanism of disease (PSV1). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). 22357542 PubMed Wu et al., 2012, J. Hum. Genet. 2 accepted 5767 1939 58 3 10191471 10193904 ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5767 https://civicdb.org/links/variants/1939 https://civicdb.org/links/genes/58 false VHL 7428 R161= (c.481C>A) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Pancreatic cysts,Renal cell carcinoma Predisposing Supports C Uncertain Significance Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This silent mutation was found in a 34-year-old VHL patient with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (proband no. 15). 22357542 PubMed Wu et al., 2012, J. Hum. Genet. 2 accepted 5768 2148 58 3 10191488 10191488 C A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/5768 https://civicdb.org/links/variants/2148 https://civicdb.org/links/genes/58 false VHL 7428 R167W (c.499C>T) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Retinal capillary hemangioma,Renal cell carcinoma,Epididymal cyst Predisposing Supports C Uncertain Significance Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This missense mutation was found in 4 VHL family members (proband no. 6). The 65-year-old father had renal cell carcinoma; The 37-year old sister had pancreatic cysts and the 33-year old sister had retinal angiomas. The 38-year-old proband had hemangioblastomas of the central nervous system, renal cell carcinoma, pancreatic cysts, and epididymal cystadenoma. Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 22357542 PubMed Wu et al., 2012, J. Hum. Genet. 2 accepted 5769 1747 58 3 10191506 10191506 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5769 https://civicdb.org/links/variants/1747 https://civicdb.org/links/genes/58 false VHL 7428 E94* (c.280G>T) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Epididymal cyst,Hemangioblastoma,Renal cell carcinoma Predisposing Supports C Uncertain Significance Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This nonsense mutation was found in 2 unrelated families. One family of 3 had a asymptomatic 27-year-old female, a 27-year-old male with epididymal cystadenoma, and a 55-year old with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (proband no. 10). The other VHL family had 2 individuals with hemangioblastomas of the central nervous system (proband no. 11). ACMG codes as follows: A nonsense variant in a gene where loss-of-function is a known mechanism of disease (PSV1). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). 22357542 PubMed Wu et al., 2012, J. Hum. Genet. 2 accepted 5771 1794 58 3 10183811 10183811 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5771 https://civicdb.org/links/variants/1794 https://civicdb.org/links/genes/58 false VHL 7428 H115R (c.344A>G) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Pancreatic cysts,Hemangioblastoma Predisposing Supports C Uncertain Significance Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This missense mutation was found in a 45-year-old VHL type 1 patient with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (proband no. 4) and no family history. HPO terms: hemangioblastoma, renal cell carcinoma, multiple pancreatic cysts. 22357542 PubMed Wu et al., 2012, J. Hum. Genet. 2 accepted 5772 2000 58 3 10188201 10188201 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5772 https://civicdb.org/links/variants/2000 https://civicdb.org/links/genes/58 false VHL 7428 I151F (c.451A>T) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Pancreatic cysts,Epididymal cyst,Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This missense mutation was found in a 43-year-old VHL type 1 patient with renal cell carcinoma, pancreatic cysts, an endolymphatic sac tumor, and an epididymal /ovarian cystadenoma (proband no. 5) and no family history. HPO terms: renal cell carcinoma, multiple pancreatic cysts, epididymal cysts, endolymphatic sac tumors. 22357542 PubMed Wu et al., 2012, J. Hum. Genet. 2 accepted 5773 2150 58 3 10188308 10188308 A T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5773 https://civicdb.org/links/variants/2150 https://civicdb.org/links/genes/58 false VHL 7428 L178R (c.533T>G) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Renal cell carcinoma,Retinal capillary hemangioma,Hemangioblastoma Predisposing Supports C Uncertain Significance Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This missense mutation was found in a VHL family of 6 individuals (proband no. 7). A 62-year-old female carrying the mutation and a male with an unknown mutation had hemangioblastomas of the central nervous system (CNS). A 58-year-old male family member had retinal angiomas and renal cell carcinoma. The 60 year-old proband had CNS hemangioblastomas, retinal angiomas, renal cell carcinoma, and pancreatic cysts. Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). 22357542 PubMed Wu et al., 2012, J. Hum. Genet. 2 accepted 5774 1888 58 3 10191540 10191540 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5774 https://civicdb.org/links/variants/1888 https://civicdb.org/links/genes/58 false VHL 7428 P86S (c.256C>T) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Pancreatic cysts,Retinal capillary hemangioma,Pheochromocytoma Predisposing N/A C N/A Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline variants. VHL P86S (c.256C>T) was found in a type 2B VHL patient (proband no. 2). The 33-year-old proband had retinal angiomas, renal cell carcinoma, pancreatic cysts, and pheochromocytoma. The proband's 8-year-old daughter also carried this variant but had no clinical manifestations of VHL disease. 22357542 PubMed Wu et al., 2012, J. Hum. Genet. 2 accepted 5775 1902 58 3 10183787 10183787 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5775 https://civicdb.org/links/variants/1902 https://civicdb.org/links/genes/58 false VHL 7428 W88* (c.263G>A) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Renal cell carcinoma,Hemangioblastoma,Epididymal cyst Predisposing Supports C Uncertain Significance Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This nonsense mutation was found in 2 unrelated VHL type 1 families. One family had a 32-year-old with hemangioblastomas of the central nervous system, renal cell carcinoma, pancreatic cysts, and epididymal cystadenoma with an 8-year-old asymptomatic son (proband no. 8). The other family had a 39-year-old with renal cell carcinoma and pancreatic cysts and their 81-year-old mother with CNS hemangioblastomas (proband no. 9). There is very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). 22357542 PubMed Wu et al., 2012, J. Hum. Genet. 3 accepted 5776 2151 58 3 10183794 10183794 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/5776 https://civicdb.org/links/variants/2151 https://civicdb.org/links/genes/58 false VHL 7428 3'UTR alteration (c.*70C>A) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Renal cell carcinoma,Hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This mutation was found in a 30-year-old VHL patient with hemangioblastomas of the central nervous system, retinal angiomas, renal cell carcinoma, and pancreatic cysts (proband no. 16). HPO terms: hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma, multiple pancreatic cysts. 22357542 PubMed Wu et al., 2012, J. Hum. Genet. 2 accepted 5777 2152 58 3 10191719 10191719 C A GRCh37 Rare Germline 2022-01-12 17:35:31 UTC https://civicdb.org/links/evidence_items/5777 https://civicdb.org/links/variants/2152 https://civicdb.org/links/genes/58 false VHL 7428 E70K (c.208G>A) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance In the analysis of 63 clinically diagnosed VHL patients, 55 patients were found with pancreatic involvement. Genetic tests on 35 of 55 VHL patients revealed VHL variants in 28 patients. Of the 55 enrolled patients, hemangioblastomas of the central nervous system were previously documented in 47 patients, renal cell carcinoma in 25, and pheochromocytoma in 11 patients. This missense variant was found in 37-year-old female with reported VHL type 1 phenotype and pancreatic lesions (case no. 1). 25562111 PubMed Park et al., 2015, Scand. J. Gastroenterol. 2 accepted 5780 1956 58 3 10183739 10183739 G A ENST00000256474.2 75 GRCh37 The VHL gene has a low rate of benign missense variation and is known to be definitively associated with VHL disease. The E70K missense mutation, located in the Beta-domain of VHL, is rare in open-source genome databases (0.00001489 allele frequency in ExAC, 4.365e-6 allele frequency in gnomAD) and was identified in several individuals with VHL disease symptoms (see evidence statements). Thus, this variant could be assigned ACMG code 'PP2' - Missense mutation in a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. Although this variant is registered once in ExAC and gnomAD, 'PM2' could be applied (Absent from controls in ESP, 1000 Genomes or ExAC) because VHL manifestations sometimes emerge later in adulthood. Thus, the allele may have been detected in a proband who was not yet affected by symptoms. Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/5780 https://civicdb.org/links/variants/1956 https://civicdb.org/links/genes/58 false ARID1A 8289 Underexpression Ovarian Clear Cell Carcinoma 0050934 Prognostic Supports B Poor Outcome In a study of 60 individuals with ovarian clear cell carcinoma, ARID1A expression was analyzed using immunohistochemistry. Of these 60 patients, 9 (15%) patients had a loss of ARID1A expression. Results showed that a low ARID1A expression was significantly related to advanced FIGO stages (P=0.02) and high CA125 levels (P=0.01). Patients with low expression experienced shorter progression free survival than those with no loss of expression (P<0.01). In a multivariate analysis it was found that a loss of ARID1A expression was significant for shorter disease free survival (P=0.03) and shorter overall survival for patients whose ovarian clear cell carcinoma was treated with platinum-based chemotherapy (P=0.015). Lastly, tumors with low expression were significantly more likely to be resistant to primary adjuvant chemotherapy than tumors with a higher expression (P=0.04). 22101352 PubMed Katagiri et al., 2012, Mod. Pathol. 3 accepted 5787 2108 6559 1 27022524 27108595 ENST00000324856.7 75 GRCh37 N/A 2020-12-03 20:30:20 UTC https://civicdb.org/links/evidence_items/5787 https://civicdb.org/links/variants/2108 https://civicdb.org/links/genes/6559 false VHL 7428 Y98FS (c.291delC) Von Hippel-Lindau Disease 14175 Multiple renal cysts,Clear cell renal cell carcinoma,Cerebellar hemangioblastoma,Spinal hemangioblastoma,Renal cyst,Pancreatic cysts Predisposing Supports C Uncertain Significance A case report of a female Korean patient with VHL. She presented initially with gestational diabetes mellitus, and on routine abdominal scan displayed renal and pancreatic cysts. Family history demonstrated 2 family members with features consistent with VHL (cerebellar hemangioblastoma), which prompted genetic testing. Molecular analysis revealed the presence of the above mutation. Subsequently, she developed spinal hemangioblastoma and clear cell renal cell carcinoma. ACMG evidence codes: 'PP4' because the patient's phenotype or family history is highly specific for a disease with a single genetic etiology, 'PVS1' because they observe a frameshift variant in a gene where loss of function is a known mechanism of disease. 24396697 PubMed Ku et al., 2013, Endocrinol Metab (Seoul) 4 accepted 5794 2160 58 3 10183822 10183822 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/5794 https://civicdb.org/links/variants/2160 https://civicdb.org/links/genes/58 false VHL 7428 Q145* (c.433C>T) Von Hippel-Lindau Disease 14175 Polycythemia Predisposing Supports C Uncertain Significance This is a case report on a 9-month-old female with polycythemia. The patient carries a paternally inherited missense mutation (EID5799) and this de novo, nonsense mutation. ACMG codes as follows: A nonsense mutation in a gene where loss-of-function is a known mechanism of disease (PVS1). Assumed de novo, but without confirmation of paternity and maternity (PM6). 25586603 PubMed Sidhu et al., 2015, Pediatr Blood Cancer 2 accepted 5798 1883 58 3 10188290 10188290 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5798 https://civicdb.org/links/variants/1883 https://civicdb.org/links/genes/58 false VHL 7428 N150S (c.449A>G) Von Hippel-Lindau Disease 14175 Polycythemia Predisposing Supports C Uncertain Significance This is a case report on a 9-month-old female with polycythemia. The patient carries a de novo nonsense mutation [Q145* (c.433C>T)] and this paternally inherited, missense mutation. The authors of this paper believed this missense mutation was the cause of the aforementioned clinical manifestations. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 25586603 PubMed Sidhu et al., 2015, Pediatr Blood Cancer 2 accepted 5799 2162 58 3 10188306 10188306 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/5799 https://civicdb.org/links/variants/2162 https://civicdb.org/links/genes/58 false VHL 7428 V84L (c.250G>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance A case report of African American twin sisters with VHL type 2C is presented. 1 twin presented at the age of 16 with unilateral vision loss determined to be caused by a Rathke's cleft cyst. Further imaging identified bilateral pheochromocytoma. The other twin presented with pheochromocytoma at the age of 7. Radiological studies identified a similar sellar lesion to the Rathke's cleft cyst found in twin 1. Genetic testing discovered the above mutation in both twins. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 24877602 PubMed Huff et al., 2014, J Neurosurg Pediatr 2 accepted 5801 1815 58 3 10183781 10183781 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/5801 https://civicdb.org/links/variants/1815 https://civicdb.org/links/genes/58 false VHL 7428 E70K (c.208G>A) Von Hippel-Lindau Disease 14175 Clear cell renal cell carcinoma,Cerebellar hemangioblastoma,Adenocarcinoma of the colon,Spinal hemangioblastoma Predisposing Supports C Uncertain Significance A case report of a 74-year-old male with colorectal adenocarcinoma, clear cell renal cell carcinoma, and hemangioblastomas of the central nervous system. The spinal hemangioblastoma was histopathologically confirmed. Bilateral multifocal cerebellar hemangioblastomas were inferred on brain MRI. Family history included a mother with a brain tumor of unconfirmed pathology, 2 brothers with the E70K variant and renal cell carcinoma, and an asymptomatic son in his 40s who was also found to have this variant. ACMG evidence codes: 'PP1' because of cosegregation with disease in multiple affected family members in a gene known to cause the disease, 'PP4' because the patient's phenotype and family history are highly specific for a disease with a single genetic etiology. 25715769 PubMed Heo et al., 2016, Cancer Res Treat 3 accepted 5805 1956 58 3 10183739 10183739 G A ENST00000256474.2 75 GRCh37 The VHL gene has a low rate of benign missense variation and is known to be definitively associated with VHL disease. The E70K missense mutation, located in the Beta-domain of VHL, is rare in open-source genome databases (0.00001489 allele frequency in ExAC, 4.365e-6 allele frequency in gnomAD) and was identified in several individuals with VHL disease symptoms (see evidence statements). Thus, this variant could be assigned ACMG code 'PP2' - Missense mutation in a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. Although this variant is registered once in ExAC and gnomAD, 'PM2' could be applied (Absent from controls in ESP, 1000 Genomes or ExAC) because VHL manifestations sometimes emerge later in adulthood. Thus, the allele may have been detected in a proband who was not yet affected by symptoms. Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/5805 https://civicdb.org/links/variants/1956 https://civicdb.org/links/genes/58 false VHL 7428 Y98H (c.292T>C) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Genetic analysis of 21 patients with known germline mutations in an inherited pheochromocytoma/paraganglioma gene, ten of which were in the VHL gene. This missense mutation was found in 8 unrelated patients with pheochromocytoma (tumor IDs P5, P6, P7, P8, P9, P10, P11, P12). ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. 25883647 PubMed Luchetti et al., 2015, Int J Endocrinol 2 accepted 5807 1741 58 3 10183823 10183823 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/5807 https://civicdb.org/links/variants/1741 https://civicdb.org/links/genes/58 false CD274 29126 Expression Lung Non-small Cell Carcinoma 3908 Pembrolizumab Predictive Supports B Sensitivity/Response PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab. 25891174 PubMed Garon et al., 2015, N. Engl. J. Med. NCT01295827 4 accepted 5811 276 11335 9 5450525 5470547 ENST00000381577.3 75 GRCh37 N/A 2020-10-21 04:32:34 UTC https://civicdb.org/links/evidence_items/5811 https://civicdb.org/links/variants/276 https://civicdb.org/links/genes/11335 false NRG1 3084 SLC3A2::NRG1 Lung Adenocarcinoma 3910 Prognostic Supports B Poor Outcome 13 patients with invasive mucinous adenocarcinoma of the lung from a cohort of 59 were found to be SLC3A2-NRG1 fusion positive. Survival was assessed according to the presence of the NRG1 fusion. NRG1 fusions positive patients demonstrated inferior overall survival (OS) and disease-free survival (DFS) compared with those without NRG1 fusion. To exclude the impact of stage on survival OS and DFS was compared only in patients with stage I disease. Patients with NRG1 fusions showed significantly inferior OS and DFS compared to those without NRG1 fusions. 27626312 PubMed Shin et al., 2016, Oncotarget 3 accepted 5814 2166 2593 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/5814 https://civicdb.org/links/variants/2166 https://civicdb.org/links/genes/2593 false BRCA1 672 Loss-of-function Her2-receptor Negative Breast Cancer 0060080 Olaparib Predictive Supports B Sensitivity/Response 302 patients (234 with progression events) with HER2-negative metastatic breast cancer and with a confirmed deleterious or suspected deleterious germline BRCA mutation (164 BRCA1, 129 BRCA2) had significantly improved progression-free survival and better response rate to olaparib (PARP inhibitor) than standard therapy (7.0 mo vs 4.2 mo, hazard ratio 0.58, 95% CI 0.43-0.8) in this randomized phase 3 trial (NCT02000622). For BRCA1 patients specifically, the hazard ratio was 0.54, 95% CI 0.37-0.79). 28578601 PubMed Robson et al., 2017, N. Engl. J. Med. NCT02000622 5 accepted 5815 131 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 BRCA1 loss of function mutations have been shown to increase risk of breast and ovarian cancer in those carrying the allele in their germline. Treating BRCA mutant patients with PARP inhibitors such as Olaparib has led to significant response. Rare Germline 2017-10-21 23:06:55 UTC https://civicdb.org/links/evidence_items/5815 https://civicdb.org/links/variants/131 https://civicdb.org/links/genes/6 false BRCA2 675 Loss-of-function Her2-receptor Negative Breast Cancer 0060080 Olaparib Predictive Supports B Sensitivity/Response 302 patients (234 with progression events) with HER2-negative metastatic breast cancer and with a confirmed deleterious or suspected deleterious germline BRCA mutation (164 BRCA1, 129 BRCA2) had significantly improved progression-free survival and better response rate to olaparib (PARP inhibitor) than standard therapy (7.0 mo vs 4.2 mo, hazard ratio 0.58, 95% CI 0.43-0.8) in this randomized phase 3 trial (NCT02000622). For BRCA2 patients specifically, the hazard ratio was 0.68, 95% CI 0.45-0.1.07. 28578601 PubMed Robson et al., 2017, N. Engl. J. Med. NCT02000622 3 accepted 5816 132 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 BRCA2 loss of function mutations have been shown to increase risk of breast and ovarian cancer in those carrying the allele in their germline. Treating BRCA mutant patients with PARP inhibitors such as Olaparib has led to significant response. Rare Germline 2018-07-12 18:17:07 UTC https://civicdb.org/links/evidence_items/5816 https://civicdb.org/links/variants/132 https://civicdb.org/links/genes/7 false RAD50 10111 L1237F Ureter Small Cell Carcinoma 6886 Checkpoint Kinase Inhibitor AZD7762,Irinotecan Combination Predictive Supports C Sensitivity/Response A 51-year-old woman with an invasive small-cell cancer of the ureter showed a durable complete response at 3-years when treated with AZD7762 (an ATP-competitive checkpoint kinase inhibitor) and irinotecan (a topoisomerase I inhibitor). Whole genome sequencing of the tumor revealed a somatic RAD50 (L1237F) mutation, which was identified as a potential sensitizing lesion contributing to the profound response. Six rad50-mutant yeast strains and genetically engineered mouse embryonic fibroblasts were established and demonstrated severe sensitivity to camptothecin (Chk1 inhibitor). 24934408 PubMed Al-Ahmadie et al., 2014, Cancer Discov 4 accepted 5829 2168 8032 Somatic 2021-04-27 18:49:06 UTC https://civicdb.org/links/evidence_items/5829 https://civicdb.org/links/variants/2168 https://civicdb.org/links/genes/8032 false BRCA1 672 Mutation Her2-receptor Negative Breast Cancer 0060080 Olaparib Predictive Supports B Sensitivity/Response Randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation HER2–negative metastatic breast cancer. 205 patients were assigned to receive olaparib and 97 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the olaparib group than in the standard-therapy group (7.0 months vs. 4.2 months; hazard ratio 0.58; 95%CI 0.43 to 0.80; P<0.001). A response to treatment occurred in 100 of the 167 patients who had measurable disease in the olaparib group (59.9%; 95% CI, 52.0 to 67.4) and in 19 of the 66 patients in the standard-therapy group (28.8%; 95% CI, 18.3 to 41.3). A complete response was seen in 9.0% of the patients who had measurable disease in the olaparib group and in 1.5% in the standard-therapy group. 28792849 PubMed 2017, N Engl J Med 4 accepted 5830 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Rare Germline 2021-04-23 19:11:37 UTC https://civicdb.org/links/evidence_items/5830 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false BRCA2 675 Mutation Breast Cancer 1612 Olaparib Predictive Supports B Sensitivity/Response Randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation HER2–negative metastatic breast cancer. 205 patients were assigned to receive olaparib and 97 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the olaparib group than in the standard-therapy group (7.0 months vs. 4.2 months; hazard ratio 0.58; 95%CI 0.43 to 0.80; P<0.001). A response to treatment occurred in 100 of the 167 patients who had measurable disease in the olaparib group (59.9%; 95% CI, 52.0 to 67.4) and in 19 of the 66 patients in the standard-therapy group (28.8%; 95% CI, 18.3 to 41.3). A complete response was seen in 9.0% of the patients who had measurable disease in the olaparib group and in 1.5% in the standard-therapy group. 28792849 PubMed 2017, N Engl J Med 4 accepted 5831 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Rare Germline 2018-07-10 18:36:07 UTC https://civicdb.org/links/evidence_items/5831 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false BTK 695 MUTATION Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome A patient cohort of 308 individuals was created from trials of Ibrutinib in CLL (see Maddocks 2015, PMID: 26182309). A secondary cohort was created from a prospective collection of 112 patients. 83/308 patients discontinued because of disease progression (27 Richter's transformation; 1 prolymphocytic leukemia; 55 progressive CLL). 46/55 progressive patients had a relapse sample available for sequencing of BTK and PLCG2. 31 patients only had BTK C481(F/R/A/S) mutations, 3 patients only had PLCG2 mutations, and 6 patients had both BTK C481 and PLCG2 mutations. In the 112 patients sequencing of BTK and PLGC2 coding regions was performed every 3 months. At publication at 8 patients had experienced relapse. All 8 had BTK C481S mutations with clonal expansion before relapse. 8 additional patients did not have clinical relapse but had BTK C481S mutations with VAF >1% and increasing CLL cells in peripheral blood. 28418267 PubMed Woyach et al., 2017, J. Clin. Oncol. 4 accepted 5833 2169 65 Somatic 2021-01-07 18:49:16 UTC https://civicdb.org/links/evidence_items/5833 https://civicdb.org/links/variants/2169 https://civicdb.org/links/genes/65 false PLCG2 5336 MUTATION Chronic Lymphocytic Leukemia 1040 Prognostic Supports B Poor Outcome Whole exome sequencing was performed on baseline and relapse samples from six patients with CLL. One relapse sample had mutations in BTK and PLCG2, and a second relapse sample only had a mutation in PLCG2. Both samples with PLCG2 mutations had a mutation at R665W. Mutations in PLCG2 at L845F and S707Y were observed in the relapse samples with an additional BTK C481S mutation. 24869598 PubMed Woyach et al., 2014, N. Engl. J. Med. 5 accepted 5834 2170 4327 Somatic 2018-07-10 18:15:07 UTC https://civicdb.org/links/evidence_items/5834 https://civicdb.org/links/variants/2170 https://civicdb.org/links/genes/4327 false MET 4233 Overexpression Stomach Carcinoma 5517 Rilotumumab Predictive Does Not Support B Sensitivity/Response In this randomised, double-blind, placebo-controlled phase 3 trial, 609 patients with MET+ (expression of at least 1+ intensity on 25% or more tumor cells) gastric cancer or gastroesophageal adenocarcinoma were randomized to chemotherapy (epirubicin, cisplatin, capecitabine) with placebo or MET inhibitor rilotumumab. Study treatment was stopped early because of a higher number of deaths in the rilotumumab arm. Median overall survival was 8·8 months (95% CI 7·7-10·2) in the rilotumumab group compared with 10·7 months (9·6-12·4) in the placebo group (stratified hazard ratio 1·34, 95% CI 1·10-1·63; p=0·003). 28958504 PubMed Catenacci et al., 2017, Lancet Oncol. NCT01697072 5 accepted 5835 621 52 7 116312459 116436396 ENST00000318493.6 75 GRCh37 N/A 2017-10-21 23:08:53 UTC https://civicdb.org/links/evidence_items/5835 https://civicdb.org/links/variants/621 https://civicdb.org/links/genes/52 false KRAS 3845 Amplification Endometrial Cancer 1380 Prognostic Supports B Poor Outcome In this study, KRAS gain (KRAS/CEP12q ratio >1 and <2) or amplification (ratio >2) was detected in 3% (13 of 414) of the primary endometrial carcinomas investigated. Presence of KRAS gain or amplification were highly significantly associated with poor prognosis with a 46% 5-year survival compared with 87% for patients with unamplified status (P<0.001). Amplification of KRAS maintains its independent prognostic impact in Cox multivariate analysis when adjusted for age, histological subtype, grade and FIGO stage (HR=2.6, 95% CI: 1.2–5.8, P=0.02). In contrast, presence of KRAS mutation did not influence prognosis (P=0.67) 23099803 PubMed Birkeland et al., 2012, Br. J. Cancer 3 accepted 5836 592 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2018-07-06 21:54:14 UTC https://civicdb.org/links/evidence_items/5836 https://civicdb.org/links/variants/592 https://civicdb.org/links/genes/30 false PTEN 5728 Loss Cancer 162 Everolimus Predictive Does Not Support B Sensitivity/Response In a single-arm, open label phase 2 trial in PIK3CA amplified/mutated and/or PTEN loss encompassing 10 patients, no objective responses were observed but a stable disease response in 4 patients, resulting in a median PFS of 1.4 months. Everolimus failed to meet its enpoint. 28330462 PubMed Kim et al., 2017, BMC Cancer NCT02449538 3 accepted 5840 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 N/A 2017-10-19 16:09:28 UTC https://civicdb.org/links/evidence_items/5840 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false VHL 7428 Splice Site (c.340+1G>A) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A study describing phenotypic and genotypic characteristics of VHL in an Indian population of 31 subjects, from 15 families diagnosed with VHL. Multi-cystic pancreas and CNS hemangioblastomas were the most common manifestations in this population. This splice site mutation was found in a VHL family of 8 individuals(family ID AD). 3 family members had renal cell carcinoma, 4 had hemangioblastomas of the central nervous system, 7 had multi-cystic pancreatic lesions, and 1 had retinal hemangioblastomas. ACMG codes as follows: A splice-site variant in a gene where loss-of-function is a known mechanism of disease (PVS1), patient's phenotypes or family history are highly specific for a disease with single genetic etiology (PP4), cosegregation with the disease in multiple affected family members in a gene definitively known to cause the disease (PP1). Relevant HPO terms: Hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma, Multiple pancreatic cysts. 25952756 PubMed Vikkath et al., 2015, Fam. Cancer 4 accepted 5845 2114 58 3 10183872 10183872 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5845 https://civicdb.org/links/variants/2114 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.464-2A>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Of 65 VHL families from central Europe, 53 were identified with germline mutations. This splice mutation was found in a German, VHL type 1 family. Only one affected patient was identified with retinal angiomas, hemangioblastomas of the central nervous system, renal cell carcinoma, pancreatic cysts and cystadenomas of the epididymis. (family VHL 31). HPO terms: hemangioblastomas, retinal hemangioblastomas, renal cell carcinoma, multiple pancreatic cysts, papillary cystadenomas of the broad ligament. 8707293 PubMed Glavac et al., 1996, Hum. Genet. 2 accepted 5851 2078 58 3 10191469 10191469 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:34 UTC https://civicdb.org/links/evidence_items/5851 https://civicdb.org/links/variants/2078 https://civicdb.org/links/genes/58 false NRG1 3084 ATP1B1::NRG1 Cholangiocarcinoma 4947 Afatinib Predictive Supports C Sensitivity/Response In a single patient with presumed cholangiocarcinoma a novel ATP1B1-NRG1 gene fusion was detected. Integrative genome analysis was used to assess the potential functional significance of the gene fusion, prioritizing a therapeutic strategy targeting the HER-family of growth factor receptors with afatinib. This patient was treated with the pan HER-family kinase inhibitor afatinib and displayed significant and durable response to treatment. 28950338 PubMed Jones et al., 2017, Ann. Oncol. NCT02155621 3 accepted 5858 2178 2593 Somatic 2020-04-16 18:48:45 UTC https://civicdb.org/links/evidence_items/5858 https://civicdb.org/links/variants/2178 https://civicdb.org/links/genes/2593 false NRG1 3084 SDC4::NRG1 Lung Adenocarcinoma 3910 Afatinib Predictive Supports C Sensitivity/Response In patient with lung adenocarcinoma an SDC4-NRG1 gene fusion was detected. Integrative genome analysis was used to assess the potential functional significance of the detected gene fusion, prioritizing therapeutic strategies targeting the HER-family of growth factor receptors. This patient was treated with the pan HER-family kinase inhibitor afatinib and displayed a significant and durable response to treatment. 28950338 PubMed Jones et al., 2017, Ann. Oncol. NCT02155621 3 accepted 5859 2179 2593 Somatic 2020-09-24 19:35:23 UTC https://civicdb.org/links/evidence_items/5859 https://civicdb.org/links/variants/2179 https://civicdb.org/links/genes/2593 false VHL 7428 V170D (c.509T>A) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance 20 patients from 6 families in the Netherlands were analyzed for Von Hippel Lindau manifestations. 1 family consisting of 12 members had the above mutation. Manifestations in this family included: renal cell carcinoma, cerebellar hemangioblastoma, pancreatic cyst, retinal hemangioblastoma, and pheochromocytoma. ACMG evidence codes: 'PP1' based on segregation results, 'PP2' because they observe a missense variant in gene where missense variants are common mechanism of disease, 'PP4' because the patients phenotypes and family history are highly specific for a disease with single genetic etiology. Relevant HPO terms: Renal cell carcinoma, Cerebellar hemangioblastoma, Multiple pancreatic cysts, Retinal hemangioblastoma, Pheochromocytoma. 9681858 PubMed Wittebol-Post et al., 1998, J. Intern. Med. 4 accepted 5863 1826 58 3 10191516 10191516 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/5863 https://civicdb.org/links/variants/1826 https://civicdb.org/links/genes/58 false VHL 7428 R82P (c.245G>C) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing N/A C N/A Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in 3 VHL type 2B family members (kindred no. V12), but not in 7 unaffected family members. ACMG evidence codes: 'PP2' because they observe a missense variant in gene where missense variants are common mechanism of disease. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 3 accepted 5864 1980 58 3 10183776 10183776 G C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:44 UTC https://civicdb.org/links/evidence_items/5864 https://civicdb.org/links/variants/1980 https://civicdb.org/links/genes/58 false VHL 7428 R177ins (c.531insCTGAGAGTAAAGCCTGAA) Von Hippel-Lindau Disease 14175 Predisposing N/A C N/A Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This in-frame insertion mutation was found in 3 VHL type 1 family members (kindred no, V31), but not found in 3 unaffected family members. No specific VHL manifestations were discussed. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 2 accepted 5865 2181 58 Rare Germline 2022-01-12 17:35:44 UTC https://civicdb.org/links/evidence_items/5865 https://civicdb.org/links/variants/2181 https://civicdb.org/links/genes/58 false DICER1 23405 D1709N Sertoli-Leydig Cell Tumor 2997 Predisposing Supports B Likely Pathogenic DICER1 mutations in the RNase IIIb domain were found in 29% of nonepithelial ovarian tumors (n=103) with high predominance in Sertoli-Lydig cell tumors (26/43; 60%). There were ten mutations in D1709N. 22187960 PubMed Heravi-Moussavi et al., 2012, N. Engl. J. Med. 3 accepted 5886 2051 9533 Rare Germline 2021-03-02 19:58:22 UTC https://civicdb.org/links/evidence_items/5886 https://civicdb.org/links/variants/2051 https://civicdb.org/links/genes/9533 false DICER1 23405 D1709G Sertoli-Leydig Cell Tumor 2997 Predisposing Supports C Likely Pathogenic DICER1 mutations in the RNase IIIb domain were found in 29% of nonepithelial ovarian tumors (n=103) with high predominance in Sertoli-Lydig cell tumors (26/43; 60%). There was one mutation in D1709G. 22187960 PubMed Heravi-Moussavi et al., 2012, N. Engl. J. Med. 3 accepted 5887 2195 9533 Rare Germline 2021-03-02 19:57:11 UTC https://civicdb.org/links/evidence_items/5887 https://civicdb.org/links/variants/2195 https://civicdb.org/links/genes/9533 false DICER1 23405 D1709E Sertoli-Leydig Cell Tumor 2997 Predisposing Supports C Likely Pathogenic DICER1 mutations in the RNase IIIb domain were found in 29% of nonepithelial ovarian tumors (n=103) with high predominance in Sertoli-Lydig cell tumors (26/43; 60%). There were two mutations in D1709E. 22187960 PubMed Heravi-Moussavi et al., 2012, N. Engl. J. Med. 2 accepted 5888 2196 9533 Rare Germline 2021-03-02 19:56:44 UTC https://civicdb.org/links/evidence_items/5888 https://civicdb.org/links/variants/2196 https://civicdb.org/links/genes/9533 false DICER1 23405 E1813Q Sertoli-Leydig Cell Tumor 2997 Predisposing Supports C Likely Pathogenic DICER1 mutations in the RNase IIIb domain were found in 29% of nonepithelial ovarian tumors (n=103) with high predominance in Sertoli-Lydig cell tumors (26/43; 60%). There were two mutations in E1813Q. 22187960 PubMed Heravi-Moussavi et al., 2012, N. Engl. J. Med. 2 accepted 5892 2052 9533 14 95557630 95557630 C G ENST00000526495.1 75 GRCh37 Rare Germline 2021-03-02 19:55:37 UTC https://civicdb.org/links/evidence_items/5892 https://civicdb.org/links/variants/2052 https://civicdb.org/links/genes/9533 false DICER1 23405 D1709G Ovarian Granulosa Cell Tumor 2999 Predisposing Supports C Likely Pathogenic DICER1 mutations in the RNase IIIb domain were found in 29% of nonepithelial ovarian tumors (n=103) with one mutation in a Juvenile ovarian granulosa-cell tumor (1/14; 7%). This individual had a germline mutation in D1709G. 22187960 PubMed Heravi-Moussavi et al., 2012, N. Engl. J. Med. 2 accepted 5897 2195 9533 Rare Germline 2018-07-06 21:41:12 UTC https://civicdb.org/links/evidence_items/5897 https://civicdb.org/links/variants/2195 https://civicdb.org/links/genes/9533 false DICER1 23405 D1709N Glandular Pattern Ovarian Yolk Sac Tumor 6511 Predisposing Supports C Likely Pathogenic DICER1 mutations in the RNase IIIb domain were found in 29% of nonepithelial ovarian tumors (n=103). There was one Yolk sac tumor that had a germline mutation in D1709N. 22187960 PubMed Heravi-Moussavi et al., 2012, N. Engl. J. Med. 2 accepted 5899 2051 9533 Rare Germline 2018-07-06 21:30:25 UTC https://civicdb.org/links/evidence_items/5899 https://civicdb.org/links/variants/2051 https://civicdb.org/links/genes/9533 false DICER1 23405 D1709E Glandular Pattern Ovarian Yolk Sac Tumor 6511 Predisposing Supports C Likely Pathogenic DICER1 mutations in the RNase IIIb domain were found in 29% of nonepithelial ovarian tumors (n=103). There was one Yolk sac tumor that had a germline mutation in D1709E. 22187960 PubMed Heravi-Moussavi et al., 2012, N. Engl. J. Med. 2 accepted 5900 2196 9533 Rare Germline 2018-07-06 21:30:10 UTC https://civicdb.org/links/evidence_items/5900 https://civicdb.org/links/variants/2196 https://civicdb.org/links/genes/9533 false BRAF 673 V600E Cholangiocarcinoma 4947 Dabrafenib,Trametinib Combination Predictive Supports C Sensitivity/Response Chemotherapy-refractory, metastatic cholangiocarcinoma with CNS involvement and a BRAF V600E mutation had a partial response at 8 weeks to dabrafenib and trametinib combination with complete radiologic regression at 12 weeks. At 6 months the patient was still on treatment. 28480077 PubMed Kocsis et al., 2017, J Gastrointest Oncol 3 accepted 5902 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2021-05-11 03:22:41 UTC https://civicdb.org/links/evidence_items/5902 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Intrahepatic Cholangiocarcinoma 4928 Dabrafenib,Trametinib Combination Predictive Supports C Sensitivity/Response Two cases of patients with BRAF V600E positive, refractory intrahepatic cholangiocarcinoma showed excellent clinical and radiographic response to combination dabrafenib and trametinib treatment. One patient achieved complete remission at 6 months with progression at 9 months and the other partial remission at 2 months and no progression as of 5 months. 28078132 PubMed Lavingia et al., 2016, J Gastrointest Oncol 3 accepted 5903 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2021-05-12 17:53:12 UTC https://civicdb.org/links/evidence_items/5903 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Intrahepatic Cholangiocarcinoma 4928 Dabrafenib,Trametinib Combination Predictive Supports C Sensitivity/Response Dabrafenib and trametinib combination showed durable response for a patient with standard chemotherapy and radiation refractory, poorly differentiated, intrahepatic cholangiocarcinoma harboring BRAF V600E. At time of publication, 8.5 months, the patient was still on treatment. 25435907 PubMed Loaiza-Bonilla et al., 2014, Ecancermedicalscience 3 accepted 5904 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2021-05-13 16:22:59 UTC https://civicdb.org/links/evidence_items/5904 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600 Cholangiocarcinoma 4947 Vemurafenib Predictive Supports B Sensitivity/Response Eight patients with BRAF V600 (7 with V600E, 1 with V600 unknown) mutated cholangiocarcinoma received vemurafenib. Only one patients showed partial response and duration of response of this patient was longer than 12 months. 26287849 PubMed Hyman et al., 2015, N. Engl. J. Med. NCT01524978 4 accepted 5905 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2018-02-13 20:04:08 UTC https://civicdb.org/links/evidence_items/5905 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false BRAF 673 V600E Cholangiocarcinoma 4947 Irinotecan,Vemurafenib,Panitumumab Combination Predictive Supports C Sensitivity/Response A 31 year old patient with metastatic cholangiocarcinoma with BRAF V600E was treated with vemurafenib, panitumumab and irinotecan triplet therapy. By 2 months, 50% reduction of tumor volume was noted, including multiple lung metastases, complete clinical response was noted by CT 6 months post therapy and this treatment was continued. 26687137 PubMed Silkin et al., 2016, J Gastrointest Cancer 3 accepted 5906 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2021-05-14 19:05:37 UTC https://civicdb.org/links/evidence_items/5906 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false FGFR2 2263 Fusion Cholangiocarcinoma 4947 Infigratinib Predictive Supports B Sensitivity/Response This Phase II trial of BGJ398 for FGFR2 aberant cholangiocarcinoma included 48 patients with FGFR2 fusions. Among these patients with FGFR2 fusions, eight showed tumor response (18.8%) and thirty-six showed tumor shrinkage (75%). 29182496 PubMed Javle et al., 2018, J. Clin. Oncol. NCT02150967 4 accepted 5908 2202 22 Somatic 2018-07-12 18:35:57 UTC https://civicdb.org/links/evidence_items/5908 https://civicdb.org/links/variants/2202 https://civicdb.org/links/genes/22 false EGFR 1956 EGFR::RAD51 Lung Adenocarcinoma 3910 Erlotinib Predictive Supports C Sensitivity/Response A 48-year-old Chinese man with right lung tumor and multiple brain metastases of a lung adenocarcinoma (T1N2M1, stage IV). NGS analysis indicated an EGFR-RAD51 fusion rather than the most common kind of EGFR mutations. The patient underwent oral erlotinib treatment and was considered to have a partial response (PR) (according to RECIST). Thus far, after 5 months, the disease is stable and he is continuing treatment with erlotinib. 29290255 PubMed Zhu et al., 2018, Lung Cancer 3 accepted 5909 2203 19 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/5909 https://civicdb.org/links/variants/2203 https://civicdb.org/links/genes/19 false FGFR2 2263 Mutation Cholangiocarcinoma 4947 Infigratinib Predictive Supports B Sensitivity/Response Eight patients with cholangiocarcinoma haboring FGFR2 mutations received BGJ398. No response was observed, but one tumor showed a 23% reduction in size. Water fall plot of this article showed 5 patients with stable disease. 29182496 PubMed Javle et al., 2018, J. Clin. Oncol. NCT02150967 4 accepted 5912 511 22 10 123239371 123357917 ENST00000457416.2 75 GRCh37 Somatic 2021-03-11 22:17:50 UTC https://civicdb.org/links/evidence_items/5912 https://civicdb.org/links/variants/511 https://civicdb.org/links/genes/22 false BRCA2 675 Mutation Pancreatic Cancer 1793 Olaparib Predictive Supports B Sensitivity/Response Twenty-three patients with pancreatic cancer havoring BRCA1/2 germline mutations received olaparib. Eighteen (78%) patients had a BRCA2 mutation. In total of patients with BRCA1/2 mutation , all but one had received prior gemcitabine, and 65% had received prior platinum. Tumor response rate was 21.7% and stable disease more than 8 weeks was 35%. 25366685 PubMed Kaufman et al., 2015, J. Clin. Oncol. 4 accepted 5913 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Rare Germline 2021-01-28 21:17:54 UTC https://civicdb.org/links/evidence_items/5913 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false BRCA1 672 Mutation Pancreatic Cancer 1793 Olaparib Predictive Supports B Sensitivity/Response Twenty-three patients with pancreatic cancer havoring BRCA1/2 germline mutations received olaparib. Five (21.7%) patients had a BRCA1 mutation. All but one had received prior gemcitabine, and 65% had received prior platinum. Tumor response rate was 21.7% and stable disease more than 8 weeks was 35%. 25366685 PubMed Kaufman et al., 2015, J. Clin. Oncol. 3 accepted 5914 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Rare Germline 2021-01-28 19:46:12 UTC https://civicdb.org/links/evidence_items/5914 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false BRCA1 672 Mutation Pancreatic Cancer 1793 Oxaliplatin,Cisplatin Substitutes Predictive Supports B Sensitivity/Response Patients with BRCA1/2 associated pancreatic adenocarcinoma were evaluated retrospectively. In patients with stage 3 and 4, the median overall survival (mOS) was 22 months for the platinum exposed (n=22), compared with 9 months for the non-platinum (n=21) treatment groups (p<0.039) 25072261 PubMed Golan et al., 2014, Br. J. Cancer 4 accepted 5915 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Rare Germline 2019-08-30 18:11:23 UTC https://civicdb.org/links/evidence_items/5915 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false BRCA2 675 Mutation Pancreatic Cancer 1793 Platinum Compound Predictive Supports B Sensitivity/Response Patients with BRCA1/2 associated pancreatic adenocarcinoma were evaluated retrospectively. In patients with stage 3 and 4, the median overall survival (mOS) was 22 months for the platinum exposed (n=22), compared with 9 months for the non-platinum (n=21) treatment groups (p<0.039) 25072261 PubMed Golan et al., 2014, Br. J. Cancer 4 accepted 5916 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Rare Germline 2018-07-10 18:36:14 UTC https://civicdb.org/links/evidence_items/5916 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false EGFR 1956 Mutation Peritoneal Mesothelioma 1788 Hyperthermic Intraperitoneal Chemotherapy,Cytoreductive Surgery Combination Predictive Supports B Sensitivity/Response 25 patients with metastatic peritoneal mesothelioma were treated with surgical cytoreduction consolidated with intraperitoneal hyperthermic chemotherapy (CRS/IPHC). 8 of the patients carried EGFR mutations in the tyrosine kinase domain. Each mutation was not found in 100 unrelated controls. At study end 10/18 wildtype patients had died with median survival of 14 months, while 2/7 EGFR mutant patients had died and median survival was not yet reached. Median time to progression (TTP) was 12 months in the wildtype group and in the mutant group median TTP was not yet reached. 3 year progression free survival was 71% in the mutant group and 28% in the wildtype group. 20942962 PubMed Foster et al., 2010, World J Surg Oncol 4 accepted 5923 442 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2019-08-29 21:52:29 UTC https://civicdb.org/links/evidence_items/5923 https://civicdb.org/links/variants/442 https://civicdb.org/links/genes/19 false EGFR 1956 Amplification Lung Non-small Cell Carcinoma 3908 Erlotinib,Gefitinib Substitutes Predictive Supports B Sensitivity/Response The result of the analysis found that EGFR gene copy number was associated with increased OS and PFS, supporting the idea that EGFR gene copy number is a biomarker for response to EGFR-TKI therapy in patients with advanced NSCLC. 20826716 PubMed Dahabreh et al., 2011, Ann. Oncol. 4 accepted 5924 190 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2021-02-12 00:30:38 UTC https://civicdb.org/links/evidence_items/5924 https://civicdb.org/links/variants/190 https://civicdb.org/links/genes/19 false EGFR 1956 Amplification Lung Non-small Cell Carcinoma 3908 Erlotinib,Gefitinib Substitutes Predictive Supports B Sensitivity/Response Among TKI-treated patients, increased EGFR gene copy number appears to be associated with improved survival outcomes. 27664271 PubMed Zhang et al., 2017, J. Investig. Med. 4 accepted 5925 190 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2021-02-12 00:31:05 UTC https://civicdb.org/links/evidence_items/5925 https://civicdb.org/links/variants/190 https://civicdb.org/links/genes/19 false BAP1 8314 ALTERNATIVE TRANSCRIPT (ATI) Malignant Mesothelioma 1790 Olaparib,Apitolisib Combination Predictive Supports D Sensitivity/Response A novel alternative splice isoform of BAP1 (BAP1Δ) that misses part of the catalytic domain showed reduced deubiquitinating activity compared with full-length BAP1. 4 MPM cell lines expressing more than 20% of BAP1Δ were more sensitive to olaparib (a PARP1 inhibitor) than 4 cell lines with less BAP1Δ expression, and this sensitivity was enhanced when olaparib treatment was combined with GDC0980 (a dual PI3K-mTOR inhibitor). 28389374 PubMed Parrotta et al., 2017, J Thorac Oncol 3 accepted 5929 2211 70 Somatic 2021-04-19 18:19:50 UTC https://civicdb.org/links/evidence_items/5929 https://civicdb.org/links/variants/2211 https://civicdb.org/links/genes/70 false BRCA1 672 Mutation Pancreatic Cancer 1793 Veliparib,Gemcitabine,Cisplatin Combination Predictive Supports B Sensitivity/Response In Phase I study for pancreatic cancer patients GEM 600 mg/m2 + CDDP 25 mg/m2 + Veliparib 20 - 80 mg twice daily showed response rate of 77.8% (7/9) and mOS of 23.3 months in germline BRCA mutation-positive patients with stage IV disease. 29338080 PubMed O'Reilly et al., 2018, Cancer 3 accepted 5932 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Rare Germline 2018-07-06 14:37:57 UTC https://civicdb.org/links/evidence_items/5932 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false BRCA2 675 Mutation Pancreatic Cancer 1793 Veliparib,Gemcitabine,Cisplatin Combination Predictive Supports B Sensitivity/Response In Phase I study for pancreatic cancer patients GEM 600 mg/m2 + CDDP 25 mg/m2 + Veliparib 20 - 80 mg twice daily showed response rate of 77.8% (7/9) and mOS of 23.3 months in germline BRCA mutation-positive patients with stage IV disease. 29338080 PubMed O'Reilly et al., 2018, Cancer 3 accepted 5933 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Rare Germline 2018-07-31 18:03:45 UTC https://civicdb.org/links/evidence_items/5933 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false BRCA1 672 Mutation Pancreatic Cancer 1793 Veliparib Predictive Does Not Support B Sensitivity/Response Veliparib 400mg BID was administered to patients with germline BRCA1/2-mutated pancreatic cancer. Sixteen patients were enrolled. All except two (12.5%) had previously been treated with platinum therapy. No confirmed partial response was observed. One patient who had received prior single-agent gemcitabine only had an unconfirmed PR. 29223478 PubMed Lowery et al., 2018, Eur. J. Cancer NCT01585805,NCT02184195 3 accepted 5934 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Rare Germline 2020-08-12 05:43:35 UTC https://civicdb.org/links/evidence_items/5934 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false BRCA2 675 Mutation Pancreatic Cancer 1793 Veliparib Predictive Does Not Support B Sensitivity/Response Veliparib 400mg bid was administered to patients with germline BRCA1/2 mutated pancreatic cancer. Sixteen pts was enrolled. All except two pts (12.5%) had previously been treated with platinum therapy. No confirmed PR was observed. One patient who had received prior single-agent gemcitabine only had an unconfirmed PR. 29223478 PubMed Lowery et al., 2018, Eur. J. Cancer NCT01585805,NCT02184195 3 accepted 5935 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Rare Germline 2018-07-31 18:03:40 UTC https://civicdb.org/links/evidence_items/5935 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false BRCA2 675 Mutation Pancreatic Cancer 1793 Iniparib Predictive Supports C Sensitivity/Response Patient with germline BRCA2 mutation underwent resection of pancreatic cancer. Around three years later, tumor recurrence was detected by MRI and PET-CT confirmed it. She was treated with gemcitabine plus iniparib in clinical trial. Excellent response to therapy was observed and surgery was performed but no residual tumor tissue was detected 21508395 PubMed Fogelman et al., 2011, Anticancer Res. 3 accepted 5936 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Rare Germline 2019-01-20 03:49:13 UTC https://civicdb.org/links/evidence_items/5936 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false EGFR 1956 M766_A767insASV Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Does Not Support C Sensitivity/Response A 43 year old female neversmoker lung adenocarcinoma patient with EGFR M766_A767insASV mutation was given erlotinib as first line treatment, and had progressive disease as best response with -3.9% change to target lesions, progression free survival of 1 month. 24353160 PubMed Yasuda et al., 2013, Sci Transl Med 3 accepted 5938 2213 19 Somatic 2021-02-18 02:30:39 UTC https://civicdb.org/links/evidence_items/5938 https://civicdb.org/links/variants/2213 https://civicdb.org/links/genes/19 false EGFR 1956 D770_N771insNPG Lung Non-small Cell Carcinoma 3908 Afatinib,Gefitinib Substitutes Predictive Does Not Support D Sensitivity/Response Ba/F3 cells transduced with EGFR D770_N771insNPG were IL3 growth independent, suggesting a driver mutation. Gefitinib growth inhibition IC50 in D770_N771insNPG transduced Ba/F3 cells was 3.356 micro molar, which was higher than cells transduced with resistance mutation T790M (IC50=2.752). Similarly, afatinib growth inhibition IC50 was 0.0724 micro molar, which was higher than cells transduced with resistance mutation T790M (IC50=0.0629). 24353160 PubMed Yasuda et al., 2013, Sci Transl Med 3 accepted 5947 1569 19 7 55249012 55249013 AACCCCGGC GRCh37 Somatic 2021-03-27 01:35:10 UTC https://civicdb.org/links/evidence_items/5947 https://civicdb.org/links/variants/1569 https://civicdb.org/links/genes/19 false ALK 238 STRN::ALK Colon Adenocarcinoma 234 Ceritinib Predictive Supports C Sensitivity/Response Patients with metastatic colorectal cancer with STRN-ALK fusion, sporadic microsatellite instability high (MSI-H) and KRAS R164Q received ALK inhibitor ceritinib. After pts received ceritinib perinumbilica cutaneous metastasis disappeared. Although the size of pelvic tumor by CT scan did not changed, there has been resolution of all contrast enhancing tumor by CT scan. 26933125 PubMed Yakirevich et al., 2016, Clin. Cancer Res. 3 accepted 5952 2218 1 Somatic 2020-04-29 19:19:50 UTC https://civicdb.org/links/evidence_items/5952 https://civicdb.org/links/variants/2218 https://civicdb.org/links/genes/1 false BARD1 580 Loss-of-function Colorectal Cancer 9256 Olaparib Predictive Supports D Sensitivity/Response Loss of BARD1 function through the expression of a BARD1 splice variant, BARD1β, results in a more malignant phenotype with decreased RAD51 foci formation, reduced BRCA1 E3 ubiquitin ligase activity, and decreased nuclear BRCA1 protein localization. BARD1β sensitizes colon cancer cells to poly ADP ribose polymerase 1 (PARP-1) inhibition even in a BRCA1 WT background. 27197561 PubMed Ozden et al., 2016, Sci Rep 3 accepted 5953 2219 549 Somatic 2020-08-12 21:37:38 UTC https://civicdb.org/links/evidence_items/5953 https://civicdb.org/links/variants/2219 https://civicdb.org/links/genes/549 false ALK 238 Fusion Thyroid Gland Anaplastic Carcinoma 0080522 Crizotinib Predictive Supports C Sensitivity/Response A patient with anaplastic thyroid carcinoma harboring ALK rearrangement received crizotinib after chemotherapy for pulmonary recurrence. Crizotinib showed confirmed response of more than 90% by tumor volume, and her response has been stable on follow-up. 24687827 PubMed Godbert et al., 2015, J. Clin. Oncol. 3 accepted 5954 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2020-12-10 19:29:27 UTC https://civicdb.org/links/evidence_items/5954 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ERBB2 2064 Overexpression Pancreatic Cancer 1793 Trastuzumab,Capecitabine Combination Predictive Does Not Support B Sensitivity/Response This is Phase II trial of Trastuzumab and capecitabine as first line treatment in patients with IHC 3+ HER2 expressing advanced pancreatic cancer or cancer with HER2 gene amplification of stage IVB. Total 207 patients could be assessed for HER2 expression. From the 23 patient with IHC 3+ HER2 expression or IHC 2+ and HER2 gene amplification, 17 patients were included in the study and could be assessed for response to the treatment. Contrary to breast and gastric cancer, only 7 out of 11 (64%) patients with IHC 3+ HER2 expression showed gene amplification. PFS rate at 12 weeks was estimated as 23.5%. Median PFS was 65 days. Median OS was 6.9 months. Authors concluded not to recommend further evaluation of anti-HER2 treatment in patients with metastatic pancreatic cancer. 22374460 PubMed Harder et al., 2012, Br. J. Cancer 4 accepted 5955 875 20 N/A 2020-11-24 07:10:59 UTC https://civicdb.org/links/evidence_items/5955 https://civicdb.org/links/variants/875 https://civicdb.org/links/genes/20 false ERBB2 2064 Overexpression Pancreatic Cancer 1793 Gemcitabine,Trastuzumab Combination Predictive Does Not Support B Sensitivity/Response Patients with metastatic pancreatic cancer with IHC 2+/3+ HER2 received gemcitabine and Trastuzumab combination. Screening logs demonstrated the rate of HER2 overexpression was 16%. Thirty-four patients were enrolled. Thirty patients (88%) had pancreatic cancers with 2+ overexpression and 4 patients (12%) had 3+ overexpression. Confirmed partial responses were observed in 2 of 32 patients (6%). The median survival for all 34 patients was 7 months. 15581051 PubMed Safran et al., 2004, Cancer Invest. 4 accepted 5956 875 20 N/A 2020-11-24 07:11:08 UTC https://civicdb.org/links/evidence_items/5956 https://civicdb.org/links/variants/875 https://civicdb.org/links/genes/20 false PTEN 5728 Loss Solid Tumor Carboplatin,Buparlisib,Paclitaxel Combination Predictive Does Not Support B Sensitivity/Response In one arm of this phase 1b study, 7 patients with PTEN deficient tumors were treated with continuous buparlisib (100 mg/daily) orally plus standard dose carboplatin AUC 5 and paclitaxel 175 mg/m2. No objective responses were observed. 2 patients had stable disease for ≥ 6 cycles. The authors recommended against the addition of buparlisib to carboplatin and paclitaxel, citing toxicity. Authors noted that combination therapy did not produce significant clinical activity amongst a small and heterogenous group of PTEN deficient tumors. 28281183 PubMed Smyth et al., 2017, Invest New Drugs NCT01297452 2 accepted 5957 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2021-04-14 22:05:31 UTC https://civicdb.org/links/evidence_items/5957 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false BRAF 673 V600E Lung Non-small Cell Carcinoma 3908 Vemurafenib Predictive Supports B Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Within the BRAF mutant group, fourteen patients had refractory BRAF V600E-mutated NSCLC (adenocarcinoma, n = 13; sarcomatoid, n = 1). Six patients (43%; 95% CI, 18% to 71%) had objective responses (one CR, five PR), and two additional patients had SD > 120 days. The median DOR was 5 months (range, 4 to 14 months). 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 4 accepted 5958 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-02-15 21:50:44 UTC https://civicdb.org/links/evidence_items/5958 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Ovarian Cancer 2394 Vemurafenib Predictive Supports B Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Among 4 patients with BRAF V600E mutant ovarian cancer, 2 had a partial response and one had stable disease > 120days. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 3 accepted 5959 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-02-15 21:52:07 UTC https://civicdb.org/links/evidence_items/5959 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Vemurafenib Predictive Supports C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Among 2 patients with BRAF V600E mutant colorectal cancer, 1 had a partial response. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5960 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-02-16 11:12:26 UTC https://civicdb.org/links/evidence_items/5960 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Thyroid Gland Anaplastic Carcinoma 0080522 Vemurafenib,Pertuzumab Combination Predictive Supports C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. One patient with BRAF V600E mutant anaplastic thyroid cancer had a complete response. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 3 accepted 5961 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-12-10 19:36:42 UTC https://civicdb.org/links/evidence_items/5961 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Laryngeal Squamous Cell Carcinoma 2876 Vemurafenib Predictive Supports C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. One patient with BRAF V600E mutant laryngeal cancer had a partial response with vemurafenib. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 3 accepted 5962 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-02-16 11:26:42 UTC https://civicdb.org/links/evidence_items/5962 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 G464V Cancer 162 Vemurafenib Predictive Does Not Support C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5964 1106 5 7 140481417 140481417 C A ENST00000288602.6 75 GRCh37 Somatic 2018-02-16 11:13:00 UTC https://civicdb.org/links/evidence_items/5964 https://civicdb.org/links/variants/1106 https://civicdb.org/links/genes/5 false BRAF 673 G469A Cancer 162 Vemurafenib Predictive Does Not Support C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5965 992 5 7 140481402 140481402 C G ENST00000288602.6 75 GRCh37 Somatic 2018-02-16 11:20:34 UTC https://civicdb.org/links/evidence_items/5965 https://civicdb.org/links/variants/992 https://civicdb.org/links/genes/5 false BRAF 673 G496A Cancer 162 Vemurafenib Predictive Does Not Support C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5966 2221 5 Somatic 2018-02-16 11:20:52 UTC https://civicdb.org/links/evidence_items/5966 https://civicdb.org/links/variants/2221 https://civicdb.org/links/genes/5 false BRAF 673 N581S Cancer 162 Vemurafenib Predictive Does Not Support C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5967 1186 5 7 140453193 140453193 T C GRCh37 Somatic 2018-02-16 11:21:16 UTC https://civicdb.org/links/evidence_items/5967 https://civicdb.org/links/variants/1186 https://civicdb.org/links/genes/5 false BRAF 673 G466V Cancer 162 Vemurafenib Predictive Does Not Support C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5968 2222 5 7 140481411 140481411 C A ENST00000288602.6 75 GRCh37 Somatic 2018-02-16 11:21:52 UTC https://civicdb.org/links/evidence_items/5968 https://civicdb.org/links/variants/2222 https://civicdb.org/links/genes/5 false BRAF 673 G596R Cancer 162 Vemurafenib Predictive Does Not Support C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5969 1627 5 7 140453149 140453149 C G ENST00000288602.6 75 GRCh37 Somatic 2018-02-16 11:22:07 UTC https://civicdb.org/links/evidence_items/5969 https://civicdb.org/links/variants/1627 https://civicdb.org/links/genes/5 false BRAF 673 G606E Cancer 162 Vemurafenib Predictive Does Not Support C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5970 2223 5 7 140453118 140453118 C T ENST00000288602.6 75 GRCh37 Somatic 2018-02-16 11:22:21 UTC https://civicdb.org/links/evidence_items/5970 https://civicdb.org/links/variants/2223 https://civicdb.org/links/genes/5 false BRAF 673 L597Q Cancer 162 Vemurafenib Predictive Does Not Support C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5971 583 5 7 140453145 140453145 A T ENST00000288602.6 75 GRCh37 Somatic 2018-02-16 11:22:45 UTC https://civicdb.org/links/evidence_items/5971 https://civicdb.org/links/variants/583 https://civicdb.org/links/genes/5 false BRAF 673 P731T Cancer 162 Vemurafenib Predictive Does Not Support C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5972 2224 5 7 140434507 140434507 G T ENST00000288602.6 75 GRCh37 Somatic 2018-02-16 11:24:30 UTC https://civicdb.org/links/evidence_items/5972 https://civicdb.org/links/variants/2224 https://civicdb.org/links/genes/5 false BRAF 673 intron 9 rearrangement Cancer 162 Vemurafenib Predictive Does Not Support C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5973 2225 5 Somatic 2018-02-16 11:23:21 UTC https://civicdb.org/links/evidence_items/5973 https://civicdb.org/links/variants/2225 https://civicdb.org/links/genes/5 false BRAF 673 intron 10 rearrangement Cancer 162 Vemurafenib Predictive Does Not Support C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5974 2226 5 Somatic 2018-02-16 00:05:12 UTC https://civicdb.org/links/evidence_items/5974 https://civicdb.org/links/variants/2226 https://civicdb.org/links/genes/5 false BRAF 673 MACF1::BRAF Cancer 162 Vemurafenib Predictive Does Not Support C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5975 2227 5 Somatic 2018-02-16 00:04:13 UTC https://civicdb.org/links/evidence_items/5975 https://civicdb.org/links/variants/2227 https://civicdb.org/links/genes/5 false BRAF 673 WASFL::BRAF Cancer 162 Vemurafenib Predictive Does Not Support C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5976 2228 5 Somatic 2018-02-16 11:23:02 UTC https://civicdb.org/links/evidence_items/5976 https://civicdb.org/links/variants/2228 https://civicdb.org/links/genes/5 false BRAF 673 CUX1::BRAF Pancreatic Cancer 1793 Vemurafenib Predictive Supports C Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. One of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5977 2229 5 Somatic 2018-02-15 23:46:29 UTC https://civicdb.org/links/evidence_items/5977 https://civicdb.org/links/variants/2229 https://civicdb.org/links/genes/5 false PTCH1 5727 Mutation Cancer 162 Vismodegib Predictive Supports B Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Twenty-one patients had mutations in the Hedgehog pathway (PTCH-1, n = 18; SMO, n = 3). Three patients with PTCH1 mutations had PRs to vismodegib (17%; unknown primary cancer, n = 1; squamous skin cancer, n = 1; salivary gland cancer, n = 1). 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 1 accepted 5978 301 4645 9 98205262 98270943 ENST00000331920.6 75 GRCh37 Somatic 2018-02-15 23:06:46 UTC https://civicdb.org/links/evidence_items/5978 https://civicdb.org/links/variants/301 https://civicdb.org/links/genes/4645 false SMO 6608 Mutation Cancer 162 Vismodegib Predictive Does Not Support B Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Twenty-one patients had mutations in the Hedgehog pathway (PTCH-1, n = 18; SMO, n = 3). None of the patients with SMO mutations responded to SHH-inhibition with vismodegib. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5979 300 5365 7 128828713 128853386 ENST00000249373.3 75 GRCh37 Somatic 2018-02-15 23:04:42 UTC https://civicdb.org/links/evidence_items/5979 https://civicdb.org/links/variants/300 https://civicdb.org/links/genes/5365 false ERBB2 2064 Mutation Lung Non-small Cell Carcinoma 3908 Pertuzumab,Trastuzumab Combination Predictive Supports B Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Among thirty-six patients that received treatment with trastuzumab plus pertuzumab because of a HER2 mutation (without amplification/overexpression) four patients (11%; 95% CI, 3% to 26%) had objective responses. Fourteen of the 36 patients with HER2-mutated tumors had NSCLC (adenocarcinoma, n = 13; adenosquamous, n = 1); in this group, three patients (21%; 95% CI, 5% to 51%) had PR and three had SD > 120 days. Only one of the other 22 patients with HER2-mutated tumors responded to treatment with pertuzumab plus trastuzumab (biliary cancer). 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5980 666 20 17 37868196 37881332 ENST00000269571.5 75 GRCh37 Somatic 2018-02-15 23:03:37 UTC https://civicdb.org/links/evidence_items/5980 https://civicdb.org/links/variants/666 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Colorectal Cancer 9256 Trastuzumab,Pertuzumab Combination Predictive Supports B Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Thirty of 114 patients (26%; 95% CI, 19% to 35%) with HER2 amplification/overexpression had objective responses to treatment with trastuzumab plus pertuzumab (two CR, 28 PR). Patients with HER2-amplified/overexpressing metastatic colorectal cancer composed the largest tumor-pathway cohort. In this group of 37 patients with refractory disease (median, four previous lines of therapy), treatment with trastuzumab plus pertuzumab produced PRs in 14 patients (38%; 95% CI, 23% to 55%; Fig 2A). An additional four patients had SD > 120 days. The median DOR was 11 months (range, < 1 to 16+ months; 95% CI, 2.8 months to not estimable). 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 4 accepted 5981 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. N/A 2018-02-15 16:18:50 UTC https://civicdb.org/links/evidence_items/5981 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Bladder Carcinoma 4007 Trastuzumab,Pertuzumab Combination Predictive Supports B Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Three of nine patients (33%; 95% CI, 8% to 70%) with advanced bladder cancer and HER2 amplification/overexpression had responses (one CR ongoing at 15 months; two PR lasting 1 and 6 months), and two patients had SD > 120 days. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 3 accepted 5982 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. N/A 2018-02-15 21:51:30 UTC https://civicdb.org/links/evidence_items/5982 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Biliary Tract Cancer 4607 Pertuzumab,Trastuzumab Combination Predictive Supports B Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Two of seven patients (29%; 95% CI, 4% to 71%) with biliary cancer and HER2 amplification/overexpression had PR, and three had SD > 120 days 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5983 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. N/A 2018-02-15 23:02:13 UTC https://civicdb.org/links/evidence_items/5983 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Salivary Gland Carcinoma 0050904 Trastuzumab,Pertuzumab Combination Predictive Supports B Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Four of five patients with HER2 amplified/overexpressing salivary gland carcinoma (80%; 95% CI, 28% to > 99%) had responses (all PR). 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5984 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. N/A 2018-02-15 23:00:39 UTC https://civicdb.org/links/evidence_items/5984 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Pancreatic Cancer 1793 Pertuzumab,Trastuzumab Combination Predictive Supports B Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Two of nine patients (22%) with HER2 amplified/overexpressing pancreatic cancer had a PR with trastuzumab/pertuzumab combination. Another patient had SD > 120days. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5985 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. N/A 2018-02-15 21:55:44 UTC https://civicdb.org/links/evidence_items/5985 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ERBB2 2064 Amplification Uterine Cancer 363 Trastuzumab,Pertuzumab Combination Predictive Does Not Support B Sensitivity/Response The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. None of the 7 patients with HER2 amplified/overexpressing uterus cancer responded to pertuzumab/trastuzumab. 29320312 PubMed Hainsworth et al., 2018, J. Clin. Oncol. NCT02091141 2 accepted 5986 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. N/A 2018-02-15 21:54:11 UTC https://civicdb.org/links/evidence_items/5986 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false IDH1 3417 R132H Pancreatic Ductal Adenocarcinoma 3498 Ivosidenib Predictive Does Not Support C Sensitivity/Response A 48-year-old female was diagnosed with metastatic pancreatic ductal adenocarcinoma and subsequently started on standard of care chemotherapy, during which her hepatic lesions progressed. Detailed molecular profiling was performed on a biopsy from a liver lesion that demonstrated an IDH1 mutation, R132H. The patient subsequently received a mutant IDH1 inhibitor (AG-120), but with no response. 27466707 PubMed Brody et al., 2016, Cancer Biol. Ther. 2 accepted 5987 420 26 2 209113112 209113112 C T ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes and acute myeloid leukemia (AML), IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2018-02-15 14:20:27 UTC https://civicdb.org/links/evidence_items/5987 https://civicdb.org/links/variants/420 https://civicdb.org/links/genes/26 false ASS1 445 Loss Sarcoma 1115 Pegargiminase,Chloroquine Combination Predictive Supports D Sensitivity/Response 90% out of 700 sarcoma samples (comprising 45 histologies) demonstrated loss or reduction of argininosuccinate synthetase 1 expression. Arginine auxotrophy confers sensitivity to arginine deprivation. In sarcoma models, arginine deprivation therapy with pegylated arginine deiminase (ADI-PEG20) maintains a prolonged state of arginine starvation without causing cell death. Combination of ADI-PEG20 and chloroquine led to synergistic cell death via necroptosis and apoptosis. 27735949 PubMed Bean et al., 2016, Cell Death Dis 3 accepted 5988 2230 450 Somatic 2018-07-06 21:28:29 UTC https://civicdb.org/links/evidence_items/5988 https://civicdb.org/links/variants/2230 https://civicdb.org/links/genes/450 false ASS1 445 Loss Ovarian Cancer 2394 Platinum Compound Predictive Supports D Resistance Preclinical evidence for epigenetic inactivation of ASS1 as a determinant of response to platinum chemotherapy suggesting that silencing of ASS1 contributes to treatment failure and clinical relapse in ovarian cancer. 19533750 PubMed Nicholson et al., 2009, Int. J. Cancer 3 accepted 5989 2230 450 Somatic 2018-07-06 21:28:14 UTC https://civicdb.org/links/evidence_items/5989 https://civicdb.org/links/variants/2230 https://civicdb.org/links/genes/450 false BCL2 596 Mutation Follicular Lymphoma 0050873 Prognostic Supports B Poor Outcome In a multivariate analysis, BCL2 mutations and high FL international prognostic index were independent risk factors for transformation and death due to lymphoma. Some mutant Bcl-2 proteins exhibited enhanced antiapoptotic capacity in vitro. 25452615 PubMed Correia et al., 2015, Blood 3 accepted 5992 2233 59 18 60790579 60987361 ENST00000398117.1 75 GRCh37 Somatic 2018-02-15 14:43:29 UTC https://civicdb.org/links/evidence_items/5992 https://civicdb.org/links/variants/2233 https://civicdb.org/links/genes/59 false RASA1 5921 Loss-of-function Lung Non-small Cell Carcinoma 3908 Trametinib Predictive Supports D Sensitivity/Response Approximately 2% of NSCLCs had RASA1 truncating mutations, and this alteration was statistically, but not completely, mutually exclusive with known activating EGFR (p=0.02) and KRAS (p=0.02) mutations. Unexpectedly, RASA1 truncating mutations had a strong tendency to co-occur with NF1 truncating mutations (p<0.001). While growth of cell lines with inactivation of only one of these two RasGAPs showed moderate and variable sensitivity to inhibitors of MEK or PI3K, cells with concurrent RASA1/NF1 mutations were profoundly more sensitive (IC50: 0.040μM trametinib). 29127119 PubMed Hayashi et al., 2018, Clin. Cancer Res. 3 accepted 5994 2235 4791 Somatic 2018-03-23 12:14:28 UTC https://civicdb.org/links/evidence_items/5994 https://civicdb.org/links/variants/2235 https://civicdb.org/links/genes/4791 false TLK2 11011 Amplification Breast Cancer 1612 GF109203X,Go6983 Substitutes Predictive Supports D Sensitivity/Response TLK2 inhibition selectively inhibits the growth of TLK2-high breast cancer cells, downregulates ERα, BCL2 and SKP2, impairs G1/S cell cycle progression, induces apoptosis and significantly improves progression-free survival in vivo. 27694828 PubMed Kim et al., 2016, Nat Commun 3 accepted 6000 2240 8787 Somatic 2018-02-15 14:19:52 UTC https://civicdb.org/links/evidence_items/6000 https://civicdb.org/links/variants/2240 https://civicdb.org/links/genes/8787 false BRAF 673 D594G Skin Melanoma 8923 Sorafenib Predictive Supports D Sensitivity/Response In this preclinical study, melanoma cell lines harboring the kinase-dead G469E- and D594G mutations were identified. These cell lines were resitant to MEK-Inhibition but underwent apoptosis after shRNA-mediated CRAF knowdown or Treatment with the pan-RAF Inhibitor sorafenib. 18794803 PubMed Smalley et al., 2009, Oncogene 3 accepted 6001 611 5 7 140453154 140453154 T C ENST00000288602.6 75 GRCh37 This BRAF mutation has a markedly reduced kinase activity and leads to paradoxical MEK-pathway activation via CRAF binding. Somatic 2018-07-24 15:33:17 UTC https://civicdb.org/links/evidence_items/6001 https://civicdb.org/links/variants/611 https://civicdb.org/links/genes/5 false BRAF 673 D594G Skin Melanoma 8923 U0126 Predictive Supports D Resistance In this preclinical study, melanoma cell lines harboring the kinase-dead G469E- and D594G mutations were identified. These cell lines were resitant to MEK-Inhibition but underwent apoptosis after shRNA-mediated CRAF knowdown or Treatment with the pan-RAF Inhibitor sorafenib. 18794803 PubMed Smalley et al., 2009, Oncogene 3 accepted 6002 611 5 7 140453154 140453154 T C ENST00000288602.6 75 GRCh37 This BRAF mutation has a markedly reduced kinase activity and leads to paradoxical MEK-pathway activation via CRAF binding. Somatic 2020-10-06 06:51:30 UTC https://civicdb.org/links/evidence_items/6002 https://civicdb.org/links/variants/611 https://civicdb.org/links/genes/5 false BRAF 673 G469E Skin Melanoma 8923 Sorafenib Predictive Supports D Sensitivity/Response In this preclinical study, melanoma cell lines harboring the kinase-dead G469E- and D594G mutations were identified. These cell lines were resitant to MEK-Inhibition but underwent apoptosis after shRNA-mediated CRAF knowdown or Treatment with the pan-RAF Inhibitor sorafenib. 18794803 PubMed Smalley et al., 2009, Oncogene 3 accepted 6003 993 5 7 140481402 140481402 C T GRCh37 The BRAF G469E mutation has a markedly reduced kinase activity and thus activates the MEK pathway through CRAF binding. Somatic 2018-07-24 15:33:46 UTC https://civicdb.org/links/evidence_items/6003 https://civicdb.org/links/variants/993 https://civicdb.org/links/genes/5 false BRAF 673 G469E Skin Melanoma 8923 U0126 Predictive Supports D Resistance In this preclinical study, melanoma cell lines harboring the kinase-dead G469E- and D594G mutations were identified. These cell lines were resitant to MEK-Inhibition (U0126) but underwent apoptosis after shRNA-mediated CRAF knowdown or treatment with the pan-RAF inhibitor sorafenib. 18794803 PubMed Smalley et al., 2009, Oncogene 3 accepted 6004 993 5 7 140481402 140481402 C T GRCh37 The BRAF G469E mutation has a markedly reduced kinase activity and thus activates the MEK pathway through CRAF binding. Somatic 2020-09-24 18:56:19 UTC https://civicdb.org/links/evidence_items/6004 https://civicdb.org/links/variants/993 https://civicdb.org/links/genes/5 false EGFR 1956 L747_P753delinsS Pancreatic Adenocarcinoma 4074 Erlotinib Predictive Supports C Sensitivity/Response Patients with recurrent pancreatic adenocarcinoma was treated with gemcitabine + nab-paclitaxel, FOLFIRINOX and docetaxel + irinotecan. After failure of these treatment, a tumor specimen from the pancreaticoduodenectomy was analyzed, which revealed an activating mutation in exon 19 (L747_P753>S) of EGFR. Mutations were also detected in CDKN2A, TP53, and amplifications of PRKCI and TERC. He began erlotinib at 150mg daily. CT imaging revealed a partial response by RECIST at 8, 24 and 32 weeks after starting erlotinib. At 40 weeks CT imaging revealed unequivocal disease progression. After disease progression to erlotinib, a repeat liver biopsy revealed an EGFR T790M mutation. He began treatment with osimertinib at 80mg daily. After 8 weeks of this treatment CT imaging revealed unequivocal disease progression. 28874593 PubMed Cecchini et al., 2017, J Natl Compr Canc Netw 3 accepted 6005 1012 19 7 55242470 55242487 TAAGAGAAGCAACATCTC ENST00000275493.2 75 GRCh37 Somatic 2022-01-20 22:23:23 UTC https://civicdb.org/links/evidence_items/6005 https://civicdb.org/links/variants/1012 https://civicdb.org/links/genes/19 false EGFR 1956 T790M Pancreatic Adenocarcinoma 4074 Osimertinib Predictive Does Not Support C Sensitivity/Response Patients with recurrent pancreatic adenocarcinoma was treated with gemcitabine + nab-paclitaxel, FOLFIRINOX and docetaxel + irinotecan. After failure of these treatment, a tumor specimen from the pancreaticoduodenectomy was analysed, which revealed an activating mutation in exon 19 (L747_P753>S) of EGFR. Mutations were also detected in CDKN2A, TP53, and amplifications of PRKCI and TERC. He began erlotinib at 150mg daily. CT imaging revealed a partial response by RECIST at 8, 24 and 32 weeks after starting erlotinib. At 40 weeks CT imaging revealed unequivocal disease progression. After disease progression to erlotinib, a repeat liver biopsy revealed an EGFR T790M mutation. He began treatment with osimertinib at 80mg daily. After 8 weeks of this treatment CT imaging revealed unequivocal disease progression. 28874593 PubMed Cecchini et al., 2017, J Natl Compr Canc Netw 2 accepted 6006 34 19 7 55249071 55249071 C T ENST00000275493.2 75 GRCh37 EGFR T790M was one of the very first mutations recognized to confer resistance to targeted therapies in non-small cell lung cancer. While successful in amplified EGFR, the efficacy of the first and second generation TKI's (erlotinib, gefitinib, neratinib) in treating patients harboring this mutation before treatment is notably lower. This lack of efficacy can likely be to blame for the poorer prognosis for patients with this mutation as compared to patients with wildtype EGFR or other types of EGFR mutations. Approximately half of EGFR mutant tumors with acquired resistance to TKI inhibition have been shown to harbor this mutation, implicating it as a mechanism of acquired therapy resistence. A third generation TKI (osimertinib) has been approved for the treatment of EGFR T790M mutant NSCLC. Patients positive for T790M in a plasma-based test have similar outcomes like those with tumor biopsy testing. Somatic 2022-01-20 22:31:28 UTC https://civicdb.org/links/evidence_items/6006 https://civicdb.org/links/variants/34 https://civicdb.org/links/genes/19 false MYCN 4613 Amplification Neuroblastoma 769 JQ1,Panobinostat Combination Predictive Supports D Sensitivity/Response JQ1 and panobinostat synergistically reduced LIN28B gene and N-Myc protein expression, and synergistically induced growth inhibition and apoptosis in neuroblastoma cells, but not normal nonmalignant cells in vitro In neuroblastoma-bearing mice, JQ1 and panobinostat synergistically and considerably reduced N-Myc protein expression in tumor tissues and blocked tumor progression. 26733615 PubMed Shahbazi et al., 2016, Clin. Cancer Res. 3 accepted 6019 298 3741 2 16080686 16087129 ENST00000281043.3 75 GRCh37 Somatic 2021-05-18 23:45:26 UTC https://civicdb.org/links/evidence_items/6019 https://civicdb.org/links/variants/298 https://civicdb.org/links/genes/3741 false VHL 7428 L184P (c.551T>C) Renal Cell Carcinoma 4450 Sporadic,Renal cell carcinoma Diagnostic Supports C Positive In a study of 31 kidney tumors from France, 14 somatic VHL mutations were found. Most tumors were found to have heterozygous pattern of mutation likely due to contamination of renal cancer tissues with non-tumor cells. Genomic DNA was extracted from tumors, lymphocytes and cell lines using standard phenol/chloroform extraction or salt extraction protocols. Three sets of primers were designed to amplify the entire exons 2 and 3 and the last one third 3'-region of exon 1, the genotyping method used was PCR-SSCP (polymerase chain reaction-single-strand conformation polymorphism). A metastatic clear cell renal cell carcinoma sample (sample 3087) was obtained from a 68 year old male who was known to smoke one pack of cigarettes per day and had intense alcohol drinking habits. In this patient's tumor (sample 3087), a c.551T>C variant (noted in the paper as nucleotide 764) was identified as a somatic mutation, found only in the tumor. The second mutation, a C>G transversion, c.183C>G (p.P61=) (noted in the paper at nucleotide 396) was present in the non-tumor DNA, a germline synonymous mutation. The patient had no metastasis after nephrectomy and patients survival was >4 months. ACMG codes: none. 7591282 PubMed Bailly et al., 1995, Int. J. Cancer 1 accepted 6027 1776 58 3 10191558 10191558 T C ENST00000256474.2 75 GRCh37 Somatic 2020-12-04 20:29:03 UTC https://civicdb.org/links/evidence_items/6027 https://civicdb.org/links/variants/1776 https://civicdb.org/links/genes/58 false FOXL2 668 C134W Ovarian Sex-cord Stromal Tumor 0080369 Diagnostic Supports A Positive FOXL2 mutations were found in 94% of pathologically confirmed A-GCTs (95/101), in one of eight juvenile granulosa cell tumours (J-GCTs), and in two of 19 SLCTs. 26033501 PubMed Goulvent et al., 2016, Histopathology 5 accepted 6034 198 72 3 138665163 138665163 G C ENST00000330315.3 75 GRCh37 The variant C134W on the FOXL2 gene was revealed to have a high frequency (95-97%) in the adult form of granulosa cell tumors that comprises 5% of ovarian cancers. Due to the mutation's high frequency, future therapeutics might target for this single apparent mechanism. However, the consequence of this mutation remain unknown. Somatic 2020-06-16 19:04:45 UTC https://civicdb.org/links/evidence_items/6034 https://civicdb.org/links/variants/198 https://civicdb.org/links/genes/72 false ALK 238 Fusion Vagina Sarcoma 1901 Crizotinib Predictive Supports C Sensitivity/Response Patient was 34-year-old woman with vaginal sarcoma, which was excised with positive surgical margins. Fluorescence in situ hybridization testing of her tumor revealed anaplastic lymphoma kinase gene rearrangements. A 3-cm mass recurred 1 month later. Treatment with crizotinib resulted in complete regression of all visible or palpable tumor within 3 weeks. 26942346 PubMed Forde et al., 2016, Obstet Gynecol 2 accepted 6042 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2018-03-20 15:53:51 UTC https://civicdb.org/links/evidence_items/6042 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ALK 238 Fusion Epithelioid Inflammatory Myofibroblastic Sarcoma 0080372 Crizotinib Predictive Supports C Sensitivity/Response This is a case report of a 22-year-old Japanese man with a pelvic mesenchymal neoplasm. Tumor analysis include IHC and RT-PCR led to diagnosis of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion. Despite two surgical excision procedures, local recurrence rapidly occurred, and the tumor developed resistance to conventional chemotherapy with doxorubicin. Subsequent administration of crizotinib resulted in relief of severe pain and durable tumor shrinkage at least 10 months. 25028698 PubMed Kimbara et al., 2014, Jpn. J. Clin. Oncol. 2 accepted 6043 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2018-03-19 18:45:03 UTC https://civicdb.org/links/evidence_items/6043 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false BRAF 673 V600 Melanoma 1909 Vemurafenib,Cobimetinib Combination Predictive Supports A Sensitivity/Response In this double-blind, randomized, placebo-controlled, multicentre study, adult patients with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) to receive cobimetinib or placebo, in combination with oral vemurafenib. Progression-free survival was the primary endpoint. Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). Investigator-assessed median progression-free survival was 12.3 months for cobimetinib and vemurafenib versus 7.2 months for placebo and vemurafenib (HR 0.58 [95% CI 0.46-0.72], p<0.0001). Median overall survival was 22.3 months for cobimetinib and vemurafenib versus 17.4 months for placebo and vemurafenib (HR 0.70, 95% CI 0.55-0.90; p=0.005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. 27480103 PubMed Ascierto et al., 2016, Lancet Oncol. NCT01689519 5 accepted 6044 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2018-11-08 15:34:34 UTC https://civicdb.org/links/evidence_items/6044 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false BRAF 673 V600E Thyroid Gland Anaplastic Carcinoma 0080522 Vemurafenib Predictive Supports B Sensitivity/Response In a phase 2 “basket” study of vemurafenib in BRAF V600-positive non-melanoma cancers, seven patients with anaplastic thyroid cancer were enrolled. All 7 patients had V600E mutations. One complete response and one partial response was observed, for a response rate of 29%. 26287849 PubMed Hyman et al., 2015, N. Engl. J. Med. NCT01524978 3 accepted 6045 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-12-11 07:19:07 UTC https://civicdb.org/links/evidence_items/6045 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600 Colorectal Cancer 9256 Cetuximab,Encorafenib Combination Predictive Supports B Sensitivity/Response In a Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab, Twenty-six patients with refractory BRAF V600 mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab). Confirmed overall response rates of 19% were observed and median progression-free survival was 3.7 months. 28363909 PubMed van Geel et al., 2017, Cancer Discov 4 accepted 6046 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2018-07-06 14:00:22 UTC https://civicdb.org/links/evidence_items/6046 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false BRAF 673 V600 Colorectal Cancer 9256 Alpelisib,Cetuximab,Encorafenib Combination Predictive Supports B Sensitivity/Response In a phase Ib dose-escalation study of encorafenib, cetuximab and alpelisib, twenty-eight patients with refractory BRAF V600-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab) with a PI3Kα inhibitor (alpelisib). Confirmed overall response rates of 18% were observed and median progression-free survival was 4.2 months 28363909 PubMed van Geel et al., 2017, Cancer Discov 3 accepted 6047 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2021-01-27 22:20:17 UTC https://civicdb.org/links/evidence_items/6047 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false CTNNB1 1499 S45F Desmoid Tumor 0080366 Meloxicam Predictive Does Not Support C Sensitivity/Response Of the 33 patients with desmoid fibromatosis treated with meloxicam, a COX-2 selective inhibitor, one showed complete remission (CR), 7 partial remission (PR), 12 stable disease (SD), and 13 progressive disease (PD). The following 3 point mutations were identified in 21 of the 33 cases (64%): T41A (16 cases), S45F (4 cases) and S45P (one case). All four cases with S45F mutation exhibited strong nuclear expression of β-catenin. S45F mutation was significantly associated with a poor response (all cases; PD) (p = 0.017) 24788118 PubMed Hamada et al., 2014, PLoS ONE 2 accepted 6049 1286 1290 3 41266137 41266137 C T ENST00000349496.5 75 GRCh37 Somatic 2020-10-09 16:10:06 UTC https://civicdb.org/links/evidence_items/6049 https://civicdb.org/links/variants/1286 https://civicdb.org/links/genes/1290 false VHL 7428 E70* (c.208G>T) Von Hippel-Lindau Disease 14175 Spinal hemangioblastoma,Hemangioblastoma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This nonsense variant was found in a VHL type 1 patient with CNS hemangioblastomas (family ID 4479). 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 6059 1834 58 3 10183739 10183739 G T ENST00000256474.2 75 GRCh37 N/A 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/6059 https://civicdb.org/links/variants/1834 https://civicdb.org/links/genes/58 false VHL 7428 R82_V84del (c.244_252del) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Hemangioblastoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This in-frame deletion was found in a VHL type 1 family of 6 individuals (family ID 3177). Four of 6 individuals were identified with angiomas and 3 had CNS hemangioblastomas. 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 6060 2264 58 3 10183775 10183783 CGCGTCGTG ENST00000256474.2 75 GRCh37 N/A 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/6060 https://civicdb.org/links/variants/2264 https://civicdb.org/links/genes/58 false VHL 7428 L188Q (c.563T>A) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Renal cell carcinoma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense variant was found in 2 family members with VHL type 1 phenotype (family ID 3513). Both individuals were identified with cerebellar hemangioblastomas and renal cell carcinoma. One also had angiomas. 7728151 PubMed Chen et al., 1995, Hum. Mutat. 4 accepted 6061 1861 58 3 10191570 10191570 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/6061 https://civicdb.org/links/variants/1861 https://civicdb.org/links/genes/58 false VHL 7428 A56_P59del (c.166_178del) Renal Cell Carcinoma 4450 Renal cell carcinoma,Sporadic Predisposing Supports C Uncertain Significance Tissue analysis from 61 VHL patients, 30 sporadic renal cell carcinoma (RCC) tumor samples, and 6 sporadic RCC cell lines revealed 22 variants within VHL patients, 10 variants in tumor samples and variants in all cell lines. All mutations cluster to the 3’ end of the VHL gene open reading frame, implicating this region as important for the tumor-suppressor function of the VHL protein. From findings VHL gene was concluded to have "an important and specific role in the etiology of sporadic RCCs." This in-frame deletion results in a premature stop codon at amino acid 62 and was found in one of the tumor samples (tumor no. 22). No phenotype described. 7977367 PubMed Whaley et al., 1994, Am. J. Hum. Genet. 3 accepted 6062 2265 58 Somatic 2018-07-10 18:09:59 UTC https://civicdb.org/links/evidence_items/6062 https://civicdb.org/links/variants/2265 https://civicdb.org/links/genes/58 false ACVR1 90 G328E Diffuse Midline Glioma, H3 K27M-mutant 0080684 Diagnostic Supports C Positive Sequencing (whole genome or exome) was performed on a series of 26 pediatric patients (1.7 to 13.6 years old), 7 had missense mutations in ACVR1. Two patients with G328E mutation were identified. This mutation had not been previously reported in other cancer types, indicating it was supportive of a diagnosis of high grade pontine glioma. PEDIATRIC 24705252 PubMed Taylor et al., 2014, Nat. Genet. 3 accepted 6091 2283 154 This mutation occurs within the kinase domain of ACVR1 and has been shown to be activating of downstream BMP signaling with increased cell proliferation in cells overexpressing this variant. Somatic 2018-10-15 23:19:02 UTC https://civicdb.org/links/evidence_items/6091 https://civicdb.org/links/variants/2283 https://civicdb.org/links/genes/154 false NRG1 3084 Fusion Mucinous Adenocarcinoma 3030 Afatinib Predictive Does Not Support C Sensitivity/Response One patient with an NRG1-rearranged invasive mucinous adenocarcinomas (IMAs) of the lung had a response with an anti-ERBB3 monoclonal antibody (GSK2849330). No response was achieved with afatinib in four NRG1-rearranged IMA patients (including the index patient post-GSK2849330). 29610121 PubMed Drilon et al., 2018, Cancer Discov NCT01966445 3 accepted 6096 2286 2593 NRG1 fusions have been described in cases of invasive mucinous adenocarcinoma of the lung, pancreatic ductal adenocarcinoma, cholangiocarcinoma and lung adenocarcinoma. In many cases these tumors were negative for the more common known driver genes of these diseases (e.g., KRAS wild-type pancreatic ductal adenocarcinoma). These events have been proposed as an attractive therapeutic target and some promising results have been observed with pan-HER inhibitors such as afatinib. Somatic 2020-11-09 22:55:30 UTC https://civicdb.org/links/evidence_items/6096 https://civicdb.org/links/variants/2286 https://civicdb.org/links/genes/2593 false NTRK2 4915 STRN::NTRK2 Sarcoma 1115 Larotrectinib Predictive Supports C Sensitivity/Response One Patient with soft tissue sarcoma and a STRN-NTRK2 fusion had a partial Response with larotrectinib. Treatment was done within a multicentre, open-label, phase 1/2 study and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion Status. In total, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) were enrolled. Among the fusion-positive patients, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. 29606586 PubMed Laetsch et al., 2018, Lancet Oncol. NCT02637687 3 accepted 6098 2287 3984 Somatic 2020-09-22 23:24:47 UTC https://civicdb.org/links/evidence_items/6098 https://civicdb.org/links/variants/2287 https://civicdb.org/links/genes/3984 false NTRK3 4916 ETV6::NTRK3 Congenital Fibrosarcoma 8418 Larotrectinib Predictive Supports A Sensitivity/Response Four out of six patients with infantile fibrosarcoma and a ETV6-NTRK3 fusion had a partial response, the remaining two had a complete response with larotrectinib. Treatment was done within a multicentre, open-label, phase 1/2 study and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion Status. In total, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) were enrolled. Among the fusion-positive patients, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. 29606586 PubMed Laetsch et al., 2018, Lancet Oncol. NCT02637687 4 accepted 6099 801 3985 12 11802788 12022903 ENST00000396373.4 15 88483984 88418230 ENST00000394480.2 75 GRCh37 Somatic 2021-07-21 18:32:16 UTC https://civicdb.org/links/evidence_items/6099 https://civicdb.org/links/variants/801 https://civicdb.org/links/genes/3985 false NTRK1 4914 LMNA::NTRK1 Sarcoma 1115 Larotrectinib Predictive Supports C Sensitivity/Response One Patient with soft tissue sarcoma and a NTRK1-LMNA fusion had a partial response with larotrectinib. Treatment was done within a multicentre, open-label, phase 1/2 study and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion Status. In total, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) were enrolled. Among the fusion-positive patients, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. 29606586 PubMed Laetsch et al., 2018, Lancet Oncol. NCT02637687 3 accepted 6100 1278 3983 1 156084498 156108548 ENST00000368300.4 1 156844363 156851434 ENST00000524377.1 75 GRCh37 Somatic 2020-09-17 04:50:27 UTC https://civicdb.org/links/evidence_items/6100 https://civicdb.org/links/variants/1278 https://civicdb.org/links/genes/3983 false NTRK1 4914 TPM3::NTRK1 Sarcoma 1115 Larotrectinib Predictive Supports C Sensitivity/Response Four patients with infantile fibrosarcoma and soft tissue sarcoma and a NTRK1-TPM3 fusion were treated with larotrectinib. Two had a partial, and two had a complete response. Treatment was done within a multicentre, open-label, phase 1/2 study and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion Status. In total, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) were enrolled. Among the fusion-positive patients, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. 29606586 PubMed Laetsch et al., 2018, Lancet Oncol. NCT02637687 4 accepted 6101 2992 3983 Somatic 2020-09-17 04:49:22 UTC https://civicdb.org/links/evidence_items/6101 https://civicdb.org/links/variants/2992 https://civicdb.org/links/genes/3983 false NTRK1 4914 PDE4DIP::NTRK1 Sarcoma 1115 Larotrectinib Predictive Supports C Sensitivity/Response One Patient with soft tissue sarcoma and a NTRK1-PDE4DIP fusion was treated with larotrectinib and exhibited a partial response. Treatment was done within a multicentre, open-label, phase 1/2 study and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion Status. In total, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) were enrolled. Among the fusion-positive patients, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. 29606586 PubMed Laetsch et al., 2018, Lancet Oncol. NCT02637687 3 accepted 6102 2289 3983 Somatic 2020-09-15 16:50:04 UTC https://civicdb.org/links/evidence_items/6102 https://civicdb.org/links/variants/2289 https://civicdb.org/links/genes/3983 false NTRK1 4914 SQSTM1::NTRK1 Congenital Fibrosarcoma 8418 Larotrectinib Predictive Supports C Sensitivity/Response One patient with infantile fibrosarcoma and a NTRK1-SQSTM1 fusion was treated with larotrectinib and exhibited a partial response. Treatment was done within a multicentre, open-label, phase 1/2 study and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion Status. In total, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) were enrolled. Among the fusion-positive patients, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. 29606586 PubMed Laetsch et al., 2018, Lancet Oncol. NCT02637687 3 accepted 6103 800 3983 Somatic 2020-09-17 04:47:57 UTC https://civicdb.org/links/evidence_items/6103 https://civicdb.org/links/variants/800 https://civicdb.org/links/genes/3983 false VHL 7428 G144E (c.431G>A) Adrenal Gland Pheochromocytoma 0050892 Pheochromocytoma Predisposing Supports C Uncertain Significance Screening of 68 patients, who had been operated on for apparently sporadic pheochromocytomas, for germline mutations in the VHL gene. This missense mutation was found in a 51 year-old female with unilateral, benign, adrenal pheochromocytoma (patient no. 48). 9663592 PubMed van der Harst et al., 1998, Int. J. Cancer 2 accepted 6106 2290 58 3 10188288 10188288 G A ENST00000256474.2 75 GRCh37 Rare Germline 2021-01-20 01:28:59 UTC https://civicdb.org/links/evidence_items/6106 https://civicdb.org/links/variants/2290 https://civicdb.org/links/genes/58 false VHL 7428 Splice Region (c.463+8C>T) Adrenal Gland Pheochromocytoma 0050892 Pheochromocytoma Predisposing Supports C Uncertain Significance Screening of 68 patients, who had been operated on for apparently sporadic pheochromocytomas, for germline mutations in the VHL gene. This splice variant causes a premature stop codon at amino acid 66 and was found in a 33 year-old male with unilateral, benign, adrenal pheochromocytoma (patient no. 54). 9663592 PubMed van der Harst et al., 1998, Int. J. Cancer 2 accepted 6108 2292 58 3 10188328 10188328 C T ENST00000256474.2 75 GRCh37 Rare Germline 2018-07-13 20:28:14 UTC https://civicdb.org/links/evidence_items/6108 https://civicdb.org/links/variants/2292 https://civicdb.org/links/genes/58 false VHL 7428 G104A (c.311G>C) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma Predisposing N/A C N/A Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in the germline of a female patient (patient no. S6150) with apparently sporadic retinal hemangioblastoma diagnosed at 42Y old. No unaffected family members were tested. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 2 accepted 6109 2043 58 3 10183842 10183842 G C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:44 UTC https://civicdb.org/links/evidence_items/6109 https://civicdb.org/links/variants/2043 https://civicdb.org/links/genes/58 false VHL 7428 G104= (c.312C>G) Von Hippel-Lindau Disease 14175 Predisposing N/A C N/A Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This silent variant was found in a VHL patient (patient no. V95). No unaffected family members were tested. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 1 accepted 6110 2293 58 3 10183843 10183843 C G ENST00000256474.2 75 GRCh37 Note that there is a different variant reported at this amino acid position of VHL in ClinVar: NM_000551.3(VHL):c.312C>T (p.Gly104=; G104=) https://www-ncbi-nlm-nih-gov/clinvar/variation/456582/ Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/6110 https://civicdb.org/links/variants/2293 https://civicdb.org/links/genes/58 false VHL 7428 F91L (c.273C>G) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma Predisposing N/A C N/A Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in the germline of a male VHL patient (patient no. S3940) with apparently sporadic cerebellar hemangioblastoma diagnosed at 56Y old. No unaffected family members were tested. 9829912 PubMed Olschwang et al., 1998, Hum. Mutat. 2 accepted 6111 2294 58 3 10183804 10183804 C G ENST00000256474.2 75 GRCh37 Note that there is a different variant reported at this amino acid position of VHL in ClinVar: NM_000551.3(VHL):c.273C>A (p.Phe91Leu; F91L) (https://www-ncbi-nlm-nih-gov/clinvar/variation/411978/) Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/6111 https://civicdb.org/links/variants/2294 https://civicdb.org/links/genes/58 false VHL 7428 L128R (c.383T>G) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Retinal capillary hemangioma,Cerebellar hemangioblastoma,Renal cyst Predisposing N/A C N/A Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This missense variant was found in a 22 year old patient with retinal and cerebellar hemangioblastomas, renal cysts, and pancreatic cysts (patient no. F41). 14722919 PubMed Ruiz-Llorente et al., 2004, Hum. Mutat. 3 accepted 6114 1886 58 3 10188240 10188240 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/6114 https://civicdb.org/links/variants/1886 https://civicdb.org/links/genes/58 false VHL 7428 V130L (c.388G>C) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Pancreatic cysts Predisposing N/A C N/A Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This missense mutation was found in a 26 year old patient with cerebellar hemangioblastomas and a pancreatic cyst (patient no. F2). 14722919 PubMed Ruiz-Llorente et al., 2004, Hum. Mutat. 3 accepted 6115 1970 58 3 10188245 10188245 G C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/6115 https://civicdb.org/links/variants/1970 https://civicdb.org/links/genes/58 false VHL 7428 R161* (c.481C>T) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Retinal capillary hemangioma,Cerebellar hemangioblastoma Predisposing N/A C N/A Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This nonsense variant was found in a 20 year old patient with retinal and cerebellar hemangioblastomas and pancreatic cysts (patient no. F9). ACMG codes: "flag for PP4" since patients phenotype is specific for gene. 14722919 PubMed Ruiz-Llorente et al., 2004, Hum. Mutat. 3 accepted 6116 1804 58 3 10191488 10191488 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/6116 https://civicdb.org/links/variants/1804 https://civicdb.org/links/genes/58 false VHL 7428 L184P (c.551T>C) Von Hippel-Lindau Disease 14175 Renal cyst,Pancreatic cysts,Cerebellar hemangioblastoma,Spinal hemangioblastoma,Retinal capillary hemangioma Predisposing N/A C N/A Thirty-five unrelated patients suspected of having von Hippel-Lindau disease had genomic DNA from peripheral blood leukocytes analyzed using sequence analysis of the coding region for VHL / Southern blot analyses. 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered, although this only reached significance when combining data from other studies (p=0.101 for present study; p=0.0086 for present study + other study data). This missense variant was found in a patient with spinal and cerebellar hemangioblastomas, retinal hemangioblastomas, pancreatic cysts, renal cysts, and cysts of the broad ligament (patient no. F43). The patient was 27 years old. ACMG PP4 as patient's phenotypes are highly specific for VHL disease. 14722919 PubMed Ruiz-Llorente et al., 2004, Hum. Mutat. 3 accepted 6119 1776 58 3 10191558 10191558 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/6119 https://civicdb.org/links/variants/1776 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Pheochromocytoma,Epididymal cyst,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This in-frame deletion variant was detected in a VHL type 2 patient with cerebellar hemangioblastoma, pheochromocytoma, renal cell carcinoma, and epididymal cysts (family no. 24). 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 6121 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-02-11 23:21:19 UTC https://civicdb.org/links/evidence_items/6121 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 true VHL 7428 W88fs (c.261dup) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Cerebellar hemangioblastoma,Renal cell carcinoma Predisposing Supports C Uncertain Significance Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This variant was detected in a VHL type 1 patient with cerebellar hemangioblastoma, retinal hemangioblastomas, and renal cell carcinoma (family no. 28). 17661816 PubMed Hes et al., 2007, Clin. Genet. 3 accepted 6122 2299 58 3 10183791 10183792 A ENST00000256474.3 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6122 https://civicdb.org/links/variants/2299 https://civicdb.org/links/genes/58 false BRAF 673 V600E Colorectal Cancer 9256 Panitumumab,Trametinib,Dabrafenib Combination Predictive Supports B Sensitivity/Response In this trial, 142 patients with metastatic, BRAF V600E mutant colorectal cancer were randomized to receive either BRAF inhibitor dabrafenib (D) + EGFR inhibitor panitumumab (P); or a triple therapy of D + P and MEK inhibition with trametinib (T) or T + P. Confirmed response rates for D+P (n=20), D+T+P (n=91), and T+P (n=31) were 10%, 21%, and 0%, respectively. 29431699 PubMed Corcoran et al., 2018, Cancer Discov 4 accepted 6123 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-05-23 18:47:26 UTC https://civicdb.org/links/evidence_items/6123 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Adenocarcinoma 0050861 Panitumumab,Trametinib Combination Predictive Does Not Support B Sensitivity/Response In this trial, 142 patients with metastatic, BRAF V600E mutant colorectal cancer were randomized to receive either BRAF inhibitor dabrafenib (D) + EGFR inhibitor panitumumab (P); or a triple therapy of D + P and MEK inhibition with trametinib (T) or T + P. Confirmed response rates for D+P (n=20), D+T+P (n=91), and T+P (n=31) were 10%, 21%, and 0%, respectively. 29431699 PubMed Corcoran et al., 2018, Cancer Discov 3 accepted 6124 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-05-23 18:47:37 UTC https://civicdb.org/links/evidence_items/6124 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false VHL 7428 S65L (c.194C>T) Clear Cell Renal Cell Carcinoma 4467 Sporadic,Clear cell renal cell carcinoma Oncogenic N/A C N/A This study analyzed tumor and non-tumor kidney tissue from 195 unrelated patients with sporadic clear cell renal cell carcinoma (CCRCC) for a relationship between VHL variants in sporadic CCRCC and 'genotypes for genes encoding several carcinogen-metabolizing enzymes.' This missense variant was found in a 68 year-old male (tumour 311). 11505222 PubMed Gallou et al., 2001, Pharmacogenetics 1 accepted 6131 1788 58 3 10183725 10183725 C T ENST00000256474.2 75 GRCh37 Somatic 2021-03-05 19:15:21 UTC https://civicdb.org/links/evidence_items/6131 https://civicdb.org/links/variants/1788 https://civicdb.org/links/genes/58 false VHL 7428 L184P (c.551T>C) Clear Cell Renal Cell Carcinoma 4467 Sporadic,Clear cell renal cell carcinoma Diagnostic Supports C Positive 195 patients with sporadic clear cell renal cell carcinoma (sporadic CCRCC) were investigated for variants in the VHL gene, in order to determine the possible relationship between VHL mutations in CCRCC patients and polymorphisms in genes encoding enzymes involved in carcinogen metabolism. For each patient, fragments of tumor and non-tumoral kidney tissue were sampled, and DNA was extracted for analysis. PCR, SSCP (single strand conformation polymorphism,) and direct sequencing were used to investigate VHL variants. Tumor number 347 (a cytological grade 1 stage I tumor) was taken from a 60 year old female, and found to have the c.551T>C (p.L184P) somatic mutation in exon 3 of the VHL gene. No other phenotypic information was available for any of the patients included in this study. Relevant ACMG evidence codes: none. 11505222 PubMed Gallou et al., 2001, Pharmacogenetics 2 accepted 6167 1776 58 3 10191558 10191558 T C ENST00000256474.2 75 GRCh37 Somatic 2020-12-04 20:42:27 UTC https://civicdb.org/links/evidence_items/6167 https://civicdb.org/links/variants/1776 https://civicdb.org/links/genes/58 false ERBB2 2064 Overexpression Salivary Gland Cancer 8850 Paclitaxel,Trastuzumab Combination Predictive Supports C Sensitivity/Response Case report of a 61-year-old caucasian male with a renal mass and subsequent liver metastases. Histopathological examination of the liver led to the diagnosis of metastastic adenocarcinoma of the salivary Gland, which had been diagnosed and treated in the Patient 20 years earlier. IHC revealed Her2/neu, 3+. The patient was treated successfully with trastuzumab/paclitaxel with near-complete response as measured by PET-CT scans for more than a year. 23826550 PubMed Firwana et al., 2012, Avicenna J Med 2 accepted 6170 875 20 N/A 2018-07-18 15:44:52 UTC https://civicdb.org/links/evidence_items/6170 https://civicdb.org/links/variants/875 https://civicdb.org/links/genes/20 false ERBB2 2064 Overexpression Salivary Gland Cancer 8850 Zoledronic Acid,Capecitabine,Trastuzumab Combination Predictive Supports C Sensitivity/Response Case report of a a 58 year old man with multiple bone metastases after local therapy of a carcinoma ex pleomorphic adenoma one year earlier. The original tumor tested strongly positive for HER2/neu by immunohistochemistry. The patient was treated with trastuzumab, capecitabine, and zoledronic acid. He experienced total resolution of symptoms and repeat FDG-PET scan after three cycles revealed interval disease resolution. Continued treatment resulted in maintenance of disease control for over 2 years. 20504363 PubMed Sharon et al., 2010, Head Neck Oncol 3 accepted 6171 875 20 N/A 2018-07-12 18:45:18 UTC https://civicdb.org/links/evidence_items/6171 https://civicdb.org/links/variants/875 https://civicdb.org/links/genes/20 false ERBB2 2064 T798I Breast Cancer 1612 Osimertinib Predictive Does Not Support D Sensitivity/Response Efficacy of osimertinib and its metabolite, AZ5104, at reducing phosphorylation of key proteins was evaluated by western blot. Osimertinib failed to induce substantial reductions in phosphorylated ERBB2 in NR6 mouse fibroblast cells transduced to co-express ERBB2 L869R and T798I or ERBB2 wt. AZ5104 blocked phosphorylation to a greater extent in the mutant and wildtype cells. MCF10A cells transduced with ERBB2 wt, ERBB2 T798I alone or ERBB2 L869R and T798I co-expressed did not show substantial reductions in phosphorylated ERBB2, AKT, ERK or S6. AZ5104 induced greater reductions. Authors note that AZ5104 is not being developed independently of osimertinib and only 10% of osimertinib is metabolized into AZ5104 in humans. Authors concluded that ERBB2 T798I is not sensitive to osimertinib. 28274957 PubMed Hanker et al., 2017, Cancer Discov NCT01953926 3 accepted 6174 2331 20 17 37881064 37881064 C T ENST00000269571.5 75 GRCh37 Somatic 2020-12-10 20:21:58 UTC https://civicdb.org/links/evidence_items/6174 https://civicdb.org/links/variants/2331 https://civicdb.org/links/genes/20 false BRAF 673 V600E Melanoma 1909 Dabrafenib,Trametinib Combination Predictive Supports B Sensitivity/Response Adjuvant dual treatment with BRAF inhibitor dabrafenib and MEK inhibitor trametinib was administered to patients with stage III resected melenoma with V600E or V600K mutation in this stage III trial (COMBO-AD, NCT01682083). 792 (91%) patients had V600E, and were administered dabrafenib and trametinib or placebo for 12 months. In subsequent analysis, relapse or death occurred in 150/397 patients (38%) in the treatment group and 229/395 patients (58%) in the placebo group for a 95% CI Hazard Ratio of 0.48 (0.39-0.58). 28891408 PubMed Long et al., 2017, N. Engl. J. Med. NCT01682083 5 accepted 6178 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-05-23 17:55:59 UTC https://civicdb.org/links/evidence_items/6178 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600K Melanoma 1909 Dabrafenib,Trametinib Combination Predictive Supports B Sensitivity/Response Adjuvant dual treatment with BRAF inhibitor dabrafenib and MEK inhibitor trametinib was administered to patients with stage III resected melenoma with V600E or V600K mutation in this stage III trial (COMBO-AD, NCT01682083). 78 (9%) patients had V600K, and were administered dabrafenib and trametinib or placebo for 12 months. In subsequent analysis, relapse or death occurred in 16/41 patients (39%) in the treatment group and 19/37 patients (51%) in the placebo group for a 95% CI Hazard Ratio of 0.54 (0.27-1.06). 28891408 PubMed Long et al., 2017, N. Engl. J. Med. NCT01682083 4 accepted 6179 563 5 7 140453136 140453137 AC TT ENST00000288602.6 75 GRCh37 Somatic 2018-07-06 14:05:02 UTC https://civicdb.org/links/evidence_items/6179 https://civicdb.org/links/variants/563 https://civicdb.org/links/genes/5 false BRAF 673 V600 Melanoma 1909 Trametinib,Dabrafenib Combination Predictive Supports B Sensitivity/Response Combination Dabrafenib and Trametinib treatment was assessed for adjuvant treatment of stage III resected BRAF V600 mutant melanoma in the COMBI-AD trial NCT01682083. Patients were treated with combination therapy or placebo for 12 months. The estimated 3-year rate of relapse-free survival was 58% in the treated group and 39% in the placebo group with hazard ratio for relapse or death of 0.47 (95% CI, 0.39 to 0.58; P<0.001). 3-year overall survival rate for treated group was 86%, and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42-0.79; P=0.0006). The level of improvement observed did not cross the prespecified interim analysis boundary of P=0.000019. Distant metastasis-free survival and freedom from relapse was higher in the combination-treated group. 28891408 PubMed Long et al., 2017, N. Engl. J. Med. NCT01682083 5 accepted 6180 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2018-07-06 13:59:30 UTC https://civicdb.org/links/evidence_items/6180 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false EGFR 1956 G719A Lung Non-small Cell Carcinoma 3908 Gefitinib,Erlotinib Substitutes Predictive Does Not Support C Sensitivity/Response In a large retrospective study, EGFR exons 18-21 were assessed using direct sequencing in 753 French NSCLC cases. Clinical details and patient outcomes were taken, including whether the first generation TKIs erlotinib or gefitinib were administered. One patient was found to have a G719A mutation, was administered a TKI, and an NSCLC progression was observed. 23749122 PubMed Locatelli-Sanchez et al., 2013, Lung 2 accepted 6181 999 19 7 55241708 55241708 G C ENST00000275493.2 75 GRCh37 Somatic 2018-05-31 19:52:03 UTC https://civicdb.org/links/evidence_items/6181 https://civicdb.org/links/variants/999 https://civicdb.org/links/genes/19 false EGFR 1956 R705K Lung Non-small Cell Carcinoma 3908 Erlotinib,Gefitinib Substitutes Predictive Does Not Support C Sensitivity/Response In a large retrospective study, EGFR exons 18-21 were assessed using direct sequencing in 753 French NSCLC cases. Clinical details and patient outcomes were taken, including whether the first generation TKIs erlotinib or gefitinib were administered. One patient was found to have a R705K mutation, was administered a TKI, and an NSCLC progression was observed. 23749122 PubMed Locatelli-Sanchez et al., 2013, Lung 2 accepted 6182 2333 19 7 55241666 55241666 G A ENST00000275493.2 75 GRCh37 Somatic 2018-05-31 19:59:11 UTC https://civicdb.org/links/evidence_items/6182 https://civicdb.org/links/variants/2333 https://civicdb.org/links/genes/19 false EGFR 1956 L858R Lung Adenocarcinoma 3910 Gefitinib Predictive Supports B Sensitivity/Response In a Japanese Phase III clinical trial, noninferiority of Gefitinib as compared to Erlotinib was assessed in 561 postoperative recurrent or stage IIIb/VI patients who had undergone prior chemotherapy treatment but no tyrosine kinase inhibitor therapy. In a subset of patients with sole EGFR L858R, there was an insignificant difference between the objective response and disease control rates for patients treated with erlotinib (N=67) and gefitinib (N=78). Progression free survival was also not significantly different and did not meet the noninferiority endpoint with Gefitinib and Erlotinib arms at 8.1 and 8.5 months, respectively (HR, 0.938; 95% CI, 0.675 to 1.304; P = .704). 27022112 PubMed Urata et al., 2016, J. Clin. Oncol. 2 accepted 6183 33 19 7 55259515 55259515 T G ENST00000275493.2 75 GRCh37 EGFR L858R has long been recognized as a functionally significant mutation in cancer, and is one of the most prevalent single mutations in lung cancer. Best described in non-small cell lung cancer (NSCLC), the mutation seems to confer sensitivity to first and second generation TKI's like gefitinib and neratinib. NSCLC patients with this mutation treated with TKI's show increased overall and progression-free survival, as compared to chemotherapy alone. Third generation TKI's are currently in clinical trials that specifically focus on mutant forms of EGFR, a few of which have shown efficacy in treating patients that failed to respond to earlier generation TKI therapies. Somatic 2021-02-26 23:53:00 UTC https://civicdb.org/links/evidence_items/6183 https://civicdb.org/links/variants/33 https://civicdb.org/links/genes/19 false EGFR 1956 Exon 19 Deletion Lung Adenocarcinoma 3910 Gefitinib Predictive Supports B Sensitivity/Response A Japanese Phase III clinical study assessed the noninferiority of gefitinib in comparison to erlotinib in 561 patients with postoperative or recurrent stage IIIB/IV lung adenocarcinoma. Patients were pretreated with at least one chemotherapy regimen, but no tyrosine kinase inhibitors. In the subgroup of 156 patients with exon 19 deletions as their sole EGFR mutation, 83 and 78 were treated with erlotinib and gefitinib, respectively. Objective response (defined as complete + partial response) was approximately 65 percent for both erlotinib gefitinib and non significantly different (p= .965). Disease control rate (defined as complete response + partial response + stable disease) was 91.6 and 83.3 percent for erlotinib and gefitinib, respectively (p=.113). The study was unable to demonstrate statistical noninferiority via the planned end point; however, the lack of statistically significant differences between erlotinib and gefitinib responses, and the milder adverse effects experienced by gefitinib treated patients, led the authors to conclude that gefitinib is a feasible alternative to erlotinib in treating patients with ex19del EGFR positive, advanced lung adenocarcinoma. 27022112 PubMed Urata et al., 2016, J. Clin. Oncol. 3 accepted 6184 133 19 7 55242415 55242513 ENST00000275493.2 75 GRCh37 Deletions within exon 19 of EGFR are most common in lung cancer. These deletions, in non-small cell lung cancer, have been shown to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib, afatinib, and erlotinib. There is also data to suggest that this event is a good prognostic marker in lung adenocarcinoma. Examples of exon 19 deletions include: p.746_A750delELREA, p.747_753delinsS, p.747_752delLREATS, and p.747_751delLREAT. Somatic 2021-01-27 01:19:05 UTC https://civicdb.org/links/evidence_items/6184 https://civicdb.org/links/variants/133 https://civicdb.org/links/genes/19 false EGFR 1956 Rare Mutation Lung Adenocarcinoma 3910 Gefitinib Predictive Supports C Sensitivity/Response A Japanese Phase III clinical study assessed the noninferiority of gefitinib as compared to erlotinib in 561 advanced stage (IIIB and IV) postoperative lung adenocarcinoma patients. All patients had prior chemotherapy but no treatment with TKIs. 19 patients had unspecified uncommon EGFR mutations, including single mutations other than ex19del and L858R and double mutations. Of those 19 patients, 7 were treated with erlotinib and 12 were treated with gefitinib. Objective response (42.9% for erlotinib and 25% for gefitinib) and disease control rate (71.4% with eflotinib and 66.7% with gefitinib) between were not significantly different between the treatments. The study failed to satisfy the primary endpoint of demonstrating statistical noninferiority in PFS of gefitinib. 27022112 PubMed Urata et al., 2016, J. Clin. Oncol. 2 accepted 6186 2334 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 This subset of EGFR mutations consists of mutations other than L858R and exon 19 deletion. Reports of responsiveness to tyrosine kinase inhibitors in this EGFR mutation subgroup do not differ widely from those reported for known common sensitizing EGFR mutations. Somatic 2021-04-14 04:26:49 UTC https://civicdb.org/links/evidence_items/6186 https://civicdb.org/links/variants/2334 https://civicdb.org/links/genes/19 false PIK3CA 5290 Mutation Breast Cancer 1612 Prognostic Supports B Better Outcome This was a Swedish study of 270 breast tumors removed from patients with unilateral operable breast cancer, and either lymph node metastases or a tumor diameter >30mm. PIK3CA missense mutations were found in 66/270 (24%) tumors. Of these, 36 tumors (55%) harbored mutations in exon 20— 33 H1047R, 1 Y1021C, 1 G1049R, and 1 H1047P. The other 30 were missense mutations in exon 9— 11 E542K, 18 E545K, 1 Q546P. The study found that the risk of relapse with a local recurrence was significantly lower among patients with a PIK3CA mutation in comparison with those who carried wild-type PIK3CA (p= 0.023). When adjusting for other factors, including ER status, node status, tumor size, and treatment (tamoxifen vs no tamoxifen or radiotherapy vs chemotherapy), mutations in the PIK3CA gene were associated with approximately half the risk for local recurrence in comparison with wtPIK3CA (p = .07). 17575221 PubMed Pérez-Tenorio et al., 2007, Clin. Cancer Res. 3 accepted 6188 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2018-07-12 18:11:48 UTC https://civicdb.org/links/evidence_items/6188 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PIK3CA 5290 Mutation Estrogen-receptor Positive Breast Cancer 0060075 Tamoxifen Predictive Does Not Support B Sensitivity/Response This was a Swedish study of 270 breast tumors removed from patients with unilateral operable breast cancer, and either lymph node metastases or a tumor diameter >30mm. PIK3CA missense mutations were found in 65/270 (24%) tumors. Of these, 36 (55%) were in exon 20— 33 H1047R, 1 Y10121C, 1 G1049R, and 1 H1047P. The other 30 were missense mutations in exon 9— 11 E542K, 18 E545K, 1 Q546P. Within the group of 188 patients with ER+ tumors, PIK3CA mutation status did not predict response to tamoxifen. 17575221 PubMed Pérez-Tenorio et al., 2007, Clin. Cancer Res. 3 accepted 6189 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2019-01-20 00:09:47 UTC https://civicdb.org/links/evidence_items/6189 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false ABL1 25 BCR::ABL T315A Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports D Resistance In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 60 of these clones had T315A mutations. To validate resistance to dasatinib, Ba/F3 cell lines stably expressing a T315A mutation in the ABL1 region of the BCR-ABL fusion were generated. T315A was associated with higher dasatinib IC50 of 125 nM vs 1.34 nM in wildtype as determined by dose response curves. 15705718 PubMed Burgess et al., 2005, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 6190 2335 4 9 133748282 133748282 A G ENST00000318560.5 75 GRCh37 Somatic 2018-06-20 00:31:37 UTC https://civicdb.org/links/evidence_items/6190 https://civicdb.org/links/variants/2335 https://civicdb.org/links/genes/4 false PIK3CA 5290 Mutation Breast Cancer 1612 Cyclophosphamide,Paclitaxel,Doxorubicin,Epirubicin,Fluorouracil Combination Predictive Does Not Support B Resistance This study of 140 patients with stage II-III breast cancer assessed the response of patients with PIK3CA mutations to 6 months of preoperative chemotherapy. 23/170 patients had PIK3CA mutations. Of those patients, 12 received six courses of chemotherapy composed of 5-fluorouracil, doxorubicin (or epirubicin), and cyclophosphamide. This treatment group represented patients with the following mutations (number of patients in parentheses): E545K (7), E542K (1), and H1047R (4). The other 11 patients received 12 weekly courses of paclitaxel followed by four courses of the chemotherapy described above. This treatment group represented patients with the following mutations: E545K (1), Q546R (1), E542K (1), E542V (1), H1047R (5), G1049R (1), H1047T (1). The study did not find evidence that PIK3CA mutations are associated with resistance to preoperative chemotherapy in breast cancer, regardless of whether paclitaxel was also administered. The lack of association was true of estrogen receptor (ER)-positive and ER-negative tumors. 18371219 PubMed Liedtke et al., 2008, Breast Cancer Res. 3 accepted 6191 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2021-04-08 17:05:52 UTC https://civicdb.org/links/evidence_items/6191 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Dasatinib,Imatinib Mesylate Combination Predictive Supports D Resistance In an in vitro study, stochastic mutations in the ABL1 region of the p210 BCR-ABL fusion were generated and stably expressed in Ba/F3 cell lines from mutagenized libraries. Combination therapy with 10 μM imatinib and 50 nM dasatinib resulted in a single clone with the T315I variant. Combination therapy with 25 nM dasatinib resulted in 11 clones, 6 of which had the T315I variant. 15705718 PubMed Burgess et al., 2005, Proc. Natl. Acad. Sci. U.S.A. 2 accepted 6192 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2018-06-20 00:51:58 UTC https://civicdb.org/links/evidence_items/6192 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Imatinib Mesylate,Dasatinib Combination Predictive Supports D Resistance In an in vitro study, stochastic mutations in the ABL1 region of the p210 BCR-ABL fusion were generated and stably expressed in Ba/F3 cell lines from mutagenized libraries. Combination therapy with 10 μM imatinib and 50 nM Dasatinib resulted in 11 clones, 5 of which had the E255K variant. 15705718 PubMed Burgess et al., 2005, Proc. Natl. Acad. Sci. U.S.A. 2 accepted 6193 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2018-06-20 00:55:28 UTC https://civicdb.org/links/evidence_items/6193 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Nilotinib,Imatinib Mesylate,Dasatinib Substitutes Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The E255K mutation was associated with resistance in 16 μM imatinib ( 1 clone recovered, ~3%) and all lower concentrations as well as in 50 nM nilotinib (5 clones, ~11%) and 5 nM dasatinib (2 clones, ~6%), the lowest concentrations tested for these two drugs. In a review of 20 publications, this mutation was described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6194 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2021-06-08 23:03:08 UTC https://civicdb.org/links/evidence_items/6194 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Nilotinib,Imatinib Mesylate Combination Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The T315I mutation was associated with resistance in 400 nM imatinib + 50 nM nilotinib (3 clones, ~16%), 2 μM imatinib + 1 μM nilotinib (8 clones, 100%), and 4 μM imatinib + 2 μM nilotinib (2 clones, 100%) combination treatments. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6196 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2019-08-30 18:15:33 UTC https://civicdb.org/links/evidence_items/6196 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false PIK3CA 5290 Exon 21 Mutation Breast Cancer 1612 Prognostic Supports B Better Outcome An Italian study of 163 malignant breast tumors assessed the association between PIK3CA mutations and clinical outcome. Of the 163 tumors sequenced, 118 had wild-type (wt) PIK3CA, 24 had exon 9 (helical domain) missense mutations, and 21 had exon 20 (kinase domain) missense mutations. The study found that patients with exon 20 mutations showed significantly better 5-year overall survival (OS) and 5-year disease free survival (DFS) compared to patients with wt PIK3CA (P=.011 and P = .01, respectively). Furthermore, patients with exon 20 mut showed especially better OS and DFS than patients with exon 9 mutations (P=.0018 and P=.0017, respectively). The 21 cases with exon 20 mutations had excellent prognosis with no recurrences or deaths, whereas there were 10 recurrences and 9 deaths among the 24 cases of exon 9 mutations, in observed period. Note these exons are now referred to as exons 10 and 21 rather than as exons 9 and 20, as it was common at the time of publication to exclude non-coding exon 1. 17947469 PubMed Barbareschi et al., 2007, Clin. Cancer Res. 4 accepted 6198 105 37 3 178951882 178952495 ENST00000263967.3 75 GRCh37 PIK3CA Exon 21 Mutations (e.g., H1047R; often referred to as Exon 20 mutations if counting only coding exons) are among the most recurrent mutations in cancer, especially breast cancer. Of PIK3CA mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between Exon 21 and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2020-05-28 18:20:26 UTC https://civicdb.org/links/evidence_items/6198 https://civicdb.org/links/variants/105 https://civicdb.org/links/genes/37 false PIK3CA 5290 Exon 10 Mutation Breast Cancer 1612 Prognostic Supports B Poor Outcome An Italian study of 163 malignant breast tumors assessed the association between PIK3CA mutations and clinical outcome. Of the 163 tumors sequenced, 118 had wild-type (wt) PIK3CA, 24 had exon 9 (helical domain) missense mutations, and 21 had exon 20 (kinase domain) missense mutations. The study found that patients with exon 9 mutations showed significantly worse 5-year overall survival (OS) and 5-year disease free survival (DFS) compared to patients with wt PIK3CA (P=.018 and P = .04, respectively). Furthermore, patients with exon 9 mut showed especially worse OS and DFS than patients with exon 20 mutations (P=.0018 and P=.0017, respectively). The 21 cases with exon 20 mutations had excellent prognosis with no recurrences or deaths, whereas there were 10 recurrences and 9 deaths among the 24 cases of exon 9 mutations, in observed period. Note these exons are now referred to as exons 10 and 21 rather than as exons 9 and 20, as it was common at the time of publication to exclude non-coding exon 1. 17947469 PubMed Barbareschi et al., 2007, Clin. Cancer Res. 4 accepted 6199 106 37 3 178935998 178936122 ENST00000263967.3 75 GRCh37 PIK3CA Exon 10 Mutations (e.g. E545K/E542K; often referred to as Exon 9 mutations if counting only coding exons) are the second most recurrent PIK3CA mutations in breast cancer, and highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that exon 10 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2020-05-28 18:23:41 UTC https://civicdb.org/links/evidence_items/6199 https://civicdb.org/links/variants/106 https://civicdb.org/links/genes/37 false ABL1 25 BCR::ABL Y253H Chronic Myeloid Leukemia 8552 Imatinib Mesylate,Nilotinib Substitutes Predictive Supports C Resistance In this open-label, phase II registration trial, patients that were imatinib resistant or intolerant underwent nilotinib monotherapy. Within 12 months of nilotinib therapy, there was no significant difference in response to nilotinib treatment between patients with mutations in the Abl1 kinase domain versus without. However, the authors identify Y253H, E255K/V, and F359C/V variants as resistant as they had an IC50 of >150 nM. In patients with Y253H mutations prior to nilotinib treatment, complete hematologic response was achieved in 0 of 6 patients, major cytogenetic response in 1 of 8 patients, complete cytogenetic response in 0 of 8 patients, and major molecular response in 0 of 7 patients. After median follow-up of 15.5 months, 3 of 8 patients with this mutation progressed or died. The Y253H mutation was present in two patients at baseline and newly emerged in two patients at progression. 19652056 PubMed Hughes et al., 2009, J. Clin. Oncol. 3 accepted 6200 1025 4 9 133738357 133738357 T C ENST00000318560.5 75 GRCh37 Somatic 2018-11-05 22:44:15 UTC https://civicdb.org/links/evidence_items/6200 https://civicdb.org/links/variants/1025 https://civicdb.org/links/genes/4 false VHL 7428 R161* (c.481C>T) Von Hippel-Lindau Disease 14175 Multiple renal cysts,Renal cyst,Cerebellar hemangioblastoma,Retinal capillary hemangioma,Hemangioblastoma,Pancreatic cysts Predisposing N/A C N/A A case report of a 32 year old male patient presenting with bilateral retinal hemangioblastoma, loss of vision in the left eye, and a history of cerebral hemangioblastoma revealed a R161X mutation in VHL. Two family members (daughter and sister) were confirmed to heterozygously harbor R161X. The patient's 12 year old daughter had no clinical presentations. The patient's sister had an optic nerve head hemangioblastoma in the left eye, peripheral temporal retina hemangioblastoma in left eye, and cystic lesions in the pancreas and kidney. The patient's mother was recalled to have advanced unilateral vision loss and dying due to renal cancer, but no genetic confirmation of VHL mutation status could be completed. ACMG codes: PVS1 (nonsense variant where LOF is a known mechanism of disease), PP4 (patient's phenotype and family history is specific for a disease with a single genetic etiology) 28630796 PubMed Şahin Atik et al., 2017, Turk J Ophthalmol 2 accepted 6201 1804 58 3 10191488 10191488 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/6201 https://civicdb.org/links/variants/1804 https://civicdb.org/links/genes/58 false PIK3CA 5290 H1047R Her2-receptor Positive Breast Cancer 0060079 Lapatinib,Trastuzumab Combination Predictive Supports D Resistance In a preclinical study, efficacy of lapatinib and trastuzumab was evaluated in vitro against HER2 amplified breast cancer cell line BT474 (heterozygous for PIK3CA K111N) retrovirally transduced with PIK3CA H1047R. The study found that H1047R abrogated the growth inhibitory effects of lapatinib and trastuzumab, either in isolation or in combination, though somewhat increased cell death was observed with combination therapy relative to monotherapy. The authors concluded that the PIK3CA H1047R induces resistance to lapatinib and trastuzumab in HER2-positive breast cancer cells. 19010894 PubMed Eichhorn et al., 2008, Cancer Res. 4 accepted 6204 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2021-01-28 21:28:59 UTC https://civicdb.org/links/evidence_items/6204 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Her2-receptor Positive Breast Cancer 0060079 Dactolisib Predictive Does Not Support D Resistance This preclinical study tested the sensitivity of HER2-positive breast cancer cell line BT-474 (heterozygous for PIK3CA K111N) retrovirally transduced with PIK3CA H1047R to NVP-BEZ235 (dactolisib; a dual PI3K/mTOR inhibitor). The study found that dactolisib was effective in inhibiting outgrowth of H1047R mutant-containing cells. Dactolisib was also combined with trastuzumab and/or lapatinib with similar abrogation of growth for PIK3CA H1047R expressing cells. Additionally, growth of untransduced BT-474 control cells was prevented by treatment with any monotherapy or combination of trastuzumab, lapatinib, or dactolisib. Authors concluded that PIK3CA H1047R induces resistance to lapatinib and trastuzumab in HER2 positive breast cancer cells, but resistance can be reversed by dactolisib. 19010894 PubMed Eichhorn et al., 2008, Cancer Res. 4 accepted 6206 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2021-01-28 21:24:07 UTC https://civicdb.org/links/evidence_items/6206 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false ABL1 25 BCR::ABL F317V Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports D Resistance In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 83 of these clones had F317V mutations. To validate resistance to dasatinib, a Ba/F3 cell line stably expressing the F317V mutation in the ABL1 region of the BCR-ABL fusion was generated and associated with higher dasatinib IC50 of 53 nM vs 1.34 nM in wildtype as determined by dose response curves. 15705718 PubMed Burgess et al., 2005, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 6208 1525 4 9 133748288 133748288 T G ENST00000318560.5 75 GRCh37 Somatic 2018-06-20 01:42:42 UTC https://civicdb.org/links/evidence_items/6208 https://civicdb.org/links/variants/1525 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L248R Chronic Myeloid Leukemia 8552 Imatinib Mesylate,Dasatinib Substitutes Predictive Supports D Resistance In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 1 of these clones had an L248R mutation. To validate resistance to dasatinib, a Ba/F3 cell line stably expressing the L248R mutation in the ABL1 region of the BCR-ABL fusion was generated. The L248R variants was associated with higher dasatinib IC50 of 16 nM vs 1.34 nM in wildtype and higher imatinib IC50 of >10,000 nM vs 323 nM in wildtype as determined by dose response curves. 15705718 PubMed Burgess et al., 2005, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 6210 2340 4 9 133738343 133738343 T G ENST00000318560.5 75 GRCh37 Somatic 2018-06-20 01:44:39 UTC https://civicdb.org/links/evidence_items/6210 https://civicdb.org/links/variants/2340 https://civicdb.org/links/genes/4 false PIK3CA 5290 E545K Her2-receptor Positive Breast Cancer 0060079 Lapatinib,Trastuzumab Combination Predictive Supports D Resistance In a preclinical study, efficacy of lapatinib and trastuzumab was evaluated in vitro against HER2 amplified breast cancer cell line BT474 (heterozygous for PIK3CA K111N) retrovirally transduced with PIK3CA E45K. The study found that E545K abrogated the growth inhibitory effects of lapatinib and trastuzumab, either in isolation or in combination, though increased cell death was observed with combination therapy relative to monotherapy. The authors concluded that the PIK3CA E545K induces resistance to lapatinib and trastuzumab in HER2-positive breast cancer cells. 19010894 PubMed Eichhorn et al., 2008, Cancer Res. 3 accepted 6211 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2021-01-28 21:19:07 UTC https://civicdb.org/links/evidence_items/6211 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false PIK3CA 5290 E545K Her2-receptor Positive Breast Cancer 0060079 Dactolisib Predictive Does Not Support D Resistance This preclinical study tested the sensitivity of HER2-positive breast cancer cell line BT-474 (heterozygous for PIK3CA K111N) retrovirally transduced with PIK3CA E545K to NVP-BEZ235 (dactolisib; a dual PI3K/mTOR inhibitor). The study found that dactolisib was effective in inhibiting outgrowth of E545K mutant-containing cells. Dactolisib was also combined with trastuzumab and/or lapatinib with similar abrogation of growth for PIK3CA E545K expressing cells. Growth of untransduced BT-474 control cells was prevented by treatment with any monotherapy or combination of trastuzumab, lapatinib, or dactolisib. 19010894 PubMed Eichhorn et al., 2008, Cancer Res. 3 accepted 6213 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2021-01-28 21:11:37 UTC https://civicdb.org/links/evidence_items/6213 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Dasatinib,Imatinib Mesylate Substitutes Predictive Supports D Resistance In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 4 of these clones had E255K mutations. To validate resistance to dasatinib, a Ba/F3 cell line stably expressing the E255K mutation in the ABL1 region of the BCR-ABL fusion was generated. The E255K variants was associated with higher dasatinib IC50 of 13 nM vs 1.34 nM in wildtype and higher imatinib IC50 of 8,400 nM vs 323 nM in wildtype as determined by dose response curves. 15705718 PubMed Burgess et al., 2005, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 6214 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2018-06-20 01:41:15 UTC https://civicdb.org/links/evidence_items/6214 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports D Resistance In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 10 of these clones had F317L mutations. To validate resistance to dasatinib, a Ba/F3 cell line stably expressing the F317L mutation in the ABL1 region of the BCR-ABL fusion was generated and associated with higher dasatinib IC50 of 18 nM vs 1.34 nM in wildtype as determined by dose response curves. 15705718 PubMed Burgess et al., 2005, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 6215 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2018-06-20 01:43:56 UTC https://civicdb.org/links/evidence_items/6215 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL V299L Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports D Resistance In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 1 of these clones had an V299L mutation. To validate resistance to dasatinib, a Ba/F3 cell line stably expressing the V299L mutation in the ABL1 region of the BCR-ABL fusion was generated and associated with higher dasatinib IC50 of 18 nM vs 1.34 nM in wildtype as determined by dose response curves. 15705718 PubMed Burgess et al., 2005, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 6216 1231 4 9 133747588 133747588 G C ENST00000318560.5 75 GRCh37 Somatic 2018-06-20 01:01:26 UTC https://civicdb.org/links/evidence_items/6216 https://civicdb.org/links/variants/1231 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317I Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports D Resistance In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 1 of these clones had an F317I mutation. 15705718 PubMed Burgess et al., 2005, Proc. Natl. Acad. Sci. U.S.A. 1 accepted 6217 1625 4 9 133748288 133748288 T A ENST00000318560.5 75 GRCh37 Somatic 2018-06-20 01:47:58 UTC https://civicdb.org/links/evidence_items/6217 https://civicdb.org/links/variants/1625 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317S Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports D Resistance In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 1 of these clones had an F317S mutation. 15705718 PubMed Burgess et al., 2005, Proc. Natl. Acad. Sci. U.S.A. 1 accepted 6218 2343 4 9 133748289 133748289 T C ENST00000318560.5 75 GRCh37 Somatic 2018-06-20 01:48:23 UTC https://civicdb.org/links/evidence_items/6218 https://civicdb.org/links/variants/2343 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Q252H Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports D Resistance In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 1 of these clones had an Q252H mutation. 15705718 PubMed Burgess et al., 2005, Proc. Natl. Acad. Sci. U.S.A. 1 accepted 6219 1024 4 9 133738356 133738356 G C ENST00000318560.5 75 GRCh37 Somatic 2018-06-20 01:46:53 UTC https://civicdb.org/links/evidence_items/6219 https://civicdb.org/links/variants/1024 https://civicdb.org/links/genes/4 false VHL 7428 R161* (c.481C>T) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Endolymphatic sac tumor,Renal cyst,Epididymal cyst,Hemangioblastoma,Clear cell renal cell carcinoma,Pancreatic cysts Predisposing N/A C N/A A retrospective cohort study was conducted at a public children’s hospital (Buenos Aires, Argentina). Eligible patients were all index cases with clinical diagnosis or clinical suspicion of type 1 VHL referred for genetic testing from 2003 to 2015. A nonsense germline mutation c.481C>T resulting in p.R161* was confirmed in 4 patients, all of which fulfilled the requirements for diagnosis of type 1 VHL, and none of which had family history of VHL disease. Patient #1 was clinically diagnosed at age 13, and presented with retinal angioma (16Y) and endolymphatic sac tumors (13Y). Patient #3 was diagnosed at age 20Y, and presented with CNS hemangioblastoma at 20Y, 25Y, 26Y, clear cell renal cancer at 27Y, pancreatic cysts at 25Y, renal cysts at 25Y, and epididymal cysts at 31Y. Patient #4 was diagnosed at 21Y and presented with CNS hemangioblastoma at 22Y, retinal angioma at 21Y, pancreatic cysts at 23Y, and epididymal cysts since birth. Patient #9 was diagnosed at 25Y and presented with CNS hemangioblastoma at 22Y, clear cell renal cell carcinoma at 22Y, renal cysts at 22Y, and pancreatic cysts at 22Y. ACMG: PVS1 (nonsense variant in gene where LOF is a known mechanism of disease), PM6 (mutations assumed de novo, without confirmation). 27617348 PubMed Mathó et al., 2016, Genet Test Mol Biomarkers 3 accepted 6221 1804 58 3 10191488 10191488 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/6221 https://civicdb.org/links/variants/1804 https://civicdb.org/links/genes/58 false VHL 7428 R167Q (c.500G>A) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Spinal hemangioblastoma,Clear cell renal cell carcinoma,Pheochromocytoma,Pancreatic endocrine tumor Predisposing N/A C N/A A case report of a 51Y male patient presenting with headaches and a family history of VHL disease revealed multiple CNS hemangioblastomas, bilateral clear cell renal cell carcinomas, pheochromocytoma, and a pancreatic neuroendocrine tumor. A germline mutation of p.Arg167Trp was confirmed in the patient's VHL gene. ACMG: PP4 as patients phenotype and family history are highly specific for a disease with a single genetic etiology. 29396065 PubMed Taylor et al., 2018, J Clin Neurosci 3 accepted 6222 1739 58 3 10191507 10191507 G A ENST00000256474.2 75 GRCh37 R167Q is the most common point mutation in hereditary Von Hippel-Lindau (VHL) disease and disrupts the VHL genes binding to elongin C reducing the levels of the VHL-elongin B-elongin C (VBC) E3 ligase complex and inhibiting the ability of VHL to regulate HIF2α. This partial function in turn leads to an increased risk of tumorgenesis. VHL derived clear cell renal cell carcinoma models however have shown the proteasome inhibitors bortezomib and carfilzomib can act to stabilize mutant VHL-R167Q leading to downregulation of HIF2α and suprressed tumorgenesis. Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/6222 https://civicdb.org/links/variants/1739 https://civicdb.org/links/genes/58 false VHL 7428 Exon 3 Deletion Von Hippel-Lindau Disease 14175 Multiple renal cysts,Epididymal cyst,Endolymphatic sac tumor,Pancreatic cysts,Hemangioblastoma,Renal cell carcinoma Predisposing N/A C N/A A 33Y male presented with multiple bilateral renal masses, epididymis cyst, pancreatic cysts and renal cysts. The patient previously underwent resections of medullary hemangioblastoma and endolymphatic sac tumors. Genetic evaluation by MLPA revealed a germline deletion of exon 3 in the VHL gene, confirming the diagnosis of VHL disease. Family history was unremarkable, and both parents tested negative for the mutation, suggesting the mutation occurred de novo in the patient. ACMG: PVS1 exon deletion, PS2 de novo mutation confirmed absent in parents, PP4 phenotype specific for disease 28256701 PubMed Allasia et al., 2017, Urologia 2 accepted 6223 1939 58 3 10191471 10193904 ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/6223 https://civicdb.org/links/variants/1939 https://civicdb.org/links/genes/58 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Imatinib Mesylate,Nilotinib Substitutes Predictive Supports C Resistance In this open-label, phase II registration trial, patients that were imatinib resistant or intolerant underwent nilotinib monotherapy. Within 12 months of nilotinib therapy, there was no significant difference in response to nilotinib treatment between patients with mutations in the Abl1 kinase domain versus without. However, the authors identify Y253H, E255K/V, and F359C/V variants as resistant as they had an IC50 greater than 150 nM. In patients with E255K and/or E255V mutations prior to nilotinib treatment, complete hematological responses were achieved in 5 of 7 patients, major cytogenetic responses in 3 of 7 patients, complete cytogenetic responses in 0 of 7 patients, and a major molecular response in 1 of 7 patients. After a median follow-up of 15.5 months, 6 of 7 patients with this mutation progressed or died. The E255K mutation was present in 6 patients at baseline and newly emerged in 4 patients at progression. The E255V mutation was present in 0 patients at baseline and newly emerged in 3 patients at progression. 19652056 PubMed Hughes et al., 2009, J. Clin. Oncol. 3 accepted 6232 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2018-11-05 22:45:24 UTC https://civicdb.org/links/evidence_items/6232 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359C Chronic Myeloid Leukemia 8552 Nilotinib,Imatinib Mesylate Substitutes Predictive Supports C Resistance In this open-label, phase II registration trial, patients that were imatinib resistant or intolerant underwent nilotinib monotherapy. Within 12 months of nilotinib therapy, there was no significant difference in response to nilotinib treatment between patients with mutations in the Abl1 kinase domain versus without. However, the authors identify Y253H, E255K/V, and F359C/V variants as resistant as they had an IC50 of >150nM. In patients with F359C and/or F359V mutations prior to nilotinib treatment, complete hematological responses were achieved in 3 of 10 patients, a major cytogenetic response in 1 of 11 patients, a complete cytogenetic response in 0 of 11 patients, and major molecular response in 0 of 10 patients. After a median follow-up of 15.5 months, 9 of 11 patients with this mutation progressed or died. The F359C mutation was present in 1 patient at baseline and newly emerged in 1 patient at progression. The F359V mutation was present in 4 patients at baseline and newly emerged in 1 patient at progression. 19652056 PubMed Hughes et al., 2009, J. Clin. Oncol. 3 accepted 6233 1184 4 9 133748415 133748415 T G ENST00000318560.5 75 GRCh37 Somatic 2018-11-05 22:44:39 UTC https://civicdb.org/links/evidence_items/6233 https://civicdb.org/links/variants/1184 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Imatinib Mesylate,Dasatinib Combination Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The T315I mutation was associated with resistance in 400 nM imatinib + 10 nM dasatinib (10 clones, ~91%), 2 μM imatinib + 50 nM dasatinib (8 clones, 100%), and 4 μM imatinib + 100 nM dasatinib (8 clones, 100%) combination treatments. 16772610 PubMed Bradeen et al., 2006, Blood 3 accepted 6234 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2018-10-08 22:35:03 UTC https://civicdb.org/links/evidence_items/6234 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Nilotinib,Dasatinib Combination Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The T315I mutation was associated with resistance in 50 nM nilotinib + 10 nM dasatinib (7 clones, 100% of viable clones in this treatment), 1 μM nilotinib + 50 nM dasatinib (9 clones, 100%), and 2 μM nilotinib + 100 nM dasatinib (2 clones, 100%) combination treatments. 16772610 PubMed Bradeen et al., 2006, Blood 3 accepted 6235 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2018-10-08 22:34:30 UTC https://civicdb.org/links/evidence_items/6235 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L248V Chronic Myeloid Leukemia 8552 Imatinib Mesylate,Nilotinib Combination Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. 61 clones grew in a combination of 400 nM imatinib and 50 nM nilotinib. Of these, 19 were sequenced and 2 (~11%) were found to have L248V mutations. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6236 1022 4 9 133738342 133738342 C G ENST00000318560.5 75 GRCh37 Somatic 2018-07-02 00:51:40 UTC https://civicdb.org/links/evidence_items/6236 https://civicdb.org/links/variants/1022 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253H Chronic Myeloid Leukemia 8552 Imatinib Mesylate,Nilotinib Combination Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. 61 clones grew in a combination of 400 nM imatinib and 50 nM nilotinib. Of these, 19 were sequenced and 5 (~26%) were found to have Y253H mutations. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6237 1025 4 9 133738357 133738357 T C ENST00000318560.5 75 GRCh37 Somatic 2018-07-02 00:54:03 UTC https://civicdb.org/links/evidence_items/6237 https://civicdb.org/links/variants/1025 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F311L Chronic Myeloid Leukemia 8552 Imatinib Mesylate,Nilotinib Combination Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. 61 clones grew in a combination of 400 nM imatinib and 50 nM nilotinib. Of these, 19 were sequenced and 1 (~5%) was found to have an F311L mutation. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6238 1528 4 9 133748270 133748270 T C ENST00000318560.5 75 GRCh37 Somatic 2018-07-02 02:19:17 UTC https://civicdb.org/links/evidence_items/6238 https://civicdb.org/links/variants/1528 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359C Chronic Myeloid Leukemia 8552 Imatinib Mesylate,Nilotinib Combination Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. 61 clones grew in a combination of 400 nM imatinib and 50 nM nilotinib. Of these, 19 were sequenced and 7 (~37%) were found to have F359C mutations. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6239 1184 4 9 133748415 133748415 T G ENST00000318560.5 75 GRCh37 Somatic 2018-07-02 02:23:24 UTC https://civicdb.org/links/evidence_items/6239 https://civicdb.org/links/variants/1184 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL H396P Chronic Myeloid Leukemia 8552 Nilotinib,Imatinib Mesylate Combination Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. 61 clones grew in a combination of 400 nM imatinib and 50 nM nilotinib. Of these, 19 were sequenced and 1 (~5%) was found to have an H396P mutation. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6240 1531 4 9 133750356 133750356 A C ENST00000318560.5 75 GRCh37 Somatic 2018-07-02 02:25:11 UTC https://civicdb.org/links/evidence_items/6240 https://civicdb.org/links/variants/1531 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL V299L Chronic Myeloid Leukemia 8552 Dasatinib,Imatinib Mesylate Combination Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. Of the 11 clones that grew in a combination of 400 nM imatinib and 10 nM dasatinib, 1 (9%) was found to have a V299L mutation. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6241 1231 4 9 133747588 133747588 G C ENST00000318560.5 75 GRCh37 Somatic 2018-07-02 02:27:00 UTC https://civicdb.org/links/evidence_items/6241 https://civicdb.org/links/variants/1231 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M244V Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The M244V mutation was associated with resistance in 2 μM imatinib (1 clone recovered, 0.71%). In a review of 20 publications, this mutation was described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6242 1021 4 9 133738330 133738330 A G ENST00000318560.5 75 GRCh37 Somatic 2018-06-27 21:13:35 UTC https://civicdb.org/links/evidence_items/6242 https://civicdb.org/links/variants/1021 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L248R Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The L248R mutation was associated with resistance in 2 μM imatinib (1 clone recovered, ~1%) and 8 μM imatinib (1 clone, ~2%). In a review of 20 publications, this mutation had not been described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6243 2340 4 9 133738343 133738343 T G ENST00000318560.5 75 GRCh37 Somatic 2018-06-27 21:14:54 UTC https://civicdb.org/links/evidence_items/6243 https://civicdb.org/links/variants/2340 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G250E Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The G250E mutation was associated with resistance in 2 μM imatinib (3 clone recovered, ~2%), 4 μM imatinib (1 clone recovered, ~0.74%), and 50 nM nilotinib (5 clone, ~11%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6244 1023 4 9 133738349 133738349 G A ENST00000318560.5 75 GRCh37 Somatic 2018-06-27 21:18:33 UTC https://civicdb.org/links/evidence_items/6244 https://civicdb.org/links/variants/1023 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Q252H Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The Q252H mutation was associated with resistance to 4 μM and 16 μM imatinib (4 clones [~3%] and 1 clone [~3%] recovered, respectively) as well as 10 nM dasatinib (1 clone [~2%]). No clones recovered at 2 μM/8 μM imatinib or 5 nM dasatinib. In a review of 20 publications, this mutation was previously described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6245 1024 4 9 133738356 133738356 G C ENST00000318560.5 75 GRCh37 Somatic 2018-07-02 02:34:41 UTC https://civicdb.org/links/evidence_items/6245 https://civicdb.org/links/variants/1024 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL D276G Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The D276G mutation was associated with resistance in 2 μM imatinib (1 clone recovered, ~0.71%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6246 1027 4 9 133747520 133747520 A G ENST00000318560.5 75 GRCh37 Somatic 2018-06-27 21:20:32 UTC https://civicdb.org/links/evidence_items/6246 https://civicdb.org/links/variants/1027 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL V299L Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The V299L mutation was associated with resistance in 10 nM dasatinib (3 clone recovered, ~5%). No clones were recovered in 5 nM dasatinib. In a review of 20 publications, this mutation was described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6247 1231 4 9 133747588 133747588 G C ENST00000318560.5 75 GRCh37 Somatic 2018-06-27 21:21:19 UTC https://civicdb.org/links/evidence_items/6247 https://civicdb.org/links/variants/1231 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317C Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The F317C mutation was associated with resistance in 5 nM dasatinib (1 clone recovered, ~ 3%) and 10 nM dasatinib (6 clones, ~11%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6250 2359 4 9 133748289 133748289 T G ENST00000318560.5 75 GRCh37 Somatic 2018-06-27 21:28:19 UTC https://civicdb.org/links/evidence_items/6250 https://civicdb.org/links/variants/2359 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317I Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The F317I mutation was associated with resistance in 5 nM dasatinib (2 clone recovered, ~ 6%) and 10 nM dasatinib (10 clones, ~18%). 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6251 1625 4 9 133748288 133748288 T A ENST00000318560.5 75 GRCh37 Somatic 2018-06-27 21:31:10 UTC https://civicdb.org/links/evidence_items/6251 https://civicdb.org/links/variants/1625 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The F317L mutation was associated with resistance in 2 μM imatinib (2 clones recovered, ~1%), 5 nM dasatinib (6 clones, ~ 17%), and 10 nM dasatinib (4 clones, ~7%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6252 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2018-06-27 21:39:02 UTC https://civicdb.org/links/evidence_items/6252 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317V Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The F317V mutation was associated with resistance in 5 nM dasatinib (1 clone recovered, ~ 3%) and 25 nM dasatinib (1 clone, ~3%). No clones were recovered at 10 nM dasatinib. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6253 1525 4 9 133748288 133748288 T G ENST00000318560.5 75 GRCh37 Somatic 2018-06-27 21:41:27 UTC https://civicdb.org/links/evidence_items/6253 https://civicdb.org/links/variants/1525 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M351T Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The M351T mutation was associated with resistance in 2 μM imatinib (1 clone recovered, ~0.71%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6254 1029 4 9 133748391 133748391 T C ENST00000318560.5 75 GRCh37 Somatic 2018-06-27 21:42:38 UTC https://civicdb.org/links/evidence_items/6254 https://civicdb.org/links/variants/1029 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E355G Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The E355G mutation was associated with resistance in 2 μM imatinib (1 clone recovered, ~0.71%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6255 1487 4 9 133748403 133748403 A G ENST00000318560.5 75 GRCh37 Somatic 2018-06-27 21:44:57 UTC https://civicdb.org/links/evidence_items/6255 https://civicdb.org/links/variants/1487 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359V Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The F359V mutation was associated with resistance in 2 μM imatinib (3 clones recovered, ~2%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6256 892 4 9 133748414 133748414 T G ENST00000318560.5 75 GRCh37 Somatic 2018-06-27 21:47:30 UTC https://civicdb.org/links/evidence_items/6256 https://civicdb.org/links/variants/892 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL V379I Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The V379I mutation was associated with resistance in 2 μM imatinib (2 clones recovered, ~1%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6257 1609 4 9 133750304 133750304 G A ENST00000318560.5 75 GRCh37 Somatic 2018-07-02 02:39:52 UTC https://civicdb.org/links/evidence_items/6257 https://civicdb.org/links/variants/1609 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL H396R Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The H396R mutation was associated with resistance in 2 μM imatinib (1 clone recovered, ~0.71%) and 4 μM imatinib (1 clone, ~0.74%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6258 1030 4 9 133750356 133750356 A G ENST00000318560.5 75 GRCh37 Somatic 2018-07-02 02:41:03 UTC https://civicdb.org/links/evidence_items/6258 https://civicdb.org/links/variants/1030 https://civicdb.org/links/genes/4 false AKT1 207 Overexpression Melanoma 1909 Vemurafenib Predictive Does Not Support D Resistance An in vitro study of M229 (a human melanoma cell line) endogenously expressing wild-type AKT1 and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that cells induced to stably over-express AKT1 (via viral transduction with additional copies of AKT1) were not significantly more resistant to vemurafenib (a BRAFi) than cells transduced with empty vectors, which served as the negative controls. 24265155 PubMed Shi et al., 2014, Cancer Discov 3 accepted 6259 2360 2 N/A 2020-12-10 02:04:12 UTC https://civicdb.org/links/evidence_items/6259 https://civicdb.org/links/variants/2360 https://civicdb.org/links/genes/2 false AKT1 207 Q79K Melanoma 1909 Dabrafenib Predictive Supports C Resistance In a retrospective study of 44 relapsed melanoma patients with BRAF V600E/K (known BRAF inhibitor sensitizing mutations), AKT1 Q79K was associated with acquired resistance to BRAF inhibitor (dabrafenib) monotherapy in one patient. This patient was a 38 year old female with stage IV M1a melanoma who took dabrafenib (35 mg twice daily to 100 mg three times a day). The best overall response was a 100% reduction in the sum of target lesions, and progression free survival lasted 119 days. Prior to dabrafenib monotherapy, this patient's baseline tumor harbored BRAF V600K—no other somatic alterations were noted. Following relapse, the patient gained AKT1 Q79K in one of two disease progressive tumors. Whole exome sequencing and Sanger re-sequencing were used for all tumors. The authors hypothesized that disruptions in the PI3K-PTEN-AKT pathway represent a core mechanism of acquired resistance to BRAF inhibitor therapy. 24265155 PubMed Shi et al., 2014, Cancer Discov 4 accepted 6260 169 2 14 105243048 105243048 G T ENST00000407796.2 75 GRCh37 Somatic 2018-07-19 20:04:31 UTC https://civicdb.org/links/evidence_items/6260 https://civicdb.org/links/variants/169 https://civicdb.org/links/genes/2 false AKT3 10000 Overexpression Melanoma 1909 Vemurafenib Predictive Supports D Resistance An in vitro study of M229 (a human melanoma cell line) endogenously expressing wildtype AKT3 and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that cells induced to stably over-express AKT3 (via viral transduction of additional copies of wild type AKT3) were significantly more resistant to BRAF inhibition by vemurafenib than cells transduced with empty vectors (30% vs 20% survival, p = .0064). 24265155 PubMed Shi et al., 2014, Cancer Discov 2 accepted 6261 1301 7936 N/A 2020-12-10 02:04:23 UTC https://civicdb.org/links/evidence_items/6261 https://civicdb.org/links/variants/1301 https://civicdb.org/links/genes/7936 false BRAF 673 V600E/K and Amplification Melanoma 1909 Dabrafenib,Vemurafenib Substitutes Predictive Supports B Resistance In a retrospective study of 44 relapsed melanoma patients harboring BRAF V600E or V600K (known BRAF inhibitor sensitizing mutations), MAPK pathway reactivation mechanisms were implicated in acquired resistance to BRAF inhibitor (vemurafenib or dabrafenib) monotherapy. The following MAPK pathway variants were found in progressive tumors with patient matched baseline tumors (some patients donated samples from multiple geographically/temporally distinct progressive tumors): NRAS mutations (G12D, G12R, G13R, Q61K, Q61R, Q61L) in 13/71 (18%) of progressive tumors, KRAS mutations (G12C, G12R, Q61H) in 5/71 (7%) of progressive tumors, mutant BRAF amplification (2-15 fold or 4-75 copies) in 11/57 (19%) of progressive tumors, mutant BRAF alternative splice variants (novel exon boundaries between 1/9, 1/11, 3/9) in 6/48 (13%) of progressive tumor RNA. 24265155 PubMed Shi et al., 2014, Cancer Discov 2 accepted 6262 2361 5 Somatic 2018-07-19 23:11:25 UTC https://civicdb.org/links/evidence_items/6262 https://civicdb.org/links/variants/2361 https://civicdb.org/links/genes/5 false NRAS 4893 Mutation Melanoma 1909 Vemurafenib,Dabrafenib Substitutes Predictive Supports B Resistance In a retrospective study of 44 relapsed melanoma patients harboring BRAF V600E or V600K (known BRAF inhibitor sensitizing mutations), MAPK pathway reactivation mechanisms were implicated in acquired resistance to BRAF inhibitor (vemurafenib or dabrafenib) monotherapy. The following MAPK pathway variants were found in progressive tumors with patient matched baseline tumors (some patients donated samples from multiple geographically/temporally distinct progressive tumors): NRAS mutations (G12D, G12R, G13R, Q61K, Q61R, Q61L) in 13/71 (18%) of progressive tumors, KRAS mutations (G12C, G12R, Q61H) in 5/71 (7%) of progressive tumors, mutant BRAF amplification (2-15 fold or 4-75 copies) in 11/57 (19%) of progressive tumors, mutant BRAF alternative splice variants (novel exon boundaries between 1/9, 1/11, 3/9) in 6/48 (13%) of progressive tumor RNA. 24265155 PubMed Shi et al., 2014, Cancer Discov 2 accepted 6263 208 36 1 115247090 115259515 ENST00000369535.4 75 GRCh37 Somatic 2018-07-19 23:09:05 UTC https://civicdb.org/links/evidence_items/6263 https://civicdb.org/links/variants/208 https://civicdb.org/links/genes/36 false KRAS 3845 Mutation Melanoma 1909 Vemurafenib,Dabrafenib Substitutes Predictive Supports B Resistance In a retrospective study of 44 relapsed melanoma patients harboring BRAF V600E or V600K (known BRAF inhibitor sensitizing mutations), MAPK pathway reactivation mechanisms were implicated in acquired resistance to BRAF inhibitor (vemurafenib or dabrafenib) monotherapy. The following MAPK pathway variants were found in progressive tumors with patient matched baseline tumors (some patients donated samples from multiple geographically/temporally distinct progressive tumors): NRAS mutations (G12D, G12R, G13R, Q61K, Q61R, Q61L) in 13/71 (18%) of progressive tumors, KRAS mutations (G12C, G12R, Q61H) in 5/71 (7%) of progressive tumors, mutant BRAF amplification (2-15 fold or 4-75 copies) in 11/57 (19%) of progressive tumors, mutant BRAF alternative splice variants (novel exon boundaries between 1/9, 1/11, 3/9) in 6/48 (13%) of progressive tumor RNA. 24265155 PubMed Shi et al., 2014, Cancer Discov 2 accepted 6264 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2018-07-19 23:07:45 UTC https://civicdb.org/links/evidence_items/6264 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false PIK3R2 5296 Overexpression Melanoma 1909 Vemurafenib Predictive Does Not Support D Resistance An in vitro study of WM2664 (a human melanoma cell line) endogenously expressing wildtype PIK3R2 and BRAF V600D (a known BRAF inhibitor sensitizing mutation) found that cells induced to stably over-express PIK3R2 (via viral transduction with additional copies of wildtype PIK3R2) were not significantly more resistant to vemurafenib (a BRAFi) than cells transduced with empty vectors, which served as the negative controls. 24265155 PubMed Shi et al., 2014, Cancer Discov 2 accepted 6266 2363 4290 N/A 2020-12-10 02:04:30 UTC https://civicdb.org/links/evidence_items/6266 https://civicdb.org/links/variants/2363 https://civicdb.org/links/genes/4290 false ABL1 25 BCR::ABL G250E Chronic Myeloid Leukemia 8552 Nilotinib Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The G250E mutation was associated with resistance in 2 μM imatinib (3 clone recovered, ~2%), 4 μM imatinib (1 clone recovered, ~0.74%), and 50 nM nilotinib (5 clone, ~11%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6267 1023 4 9 133738349 133738349 G A ENST00000318560.5 75 GRCh37 Somatic 2018-07-02 02:31:03 UTC https://civicdb.org/links/evidence_items/6267 https://civicdb.org/links/variants/1023 https://civicdb.org/links/genes/4 false PREX2 80243 R172I Melanoma 1909 Vemurafenib Predictive Supports C Resistance In a retrospective study of 44 relapsed melanoma patients harboring BRAF V600E/K (known BRAF inhibitor sensitizing mutations), PREX2 R172I was associated with a case of acquired resistance to BRAF inhibitor (vemurafenib) monotherapy in one patient. This patient was an 83 year old male with stage IV M1c melanoma who took vemurafenib (960mg twice daily). The best overall response was a 5% increase in sum of target lesions, and progression free survival lasted 132 days. Prior to vemurafenib monotherapy, this patient harbored BRAF V600K and no other somatic genetic alterations noted in the baseline tumor. Following relapse, the patient gained PREX2 R172I in one of two disease progressive tumors. Whole exome sequencing and Sanger re-sequencing were used for all tumors. The authors indicated that the biology behind this potential resistance mutation was unknown. 24265155 PubMed Shi et al., 2014, Cancer Discov 4 accepted 6268 2364 15344 8 68939530 68939530 G T ENST00000288368.4 75 GRCh37 Somatic 2018-07-19 20:43:06 UTC https://civicdb.org/links/evidence_items/6268 https://civicdb.org/links/variants/2364 https://civicdb.org/links/genes/15344 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The F317L mutation was associated with resistance in 2 μM imatinib (2 clones recovered, ~1%), 5 nM dasatinib (6 clones, ~ 17%), and 10 nM dasatinib (4 clones, ~7%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6270 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2018-07-02 02:38:52 UTC https://civicdb.org/links/evidence_items/6270 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false PTEN 5728 Loss Melanoma 1909 Vemurafenib Predictive Supports D Resistance An in vitro study of M229 (a human melanoma cell line) endogenously expressing wildtype PTEN and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that PTEN knockdown cells (achieved via lentiviral transduction of shPTEN) were more resistant to vemurafenib (a BRAF inhibitor) than cells expressing wildtype PTEN. Lentiviral mediated reintroduction of PTEN restored vemurafenib sensitivity in WM2664, a vemurafenib resistant, PTEN non-expressing and BRAF V600D mutated human melanoma cell line. 24265155 PubMed Shi et al., 2014, Cancer Discov 4 accepted 6271 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2018-07-19 20:44:27 UTC https://civicdb.org/links/evidence_items/6271 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false NRG1 3084 Fusion Pancreatic Adenocarcinoma 4074 Afatinib Predictive Supports C Sensitivity/Response In patients with KRAS wild-type (KRASwt) tumors druggable gene fusions have been identified. These alterations included recurrent NRG1 rearrangements predicted to drive PDAC development through aberrant ERBB receptor-mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in two patients with NRG1-rearranged tumors that had proved resistant to standard treatment. One patient (30) was treated with afatinib monotherapy and showed improvement at 7 weeks, followed by progression at 3 months after necessary dose reduction. 29802158 PubMed Heining et al., 2018, Cancer Discov 4 accepted 6273 2286 2593 NRG1 fusions have been described in cases of invasive mucinous adenocarcinoma of the lung, pancreatic ductal adenocarcinoma, cholangiocarcinoma and lung adenocarcinoma. In many cases these tumors were negative for the more common known driver genes of these diseases (e.g., KRAS wild-type pancreatic ductal adenocarcinoma). These events have been proposed as an attractive therapeutic target and some promising results have been observed with pan-HER inhibitors such as afatinib. Somatic 2019-08-29 20:54:59 UTC https://civicdb.org/links/evidence_items/6273 https://civicdb.org/links/variants/2286 https://civicdb.org/links/genes/2593 false ABL1 25 BCR::ABL Q252H Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The Q252H mutation was associated with resistance to 4 μM and 16 μM imatinib (4 clones [~3%] and 1 clone [~3%] recovered, respectively) as well as 10 nM dasatinib (1 clone [~2%]). No clones recovered at 2 μM/8 μM imatinib or 5 nM dasatinib. In a review of 20 publications, this mutation was previously described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6274 1024 4 9 133738356 133738356 G C ENST00000318560.5 75 GRCh37 Somatic 2018-07-02 02:35:56 UTC https://civicdb.org/links/evidence_items/6274 https://civicdb.org/links/variants/1024 https://civicdb.org/links/genes/4 false PIK3CA 5290 Amplification Melanoma 1909 Vemurafenib Predictive Supports D Resistance An in vitro study of M229 (a human melanoma cell line) endogenously expressing wildtype PIK3CA and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that cells induced to stably over-express PIK3CA (via viral transduction with additional copies of wild type PIK3CA) were significantly more resistant to vemurafenib (a BRAFi) than cells transduced with an empty vector (30% vs 20% survival, p < .0001). Though statistics were not provided, it appears that amplification of wildtype PIK3CA confers less resistance than the positive control variant, PIK3CA E545K. 24265155 PubMed Shi et al., 2014, Cancer Discov 2 accepted 6275 212 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 Somatic 2018-07-19 20:27:04 UTC https://civicdb.org/links/evidence_items/6275 https://civicdb.org/links/variants/212 https://civicdb.org/links/genes/37 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The E255K mutation was associated with resistance in 16 μM imatinib ( 1 clone recovered, ~3%) and all lower concentrations as well as in 50 nM nilotinib (5 clones, ~11%) and 5 nM dasatinib (2 clones, ~6%), the lowest concentrations tested for these two drugs. In a review of 20 publications, this mutation was described in imatinib resistant patients. 16772610 PubMed Bradeen et al., 2006, Blood 2 accepted 6282 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2018-10-08 21:26:42 UTC https://civicdb.org/links/evidence_items/6282 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Nilotinib,Imatinib Mesylate,Dasatinib Substitutes Predictive Supports D Resistance In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The T315I mutation was associated with resistance in 16 μM imatinib ( 15 clones, 45% of viable clones in this treatment), 5000 nM nilotinib (10 clones, 100%), and 25 nM dasatinib (32 clones, 100%) which were the highest concentrations used. T315I resistant clones were also found at all lower concentrations tested. 16772610 PubMed Bradeen et al., 2006, Blood 3 accepted 6285 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2018-10-08 21:57:01 UTC https://civicdb.org/links/evidence_items/6285 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false VHL 7428 3p26.3-25.3 11Mb del Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma Predisposing N/A C N/A A case report of a woman with de novo 3p deletion syndrome (encompassing the VHL gene) was associated with cerebellar hemangioblastoma at the age of 16 years old. This is the first report of a patient with 3p- with cerebral hemangioblastoma that may be associated with VHL disease. ACMG: PVS1, PS2, PP4 26365017 PubMed Suzuki-Muromoto et al., 2016, Brain Dev. 3 accepted 6287 2367 58 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/6287 https://civicdb.org/links/variants/2367 https://civicdb.org/links/genes/58 false VHL 7428 N78S (c.233A>G) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Retinal capillary hemangioma,Multiple renal cysts,Pancreatic cysts,Pancreatic endocrine tumor Predisposing Supports C Uncertain Significance A male patient with Type 1 VHL disease presented with vision loss and retinal angiomatosis in the right eye at 19Y, left retinal angiomatosis at 23Y as well as CNS hemangioblastomas, neuroendocrine tumor of the pancreas which metastases to the liver, and renal tumors at 25Y. Patient was found to carry c.233A>G (p.Asn78Ser) mutation in the VHL gene. Patient had a positive family history of VHL clinical manifestations, although the genotype of affected family members was not confirmed. His mother presented with pancreatic and renal cysts at 37Y and retinal angiomatosis at 47Y. Patient's grandmother suffered from loss of vision in her 30s, and renal cancer and brain tumour at 58Y. ACMG: PP2, PP4 26984080 PubMed Kobayashi et al., 2016, Intern. Med. 2 accepted 6289 1755 58 3 10183764 10183764 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/6289 https://civicdb.org/links/variants/1755 https://civicdb.org/links/genes/58 false VHL 7428 Exon 3 Deletion Von Hippel-Lindau Disease 14175 Spinal hemangioblastoma,Retinal capillary hemangioma,Cerebellar hemangioblastoma,Clear cell renal cell carcinoma,Pheochromocytoma,Pancreatic cysts Predisposing N/A C N/A A 22-year-old woman diagnosed in childhood with type IIb VHL, with known multiple retinal angiomas, pancreatic cysts, and spinal and cerebellar hemangioblastomas presented to the ER with signs of acute decompensated heart failure leading to the discovery of dilated left ventricle with severely depressed ejection fraction. Pheochromocytoma and clear cell renal carcinoma was also discovered at this time. Genetic analysis revealed a de novo germline exon 3 deletion mutation in the VHL gene, with no family history of disease. ACMG: PVS1, PS2, PP4 26584481 PubMed Valero et al., 2016, Med Princ Pract 3 accepted 6290 1939 58 3 10191471 10193904 ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/6290 https://civicdb.org/links/variants/1939 https://civicdb.org/links/genes/58 false KRAS 3845 G12/G13 Colorectal Cancer 9256 Prognostic Does Not Support B Poor Outcome This was a retrospective clinical study of 168 metastatic colorectal cancer patients who received first line chemotherapy (5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan) alone or with monoclonal antibodies (bevacizumab or cetuximab). It assessed the relationship between KRAS mutation status in primary tumors and post treatment progression free survival (PFS) and overall survival (OS). Of the 168 patients, 106 had wildtype KRAS and 62 had mutations in KRAS—including G12A, G12C, G12D, G12R, G12S, G12V, and G13D. Regardless of first line chemotherapy regimen or use of monoclonal antibody treatment, patients with KRAS-mutated tumors did not have a significantly worse outcome than patients with wtKRAS tumors, as evidenced by non-significant differences in PFS (12.3 vs 11.8 months, respectively) and OS (35.8 and 40.5 months, respectively). 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6292 77 30 12 25398280 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2018-07-12 20:12:48 UTC https://civicdb.org/links/evidence_items/6292 https://civicdb.org/links/variants/77 https://civicdb.org/links/genes/30 false KRAS 3845 G12/G13 Colorectal Cancer 9256 Oxaliplatin Predictive Does Not Support B Resistance This was a retrospective clinical study of 100 metastatic colorectal cancer patients who received FOLFOX (oxaliplatin + 5-fluorouracil + folinic acid) first-line therapy alone or with monoclonal antibodies (bevacizumab or cetuximab). It assessed the relationship between KRAS mutation status in primary tumors and response to oxaliplatin-based first-line therapy, as measured by post treatment PFS. Of 100 patients, 61 had wildtype KRAS and 39 had mutations in KRAS—including G12A, G12C, G12D, G12R, G12S, G12V, and G13D. The study found that patients with KRAS-mutated tumors were not significantly more resistant to oxaliplatin-based first-line therapy than patients with wildtype KRAS, as evidenced by a nonsignificant difference in PFS (11.7 and 11.4 months, respectively). 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6293 77 30 12 25398280 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2018-07-12 20:24:06 UTC https://civicdb.org/links/evidence_items/6293 https://civicdb.org/links/variants/77 https://civicdb.org/links/genes/30 false KRAS 3845 G12/G13 Colorectal Cancer 9256 Irinotecan Predictive Does Not Support B Resistance This was a retrospective clinical study of 44 metastatic colorectal cancer patients who recieved FOLFIRI (5-Fluorouacil + Folinic acid + irinotecan) first-line therapy alone or with bevacizumab. It assessed the relationship between KRAS mutation status in primary tumors and response to irinotecan-based first line therapy, as measured by PFS. Of the 44 patients, 26 had wildtype KRAS and 18 had mutations in KRAS—including G12A, G12C, G12D, G12R, G12S, G12V, and G13D. The study found that patients harboring a KRAS mutation were not significantly more resistant to irinotecan-based first-line therapy than patients with wildtype KRAS. The difference in PFS between patients with KRAS-mutated tumors and the patients with wtKRAS tumors was nonsignificant (PFS: 13.7 and 12.0 months; p= 0.074). 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6294 77 30 12 25398280 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2018-07-12 20:22:20 UTC https://civicdb.org/links/evidence_items/6294 https://civicdb.org/links/variants/77 https://civicdb.org/links/genes/30 false KRAS 3845 G12/G13 Colorectal Cancer 9256 Bevacizumab Predictive Does Not Support B Resistance This was a retrospective clinical study of 97 metastatic colorectal cancer patients who received bevacizumab in conjunction with first-line chemotherapy (composed of 5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan). It assessed the relationship between KRAS mutation status in primary tumors and response to bevacizumab-containing first line chemotherapy, as measured by PFS. Of the 97 patients, 58 had wildtype KRAS and 39 had mutations in KRAS—including G12A, G12C, G12D, G12R, G12S, G12V, and G13D. The study found that patients with KRAS-mutated tumors were not significantly more resistant to bevacizumab-containing first-line chemotherapy than patients with wildtype KRAS, as evidenced by a non-significant difference in PFS between the two groups (12.1 and 11.7 months, respectively). 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6295 77 30 12 25398280 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2018-07-12 20:15:54 UTC https://civicdb.org/links/evidence_items/6295 https://civicdb.org/links/variants/77 https://civicdb.org/links/genes/30 false KRAS 3845 G12/G13 Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance This was a retrospective clinical study of 92 metastatic colorectal cancer patients who received cetuximab in conjunction with salvage chemotherapy (refractory to at least one line of treatment). Salvage chemotherapy was composed of 5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan. The study assessed the relationship between KRAS mutation status in primary tumors and response to cetuximab-containing salvage chemotherapy, as measured by PFS. Of the 92 patients, 60 had wildtype KRAS and 32 had mutations in KRAS—including G12A, G12C, G12D, G12R, G12S, G12V, and G13D. The study found that patients harboring a KRAS mutation were trending toward resistance to cetuximab-containing salvage chemotherapy as compared to patients with wildtype KRAS (p=0.094). Note: while differences in PFS were nonsignificant between patients with wildtype or mutant KRAS, differences in objective response (defined as reduction by at least 30% in the sum of the longest diameters of target lesions compared to baseline) were significantly different. Of the 32 patients with mutant KRAS, none responded to cetuximab-containing salvage therapy, while 14/60 of the patients with wildtype KRAS (23%) responded (p=.002). 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6296 77 30 12 25398280 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2018-07-12 20:11:58 UTC https://civicdb.org/links/evidence_items/6296 https://civicdb.org/links/variants/77 https://civicdb.org/links/genes/30 false PIK3CA 5290 Mutation Colorectal Cancer 9256 Prognostic Does Not Support B Poor Outcome This was a retrospective clinical study of 168 metastatic colorectal cancer patients who received first line chemotherapy (made up of 5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan) alone or with monoclonal antibodies (bevacizumab or cetuximab). It assessed the relationship between PIK3CA mutation status in primary tumors and post treatment PFS. Of 168 patients, 142 had wildtype PIK3CA and 26 had mutations in PIK3CA on either exon 9 or 20 (exon 9 mutations: E542K, E545K, E545G, E545D, Q546K, D549N. Exon 20 mutations: R1023Q, H1047R, H1047L, G1049A). The study found that patients harboring a PIK3CA mutation did not have a significantly worse outcome than patients expressing wildtype PIK3CA, regardless of first line chemotherapy regimen or use of monoclonal antibody treatment. 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6297 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2018-07-12 18:12:37 UTC https://civicdb.org/links/evidence_items/6297 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PIK3CA 5290 Mutation Colorectal Cancer 9256 Oxaliplatin Predictive Does Not Support B Resistance This was a retrospective clinical study of 100 metastatic colorectal cancer patients who received FOLFOX (oxaliplatin + 5-fluorouracil + folinic acid) first-line therapy alone or with monoclonal antibodies (bevacizumab or cetuximab). It assessed the relationship between PIK3CA mutation status in primary tumors and response to oxaliplatin-based first-line therapy, as measured by post treatment PFS. Of 100 patients, 81 had wildtype PIK3CA and 19 had mutations in PIK3CA on either exon 9 or 20 (exon 9 mutations: E542K, E545K, E545G, E545D, Q546K, D549N. Exon 20 mutations: R1023Q, H1047R, H1047L, G1049A). The study found that patients harboring a PIK3CA mutation were not significantly more resistant to oxaliplatin-based first-line therapy than patients with wildtype PIK3CA, as evidenced by a nonsignificant difference in PFS between the two groups (10.7 and 11.7 months, respectively). 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6298 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2018-07-12 18:11:15 UTC https://civicdb.org/links/evidence_items/6298 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PIK3CA 5290 Mutation Colorectal Cancer 9256 Irinotecan Predictive Does Not Support B Resistance This was a retrospective clinical study of 44 metastatic colorectal cancer patients who received FOLFIRI (5-Fluorouacil + Folinic acid + irinotecan) first-line therapy alone or with bevacizumab. It assessed the relationship between PIK3CA mutation status in primary tumors and response to irinotecan-based first line therapy, as measured by PFS. Of the 44 patients, 40 had wildtype PIK3CA and 4 had mutations in PIK3CA on either exon 9 or 20 (exon 9 mutations: E542K, E545K, E545G, E545D, Q546K, D549N. Exon 20 mutations: R1023Q, H1047R, H1047L, G1049A). The study found that patients harboring a PIK3CA mutation were not significantly more resistant to irinotecan-based first-line therapy than patients with wildtype PIK3CA, as evidenced by a nonsignificant difference in PFS between the two groups. 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6299 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2018-07-10 22:01:15 UTC https://civicdb.org/links/evidence_items/6299 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PIK3CA 5290 Mutation Colorectal Cancer 9256 Bevacizumab Predictive Does Not Support B Resistance This was a retrospective clinical study of 97 metastatic colorectal cancer patients who received bevacizumab in conjunction with first-line chemotherapy (composed of 5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan). It assessed the relationship between PIK3CA mutation status in primary tumors and response to bevacizumab-containing first line chemotherapy, as measured by PFS. Of the 97 patients, 83 had wildtype PIK3CA and 14 had mutations in PIK3CA on either exon 9 or 20 (exon 9 mutations: E542K, E545K, E545G, E545D, Q546K, D549N. Exon 20 mutations: R1023Q, H1047R, H1047L, G1049A). The study found that patients harboring a PIK3CA mutation were not significantly more resistant to bevacizumab-containing first-line chemotherapy than patients with wildtype PIK3CA, as evidenced by a nonsignificant difference in PFS between the two groups. 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6300 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2018-07-10 22:02:35 UTC https://civicdb.org/links/evidence_items/6300 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PIK3CA 5290 Mutation Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance This was a retrospective clinical study of 92 metastatic colorectal cancer patients who received cetuximab in conjunction with salvage chemotherapy (refractory to at least one line of treatment). Salvage chemotherapy was composed of 5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan. The study assessed the relationship between PIK3CA mutation status in primary tumors and response to cetuximab-containing salvage chemotherapy, as measured by PFS. Of the 92 patients, 79 had wildtype PIK3CA and 19 had mutations in PIK3CA on either exon 9 or 20 (exon 9 mutations: E542K, E545K, E545G, E545D, Q546K, D549N. Exon 20 mutations: R1023Q, H1047R, H1047L, G1049A). The study found that patients harboring a PIK3CA mutation were significantly more resistant to cetuximab-containing salvage chemotherapy than patients with wildtype PIK3CA (Median PFS: 2.5 and 3.9 months, respectively; p = .014). 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6301 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2018-07-10 22:02:47 UTC https://civicdb.org/links/evidence_items/6301 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false BRAF 673 Mutation Colorectal Cancer 9256 Prognostic Supports B Poor Outcome This was a retrospective clinical study of 168 metastatic colorectal cancer patients who received first line chemotherapy (made up of 5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan) alone or with monoclonal antibodies (bevacizumab or cetuximab). It assessed the relationship between BRAF mutation status in primary tumors and post treatment PFS. Of 168 patients, 155 had wildtype BRAF and 13 had mutations in BRAF—including V600E and D594K. The study found that patients harboring a BRAF mutation had a significantly worse outcome than patients expressing wildtype BRAF, regardless of first line chemotherapy regimen or use of monoclonal antibody treatment (Median PFS: 4.3 and 12.5 months, respectively; p <.0001). 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6302 399 5 7 140453136 140481403 ENST00000288602.6 75 GRCh37 Somatic 2018-07-11 21:53:13 UTC https://civicdb.org/links/evidence_items/6302 https://civicdb.org/links/variants/399 https://civicdb.org/links/genes/5 false BRAF 673 Mutation Colorectal Cancer 9256 Oxaliplatin Predictive Supports B Resistance This was a retrospective clinical study of 100 metastatic colorectal cancer patients who received FOLFOX (oxaliplatin + 5-fluorouracil + folinic acid) first-line therapy alone or with monoclonal antibodies (bevacizumab or cetuximab). It assessed the relationship between BRAF mutation status in primary tumors and response to oxaliplatin-based first-line therapy, as measured by post treatment PFS. Of 100 patients, 94 had wildtype BRAF and 6 had mutations in BRAF—including V600E and D594K. The study found that patients harboring a BRAF mutation were significantly more resistant to oxaliplatin-based first-line therapy than patients with wildtype BRAF (Median PFS: 5.0 and 11. 7 months, respectively; p < .0001). 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6303 399 5 7 140453136 140481403 ENST00000288602.6 75 GRCh37 Somatic 2018-07-11 21:59:16 UTC https://civicdb.org/links/evidence_items/6303 https://civicdb.org/links/variants/399 https://civicdb.org/links/genes/5 false BRAF 673 Mutation Colorectal Cancer 9256 Irinotecan Predictive Supports B Resistance This was a retrospective clinical study of 44 metastatic colorectal cancer patients who received FOLFIRI (5-Fluorouacil + Folinic acid + irinotecan) first-line therapy alone or with bevacizumab. It assessed the relationship between BRAF mutation status in primary tumors and response to irinotecan-based first line therapy, as measured by PFS. Of the 44 patients, 39 had wildtype BRAF and 5 had mutations in BRAF—including V600E and D594K. The study found that patients harboring a BRAF mutation were significantly more resistant to irinotecan-based first-line therapy than patients with wildtype BRAF (Median PFS: 3.5 and 12.8 months, respectively; p = .006). 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6304 399 5 7 140453136 140481403 ENST00000288602.6 75 GRCh37 Somatic 2018-07-11 22:08:47 UTC https://civicdb.org/links/evidence_items/6304 https://civicdb.org/links/variants/399 https://civicdb.org/links/genes/5 false BRAF 673 Mutation Colorectal Cancer 9256 Bevacizumab Predictive Supports B Resistance This was a retrospective clinical study of 97 metastatic colorectal cancer patients who received bevacizumab in conjunction with first-line chemotherapy (composed of 5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan). It assessed the relationship between BRAF mutation status in primary tumors and response to bevacizumab-containing first line chemotherapy, as measured by PFS. Of the 97 patients,89 had wildtype BRAF and 8 had mutations in BRAF—including V600E and D594K. The study found that patients harboring a BRAF mutation were significantly more resistant to bevacizumab-containing first-line chemotherapy than patients with wildtype BRAF (Median PFS: 4.2 and 12.5 months, respectively; p < .0001). 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6305 399 5 7 140453136 140481403 ENST00000288602.6 75 GRCh37 Somatic 2018-07-11 22:13:05 UTC https://civicdb.org/links/evidence_items/6305 https://civicdb.org/links/variants/399 https://civicdb.org/links/genes/5 false BRAF 673 Mutation Colorectal Cancer 9256 Cetuximab Predictive Supports B Resistance This was a retrospective clinical study of 92 metastatic colorectal cancer patients who received cetuximab in conjunction with salvage chemotherapy (refractory to at least one line of treatment). Salvage chemotherapy was composed of 5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan. The study assessed the relationship between BRAF mutation status in primary tumors and response to cetuximab-containing salvage chemotherapy, as measured by PFS. Of the 92 patients, 83 had wildtype BRAF and 9 had mutations in BRAF—including V600E and D594K. The study found that patients harboring a BRAF mutation were significantly more resistant to cetuximab-containing salvage chemotherapy than patients with wildtype BRAF (Median PFS: 2.0 and 3.9, respectively; p = .0005). 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6306 399 5 7 140453136 140481403 ENST00000288602.6 75 GRCh37 Somatic 2018-07-11 22:14:21 UTC https://civicdb.org/links/evidence_items/6306 https://civicdb.org/links/variants/399 https://civicdb.org/links/genes/5 false BRAF 673 Mutation Colorectal Cancer 9256 Prognostic Supports B Poor Outcome This was a retrospective clinical study of 168 metastatic colorectal cancer patients who received first line chemotherapy (made up of 5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan) alone or with monoclonal antibodies (bevacizumab or cetuximab). It assessed the relationship between BRAF mutation status in primary tumors and post treatment OS. Of 168 patients, 155 had wildtype BRAF and 13 had mutations in BRAF—including V600E and D594K. The study found that patients harboring a BRAF mutation had a significantly worse outcome than patients expressing wildtype BRAF, regardless of first line chemotherapy regimen or use of monoclonal antibody treatment (Median OS: 10.9 and 40.5 months, respectively; p <.0001). 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6307 399 5 7 140453136 140481403 ENST00000288602.6 75 GRCh37 Somatic 2018-07-11 22:15:11 UTC https://civicdb.org/links/evidence_items/6307 https://civicdb.org/links/variants/399 https://civicdb.org/links/genes/5 false ABL1 25 BCR::ABL L248V Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support B Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 15 patients with L248V mutations, 6, 10, and 15 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 6308 1022 4 9 133738342 133738342 C G ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 21:58:14 UTC https://civicdb.org/links/evidence_items/6308 https://civicdb.org/links/variants/1022 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports B Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase) patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 14 patients with F317L mutations, 1, 2, and 13 achieved CCyR, MCyR, and CHR to dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. Despite high CHR in patients with the F317L variant, of the 63 variants considered, the authors associate T315I, F317L, and V299L with resistance or lower levels of response to dasatinib due to clinical resistance and low in vitro sensitivity. They suggest considering alternative treatment options for patients with these three variants. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 6309 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2018-07-19 21:49:50 UTC https://civicdb.org/links/evidence_items/6309 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E459K Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support B Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 12 patients with the E459K mutations, 4, 6, and 11 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 6310 2370 4 9 133753906 133753906 G A ENST00000318560.5 75 GRCh37 Somatic 2018-07-19 22:03:23 UTC https://civicdb.org/links/evidence_items/6310 https://civicdb.org/links/variants/2370 https://civicdb.org/links/genes/4 false ABL1 25 TKD MUTATION Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support B Resistance This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, imatinib-resistant patients with and without ABL1 mutation had comparable complete hematologic response [CHR= 90% (345/384) vs. 93% (390/421)], major cytogenetic response [MCyR= 56% (211/384) vs. 58% (243/421)], complete cytogenetic response [CCyR= 43% (164/384) vs. 47% (196/421)], and major molecular response [MMR= 31% (115/367) vs. 36% (145/404)]. Of the 63 imatinib-resistant variants observed (see comment), the authors associate T315I, F317L, and V299L with resistance to dasatinib or lower levels of response due to clinical resistance and low in vitro sensitivity. However, F317L does have a high CHR. They suggest considering alternative treatment options for patients with these three variants. 19779040 PubMed Müller et al., 2009, Blood NCT00101660,NCT00103844,NCT00123474 3 accepted 6311 2371 4 Somatic 2018-07-12 21:00:34 UTC https://civicdb.org/links/evidence_items/6311 https://civicdb.org/links/variants/2371 https://civicdb.org/links/genes/4 false KRAS 3845 G13V Colorectal Cancer 9256 Cetuximab,Panitumumab Substitutes Predictive Supports C Resistance In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS PIK3CA and PTEN were tested for mutation; KRAS G13V was the only variant noted in the primary colon tumor of one patient who experienced disease progression (Patient 4; Supplemental Table 1) following treatment. In the larger cohort, patients with tumors harboring any KRAS mutation had significantly decreased incidence of objective response than patients with wtKRAS tumors. Authors noted that patients with tumors harboring KRAS mutations tended to have decreased PFS and OS compared to those with wild-type tumors though the differences were not statistically significant. 19223544 PubMed Sartore-Bianchi et al., 2009, Cancer Res. 2 accepted 6312 1517 30 12 25398280 25398281 GC AA ENST00000256078.4 75 GRCh37 Somatic 2018-11-02 22:00:24 UTC https://civicdb.org/links/evidence_items/6312 https://civicdb.org/links/variants/1517 https://civicdb.org/links/genes/30 false KRAS 3845 G12S Colorectal Cancer 9256 Cetuximab,Panitumumab Substitutes Predictive Supports C Resistance In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS PIK3CA and PTEN were tested for mutation; KRAS G12S was the only variant noted in the primary tumor of one patient who experienced disease progression following treatment (colon tumor of patient 20; Supplemental Table 1). In the larger cohort, patients with tumors harboring any KRAS mutation had significantly decreased incidence of objective response than patients with wtKRAS tumors. Authors noted that patients with tumors harboring KRAS mutations tended to have decreased PFS and OS compared to those with wild-type tumors though the differences were not statistically significant. 19223544 PubMed Sartore-Bianchi et al., 2009, Cancer Res. 2 accepted 6314 913 30 12 25398285 25398285 C T ENST00000256078.4 75 GRCh37 Somatic 2018-11-02 22:02:19 UTC https://civicdb.org/links/evidence_items/6314 https://civicdb.org/links/variants/913 https://civicdb.org/links/genes/30 false PTEN 5728 Loss Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Supports B Resistance In this study, 81 metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). Multivariate analysis demonstrated a significant association between PTEN protein expression loss and lack of response to panitumumab or cetuximab (P = 0.0012). Patients with PTEN non-expressing tumors (32/80) had shorter overall survival, compared to those with PTEN expressing tumors (P = 0.0048), though they had a nonsignificant difference in progression free survival (p = .0681). PIK3CA, PTEN, and KRAS were evaluated for mutations; PTEN loss was the only variant noted in 17 of the patients who experienced either stable disease or disease progression, while the other patients experienced PTEN loss in combination with a KRAS or PIK3CA mutation. 19223544 PubMed Sartore-Bianchi et al., 2009, Cancer Res. 3 accepted 6315 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2018-11-02 23:40:57 UTC https://civicdb.org/links/evidence_items/6315 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false KRAS 3845 G12D Colorectal Cancer 9256 Cetuximab,Panitumumab Substitutes Predictive Supports C Resistance In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS, PIK3CA, and PTEN were tested for mutation; KRAS G12D was the only variant noted in the primary tumor of two patients who experienced stable disease following treatment (Patients 22 and 36; colon and rectum tumors; Supplemental Table 1). In the larger cohort, patients with tumors harboring any KRAS mutation had significantly decreased incidence of objective response than patients with wtKRAS tumors. Authors noted that patients with tumors harboring KRAS mutations tended to have decreased PFS and OS compared to those with wild-type tumors though the differences were not statistically significant. 19223544 PubMed Sartore-Bianchi et al., 2009, Cancer Res. 2 accepted 6316 79 30 12 25398284 25398284 C T ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still actively debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. However, cetuximab treatment was shown to extend survival in a single cohort of colorectal patients with G12D mutations. Overall, the interpretation for KRAS mutations in most clinical scenarios is still undecided. Somatic 2018-11-02 22:11:10 UTC https://civicdb.org/links/evidence_items/6316 https://civicdb.org/links/variants/79 https://civicdb.org/links/genes/30 false KRAS 3845 Amplification Melanoma 1909 Vemurafenib Predictive Supports D Resistance In vitro studies of M229 (a human melanoma cell line) endogenously expressing wildtype KRAS and BRAF V600E (a known BRAF sensitizing mutation) found that cells induced to stably over-express wildtype KRAS4a or KRAS4b (via viral transduction with additional copies of KRAS4a or KRAS4b) were more resistant to vemurafenib (a BRAFi) than cells transduced with empty vectors. Resistance was determined by assessing cell survival. 24265155 PubMed Shi et al., 2014, Cancer Discov 2 accepted 6317 592 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2018-07-19 20:21:39 UTC https://civicdb.org/links/evidence_items/6317 https://civicdb.org/links/variants/592 https://civicdb.org/links/genes/30 false KRAS 3845 G12A Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Supports C Resistance In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS, PIK3CA, and PTEN were tested for mutation; KRAS G12A was the only variant noted in the both the primary and metastatic colon tumors of one patient (Patient 29; Supplemental table 1) , and the primary colon tumor of another patient (104; Table S1), who both experienced stable disease following treatment. In the larger cohort, patients with tumors harboring any KRAS mutation had significantly decreased incidence of objective response than patients with wtKRAS tumors. Authors noted that patients with tumors harboring KRAS mutations tended to have decreased PFS and OS compared to those with wild-type tumors though the differences were not statistically significant. 19223544 PubMed Sartore-Bianchi et al., 2009, Cancer Res. 2 accepted 6319 148 30 12 25398284 25398284 C G ENST00000256078.4 75 GRCh37 KRAS G12A, like EGFR T790M, has been shown to be capable of driving acquired resistance to tyrosine kinase inhibitors in lung adenocarcinoma. Somatic 2018-11-02 22:23:42 UTC https://civicdb.org/links/evidence_items/6319 https://civicdb.org/links/variants/148 https://civicdb.org/links/genes/30 false KRAS 3845 G13D Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Does Not Support C Resistance In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS, PIK3CA, and PTEN were tested for mutation; KRAS G13D was the only variant noted in the primary colon tumors of two patients who experienced partial response following treatment (Patients 37, 47; Supplemental Table 1). In the larger cohort, patients with tumors harboring any KRAS mutation had significantly decreased incidence of objective response than patients with wtKRAS tumors. Authors noted that patients with tumors harboring KRAS mutations tended to have decreased PFS and OS compared to those with wild-type tumors though the differences were not statistically significant. 19223544 PubMed Sartore-Bianchi et al., 2009, Cancer Res. 2 accepted 6320 81 30 12 25398281 25398281 C T ENST00000256078.4 75 GRCh37 While the KRAS G13 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort. This mutation, along with the mutations affecting the neighboring G12 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, results are conflicting with retrospective analyses suggesting a better response to EGFR-Inhibition. A recent prospective phase-II study (12 patients, Schirripa et. al. 2015) could not reproduce this finding and another prospective phase II trial is currently ongoing. Somatic 2018-11-02 22:26:41 UTC https://civicdb.org/links/evidence_items/6320 https://civicdb.org/links/variants/81 https://civicdb.org/links/genes/30 false KRAS 3845 G13D Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Supports C Resistance In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS G13D was the only variant noted in the primary rectal tumor of one patient who experienced disease progression following treatment (Patient 45; Supplemental Table 1). This is response is consistent with observations made of the larger cohort, where patients with tumors harboring any KRAS mutation had significantly decreased incidence of objective response than patients with wtKRAS tumors. Authors noted that patients with tumors harboring KRAS mutations tended to have decreased PFS and OS compared to those with wild-type tumors though the differences were not statistically significant. However, two other patients (37 and 47; Table S1) had G13D as their only noted variant, but experienced partial response. 19223544 PubMed Sartore-Bianchi et al., 2009, Cancer Res. 2 accepted 6322 81 30 12 25398281 25398281 C T ENST00000256078.4 75 GRCh37 While the KRAS G13 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort. This mutation, along with the mutations affecting the neighboring G12 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, results are conflicting with retrospective analyses suggesting a better response to EGFR-Inhibition. A recent prospective phase-II study (12 patients, Schirripa et. al. 2015) could not reproduce this finding and another prospective phase II trial is currently ongoing. Somatic 2018-11-02 22:33:05 UTC https://civicdb.org/links/evidence_items/6322 https://civicdb.org/links/variants/81 https://civicdb.org/links/genes/30 false KRAS 3845 G12V Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Supports C Resistance In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS, PIK3CA, and PTEN were tested for mutation; KRAS G12V was the only variant noted in the primary rectal tumor of one patient who experienced disease progression (patient 56; Supplemental Table 1), and the primary colon tumors of two patients (9, 13; Supplemental Table 1) who experienced stable disease following treatment. In the larger cohort, patients with tumors harboring any KRAS mutation had significantly decreased incidence of objective response than patients with wtKRAS tumors. Authors noted that patients with tumors harboring KRAS mutations tended to have decreased PFS and OS compared to those with wild-type tumors though the differences were not statistically significant. 19223544 PubMed Sartore-Bianchi et al., 2009, Cancer Res. 2 accepted 6323 425 30 12 25398284 25398284 C A ENST00000256078.4 75 GRCh37 KRAS mutations are the most common mutations in pancreatic cancer occurring in > 90% of cases. Of these the G12D activating mutation is the most prevalent and results in a loss of GTPase activity which in turn leads to a constitutively active form of KRAS. This is enough to cause pre-cancerous pancreatic intraepithelial lesions Somatic 2018-11-02 22:14:59 UTC https://civicdb.org/links/evidence_items/6323 https://civicdb.org/links/variants/425 https://civicdb.org/links/genes/30 false VHL 7428 c.128-?_250+? Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Hemangioblastoma,Pancreatic cysts,Renal cyst Predisposing Supports C Uncertain Significance Eleven RCCs and 16 renal cysts from eight patients with VHL were analyzed. All patients had known germline VHL mutations. One male patient had a germline deletion (c.128−?_250+?) in the VHL gene and presented with bilateral RCC and cysts, CNS hemangioblastoma, and pancreatic cysts. Family history was not described for the patient. 15709172 PubMed Lee et al., 2005, Clin. Cancer Res. 2 accepted 6329 2373 58 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/6329 https://civicdb.org/links/variants/2373 https://civicdb.org/links/genes/58 false ABL1 25 TKD MUTATION Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support B Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Among 115 patients with mutational analysis at baseline, subsets were evaluated for complete hematologic response (CHR) and major cytogenetic response (MCyR). Both were comparable for patients with Abl1 mutation versus without [CHR = 33/34 vs. 27/27; MCyR = 41/59 (69%) vs. 19/35 (54%)]. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 3 accepted 6335 2371 4 Somatic 2018-07-12 21:30:27 UTC https://civicdb.org/links/evidence_items/6335 https://civicdb.org/links/variants/2371 https://civicdb.org/links/genes/4 false ABL1 25 P-Loop Mutation Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support B Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Among 115 patients with mutational analysis at baseline, subsets were evaluated for complete hematologic response (CHR) and major cytogenetic response (MCyR). Both were comparable for patients with P-loop mutations versus patients without Abl1 mutations [ CHR = 9/9 vs. 27/27; MCyR = 7/10 vs. 19/35 (54%)]. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 3 accepted 6336 2375 4 Somatic 2018-07-12 21:31:56 UTC https://civicdb.org/links/evidence_items/6336 https://civicdb.org/links/variants/2375 https://civicdb.org/links/genes/4 false ABL1 25 Non-P-Loop Mutation Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support B Resistance In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Among 115 patients with mutational analysis at baseline, subsets were evaluated for complete hematologic response (CHR) and major cytogenetic response (MCyR). Both were comparable for patients with non-P-loop mutations versus patient without Abl1 mutations [ CHR = 22/23 (96%) vs. 27/27; MCyR = 26/39 (67%) vs. 19/35 (54%)]. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. 21865346 PubMed Cortes et al., 2011, Blood NCT00261846 3 accepted 6337 2376 4 Somatic 2018-07-12 21:32:22 UTC https://civicdb.org/links/evidence_items/6337 https://civicdb.org/links/variants/2376 https://civicdb.org/links/genes/4 false BRCA1 672 Mutation Ovarian Cancer 2394 Rucaparib Predictive Supports B Sensitivity/Response A phase 2 trial on patients with relapsed, platinum-sensitive high grade ovarian, fallopian tube or primary peritoneal carcinoma (ARIEL2 Part1, NCT01891344) was held to assess PARP inhibitor rucaparib on 3 genetically defined subsets of patients. Out of 40 BRCA (BRCA1 or BRCA2) mutant patients, 14 had germline BRCA1 mutation, 13 of which were homozygous mutation and one with unknown zygosity. Confirmed objective response was seen in 86% (12/14) of the germline BRCA1 mutant subgroup. Authors note that response rate was similar regardless of whether the BRCA mutation was somatic or germline, in BRCA 1 or BRCA 2. In a BRCA wild-type subgroup, with low levels of loss of heterozygosity (LOH), confirmed objective response was observed in 10% (7/70) of the patients. Patients with BRCA mutant tumors experienced significantly longer median progression free survival than patients with BRCA wildtype, LOH low tumors (12.8 vs 5.2 mo, HR: 0.27, P<0.0001). 27908594 PubMed Swisher et al., 2017, Lancet Oncol. NCT01891344 3 accepted 6341 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Rare Germline 2020-08-27 23:20:15 UTC https://civicdb.org/links/evidence_items/6341 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false ABL1 25 TKD MUTATION Chronic Myeloid Leukemia 8552 Nilotinib Predictive Does Not Support B Resistance In this open-label, phase II registration trial, patients that were imatinib resistant (n = 192) or intolerant (n = 89) underwent nilotinib monotherapy. Prior to nilotinib treatment, 105 and 9 patients with baseline BCR-ABL mutations were imatinib resistant and intolerant, respectively. Within 12 months of therapy, among patients with baseline mutations, complete hematologic response was achieved in 57 (71%) of 80 [vs. 35 (80%) of 80 Abl1 wildtype patients, P = .393], major cytogenetic response in 49 of 100 [vs. 52 (60%) of 87, P = .145], complete cytogenetic response in 32 of 100 [vs. 35 (40%) of 87, P = .285], and major molecular response in 19 (22%) of 87 [vs. 22 (29%) of 76, P = .366]. These data shows no significant difference in nilotinib efficacy between patients with baseline mutations in the Abl1 kinase domain versus without. The authors observe clinical efficacy of nilotinib for many of the 29 variants found and identify only Y253H, E255K/V, and F359C/V as resistance conferring variants with IC50 greater than 150 nM. Individuals with T315I variants (3% of total population) were excluded. 19652056 PubMed Hughes et al., 2009, J. Clin. Oncol. 3 accepted 6342 2371 4 Somatic 2018-11-05 22:51:04 UTC https://civicdb.org/links/evidence_items/6342 https://civicdb.org/links/variants/2371 https://civicdb.org/links/genes/4 false BRCA2 675 Mutation Ovarian Cancer 2394 Rucaparib Predictive Supports B Sensitivity/Response A phase 2 trial on patients with relapsed, platinum-sensitive high grade ovarian, fallopian tube or primary peritoneal carcinoma (ARIEL2 Part1, NCT01891344) was held to assess PARP inhibitor rucaparib on 3 genetically defined subsets of patients. Out of 40 BRCA (BRCA1 or BRCA2) mutant patients, 6 had germline homozygous BRCA2 mutation. Confirmed objective response was seen in 83% (5/6) of the germline BRCA2 mutant subgroup. Authors note that response rate was similar regardless of whether the BRCA mutation was somatic or germline, in BRCA 1 or BRCA 2. In a BRCA wild-type subgroup, with low levels of loss of heterozygosity (LOH), confirmed objective response was observed in 10% (7/70) of the patients. Patients with BRCA mutant tumors experienced significantly longer median progression free survival than patients with BRCA wildtype, LOH low tumors (12.8 vs 5.2 mo, HR: 0.27, P<0.0001). 27908594 PubMed Swisher et al., 2017, Lancet Oncol. NCT01891344 3 accepted 6343 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Rare Germline 2020-08-27 23:23:11 UTC https://civicdb.org/links/evidence_items/6343 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false VHL 7428 S65W (c.194C>G) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Hemangioblastoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance 37 Danish patients diagnosed with VHL before 18 years from a prospective cohort study from Denmark's National vHL Research Database (Binderup et al., 2013) were assessed. Two families (Family ID 9 and 13) were found with a germline missense mutation in the VHL gene (S65W; c.194C>G). Family ID9 had 3 patients: Patient 1 and 2 were both diagnosed at 0Y and had no manifestations by the end of the study at 5Y and 10Y respectively. Patient 3 was diagnosed at 16Y and developed 2 CNS hemangioblastomas at 16Y and 2 pancreatic cysts at 16Y. Family ID13 had 1 patient who was diagnosed at age 13Y and had 8 retinal hemangioblastomas at 13Y, 16Y, 17Y, and 18Y, 1 pancreatic cyst at 17Y, and 1 CNS hemangioblastoma at 17Y. ACMG codes: PM1, PM5, PS3; and PP5. 28650583 PubMed Launbjerg et al., 2017, Am. J. Med. Genet. A 3 accepted 6352 1787 58 3 10183725 10183725 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6352 https://civicdb.org/links/variants/1787 https://civicdb.org/links/genes/58 false PIK3CA 5290 Mutation Colorectal Cancer 9256 Cetuximab,Panitumumab Substitutes Predictive Supports B Resistance Mutational analysis of 110 metastatic colorectal cancer patients was used to examine objective tumor response, progression free survival (PFS), and overall survival (OS) following treatment with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). In univariate analysis, PIK3CA mutations (H1047R or E545K) were significantly associated with lack of response to panitumumab or cetuximab (objective response rate: 0/15 vs 22/95 for patients harboring PIK3CA mutated or wildtype tumors, respectively; P = 0.038). Multivariate logistic regression of KRAS mutations, PIK3CA mutations and PTEN protein expression also confirmed an independent effect of PIK3CA mutation on objective response (P = 0.0337; OR = 0.1153; CI for OR: 0.000–0.865). Patients with tumors harboring either PIK3CA H1047R or E545K mutations (15/109) had decreased PFS, compared to those with wild-type tumors (P = 0.0035), though they had a nonsignificant difference in OS. Authors note a trend in decreasing OS in patients with PIK3CA mutated tumors. 19223544 PubMed Sartore-Bianchi et al., 2009, Cancer Res. 3 accepted 6362 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2018-07-06 20:17:31 UTC https://civicdb.org/links/evidence_items/6362 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false KRAS 3845 G12/G13 Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Supports B Resistance Mutational analysis of 109 metastatic colorectal cancer patients was used to examine objective tumor response, progression free survival (PFS), and overall survival (OS) following treatment with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). In univariate analysis, KRAS mutations (G12V, G12S, G12D, G12A, G13V, G13D) were significantly associated with lack of response to panitumumab or cetuximab (objective response rate: 2/32 vs 20/77 for patients harboring KRAS mutated or wildtype tumors, respectively; P = 0.019). Multivariate logistic regression of KRAS mutations, PIK3CA mutations and PTEN protein expression also confirmed an independent effect of KRAS mutations on objective response (p = 0.0029). Authors noted that patients with tumors harboring KRAS mutations (32/108) tended to have decreased PFS and OS compared to those with wild-type tumors though the differences were not statistically significant. 19223544 PubMed Sartore-Bianchi et al., 2009, Cancer Res. 3 accepted 6363 77 30 12 25398280 25398285 ENST00000256078.4 75 GRCh37 While the KRAS G12 region is a widely studied recurrent region in cancer, its impact on clinical action is still debated. Often associated with tumors that are wild-type for other drivers (EGFR and ALK specifically), the prognosis for patients with this mutation seems to be worse than the KRAS wild-type cohort in patients with colorectal and pancreatic cancer, however this hypothesis is in need of further validation. This mutation, along with the mutations affecting the neighboring G13 position, may result in a less responsive tumor when treated with first-generation TKI's like gefitinib. However, cetuximab treatment was shown to extend survival in a cohort of colorectal patients. Somatic 2018-10-09 21:44:24 UTC https://civicdb.org/links/evidence_items/6363 https://civicdb.org/links/variants/77 https://civicdb.org/links/genes/30 false PIK3CA 5290 Mutation Colorectal Cancer 9256 Aspirin Predictive Supports B Sensitivity/Response This was a retrospective study of 964 colorectal cancer patients who participated in the Nurses' Health Study and the Health Professionals Follow-up Study. Of 964 patients, 803 patients had wildtype PIK3CA (aspirin use: 337/803, no aspirin use: 466/803) and 161 had mutated PIK3CA (aspirin use: 66/161, no aspirin use: 95/161). This study found that—among patients with mutated PIK3CA cancer— regular use of aspirin following diagnosis was correlated with superior colorectal cancer specific survival (multivariate hazard ratio, 0.18; 95% CI, 0.06-0.61; P<0.001) and overall survival (multivariate hazard ratio, 0.54; 95% CI, 0.31-0.94; P = 0.01). Conversely, among patients with wild-type PIK3CA, regular use of aspirin after diagnosis was not significantly associated with colorectal cancer–specific survival or overall survival. Among patients with mutated-PIK3CA tumors, 23 of 90 patients who did not use aspirin after diagnosis (26%) died within 5 years after diagnosis, whereas only 2 of 62 regular users of aspirin after diagnosis (3%) died within 5 years after diagnosis (P<0.001). In contrast, among patients with wild-type PIK3CA tumors, the 5-year cumulative colorectal cancer–specific mortality was the same (15%) for users and nonusers of aspirin after diagnosis (P = 0.92). The authors conclude that PIK3CA mutation may predict response to aspirin therapy in patients with newly diagnosed colorectal cancer. 23094721 PubMed Liao et al., 2012, N. Engl. J. Med. 3 accepted 6375 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2018-07-11 22:30:34 UTC https://civicdb.org/links/evidence_items/6375 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false ABL1 25 R351W Lung Non-small Cell Carcinoma 3908 Imatinib Predictive Supports D Sensitivity/Response In this in vitro study, the H1915 non-small cell lung cancer cell line (homozygous for a R351W mutation) was shown to be susceptible to imatinib. This line showed a significant reduction in colony formation (P = 0.0004) and MTT assay, which tests for NADH activity (P < 0.001), with imatinib vs vehicle treatment. There was no significant difference in a lung cancer cell line without a known driver (H2126) nor in an immortalized bronchial epithelial line (Beas-2B) with either drug treatment in colony forming and MTT assays. Additionally, reduction in cell viability upon kinase inhibitor treatment was rescued with tetracycline-induced overexpression of resistant ABL1-T315I (P < 0.001) confirming the genetic dependency of this cell line on ABL1. Moreover, siRNA facilitated depletion of ABL1 expression resulted in significantly increased cytotoxicity (P < 0.004) with no significant change in H2126 or Beas-2B lines for 2/3 siRNAs supporting ABL1 as the primary drug target. Significant tumor reduction was observed in murine NSCLC xenografts of the H1915 cell line treated with imatinib compared to vehicle treatment (P = 0.0016). No change in tumor growth was observed in xenografts of the H650 cell line containing a wildtype ABL1 locus. In both in vitro and in vivo experiments, doxycycline-inducible expression of drug-resistant ABL1-T315I rescued imatinib-mediated inhibitory effects supporting the specificity of drug responses. 26758680 PubMed Testoni et al., 2016, EMBO Mol Med 5 accepted 6376 1656 4 9 133748333 133748333 C T ENST00000372348.2 75 GRCh37 Somatic 2018-11-05 23:10:28 UTC https://civicdb.org/links/evidence_items/6376 https://civicdb.org/links/variants/1656 https://civicdb.org/links/genes/4 false KIT 3815 Exon 11 Mutation Gastrointestinal Stromal Tumor 9253 Regorafenib Predictive Supports B Sensitivity/Response This phase II clinical trial of regorafenib (NCT01068769) examined the long term safety and efficacy of regorafenib in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GISTs) who failed previous treatments with imatinib. Patients whose GISTs harbored KIT exon 11 mutations (n=19) experienced higher rates of clinical benefit (defined as complete response, partial response, or stable disease lasting >16 weeks) than patients whose GISTs harbored KIT exon 9 mutations. 15/19 patients with exon 11 mutant GISTs experienced clinical benefit (including 2 PRs). KIT exon 11 mutant GISTs treated with regorafenib monotherapy were associated with improved median progression free survival (13.4 months vs. 5.7 and 1.6 months, P<0.0001), as compared to patients with KIT exon 9 mutation (n=2) and patients with KIT wildtype, non-succinate dehydrogenase-deficient tumors (n=2). 27371698 PubMed Ben-Ami et al., 2016, Ann. Oncol. NCT01068769 3 accepted 6377 66 29 4 55593582 55593708 ENST00000288135.5 75 GRCh37 c-KIT mutations in exon 11 lie within the juxtamembrane domain, and are very recurrent in gastrointestinal stromal tumors, often bearing a poorer prognosis than other KIT mutations. Cells harboring exon 11 mutations have shown sensitivity to the tyrosine kinase inhibitor imatinib, offering a better prognosis to patients treated with the drug in the first year. Small cohorts of melanoma patients harboring exon 11 KIT mutations have shown response to imatinib and sunitinib. Somatic 2019-03-08 21:21:24 UTC https://civicdb.org/links/evidence_items/6377 https://civicdb.org/links/variants/66 https://civicdb.org/links/genes/29 false CSF3R 1441 T618I Chronic Neutrophilic Leukemia 0080187 Ruxolitinib Predictive Supports D Sensitivity/Response Demonstrates that activating mutations in CSF3R are sufficient to drive a myeloproliferative disorder resembling aCML and CNL that is sensitive to pharmacologic JAK inhibition. 24081659 PubMed Fleischman et al., 2013, Blood 4 accepted 6380 2387 1239 1 36933434 36933434 G A ENST00000373103.1 75 GRCh37 Somatic 2018-07-13 13:56:17 UTC https://civicdb.org/links/evidence_items/6380 https://civicdb.org/links/variants/2387 https://civicdb.org/links/genes/1239 false CSF3R 1441 T618I Chronic Neutrophilic Leukemia 0080187 Ruxolitinib Predictive Supports C Sensitivity/Response Case report of a patient treated with ruxolitinib, an FDA-approved JAK1/2 inhibitor, which resulted in dramatic improvement of his blood counts. He also had significant reduction of spleen volume and constitutional symptoms. 25180155 PubMed Dao et al., 2014, Leuk Res Rep NCT02092324 4 accepted 6381 2387 1239 1 36933434 36933434 G A ENST00000373103.1 75 GRCh37 Somatic 2018-07-13 13:56:22 UTC https://civicdb.org/links/evidence_items/6381 https://civicdb.org/links/variants/2387 https://civicdb.org/links/genes/1239 false CALR 811 Mutation Essential Thrombocythemia 2224 Diagnostic Supports A Positive Diagnostic criterion for essential thrombocytemia according to the World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues 2016. 27069254 PubMed Arber et al., 2016, Blood 5 accepted 6382 2388 732 Somatic 2020-10-08 20:16:31 UTC https://civicdb.org/links/evidence_items/6382 https://civicdb.org/links/variants/2388 https://civicdb.org/links/genes/732 false NTRK1 4914 TRIM63::NTRK1 Melanoma 1909 Melanoma Larotrectinib Predictive Supports E Sensitivity/Response In this study we report that nonspitzoid metastasizing melanomas of adults may also harbor NTRK fusions and that NTRK expression can be immunohistochemically detected in these tumors. Of 751 melanomas analyzed by next-generation sequencing, 4 metastatic melanomas were identified with NTRK fusions, 3 involving NTRK1 (TRIM63, DDR2, and GON4L), 1 involving NTRK2 (TRAF2). All tumors were cytologically characterized by the presence of large epithelioid melanocytes and were immunoreactive with anti-Trk antibody. The NTRK1-TRIM63 fusion occurred in a 63 yo man with a nodular melanoma with the primary tumor on the shin and skin and lymph node metastases. No known melanoma drivers were identified as co-occurring in this patient. Thus, the presence of an NTRK family fusion in nonspitzoid metastasizing melanomas of adults may provide a therapeutic opportunity for NTRK inhibitors such as larotrectinib in a small subset of patients with metastatic melanoma. 29683819 PubMed Lezcano et al., 2018, Am. J. Surg. Pathol. 2 accepted 6392 2393 3983 Somatic 2018-08-20 21:50:21 UTC https://civicdb.org/links/evidence_items/6392 https://civicdb.org/links/variants/2393 https://civicdb.org/links/genes/3983 false NTRK1 4914 DDR2::NTRK1 Melanoma 1909 Melanoma Larotrectinib Predictive Supports E Sensitivity/Response In this study we report that nonspitzoid metastasizing melanomas of adults may also harbor NTRK fusions and that NTRK expression can be immunohistochemically detected in these tumors. Of 751 melanomas analyzed by next-generation sequencing, 4 metastatic melanomas were identified with NTRK fusions, 3 involving NTRK1 (TRIM63, DDR2, and GON4L), 1 involving NTRK2 (TRAF2). All tumors were cytologically characterized by the presence of large epithelioid melanocytes and were immunoreactive with anti-Trk antibody. The NTRK1-DDR2 fusion occurred in a 55 yo woman with a nodular melanoma. Her primary tumor was umbilical with a metastasis to the colon. NF1 truncation and RAC1 p295 were identified as co-occurring melanoma drivers in this patient. Thus, the presence of an NTRK family fusion in nonspitzoid metastasizing melanomas of adults may provide a therapeutic opportunity for NTRK inhibitors such as larotrectinib in a small subset of patients with metastatic melanoma. 29683819 PubMed Lezcano et al., 2018, Am. J. Surg. Pathol. 2 accepted 6393 2394 3983 Somatic 2018-08-20 21:41:35 UTC https://civicdb.org/links/evidence_items/6393 https://civicdb.org/links/variants/2394 https://civicdb.org/links/genes/3983 false NTRK1 4914 GON4L::NTRK1 Melanoma 1909 Larotrectinib Predictive Supports E Sensitivity/Response In this study we report that nonspitzoid metastasizing melanomas of adults may also harbor NTRK fusions and that NTRK expression can be immunohistochemically detected in these tumors. Of 751 melanomas analyzed by next-generation sequencing, 4 metastatic melanomas were identified with NTRK fusions, 3 involving NTRK1 (TRIM63, DDR2, and GON4L), 1 involving NTRK2 (TRAF2). All tumors were cytologically characterized by the presence of large epithelioid melanocytes and were immunoreactive with anti-Trk antibody. The NTRK1-GON4L fusion occurred in a 36 yo woman with a nodular melanoma. Her primary tumor was on her back with a metastasis to the duodenum. NRAS Q61L was identified as a co-occurring melanoma driver in this patient. Thus, the presence of an NTRK family fusion in nonspitzoid metastasizing melanomas of adults may provide a therapeutic opportunity for NTRK inhibitors such as larotrectinib in a small subset of patients with metastatic melanoma. 29683819 PubMed Lezcano et al., 2018, Am. J. Surg. Pathol. 2 accepted 6394 2395 3983 Somatic 2018-08-20 21:57:25 UTC https://civicdb.org/links/evidence_items/6394 https://civicdb.org/links/variants/2395 https://civicdb.org/links/genes/3983 false NTRK2 4915 ETV6::NTRK2 Acute Myeloid Leukemia 9119 Hematological neoplasm Larotrectinib Predictive Supports C Sensitivity/Response Rearrangements involving the neurotrophic receptor kinase genes (NTRK1, NTRK2, and NTRK3; hereafter referred to as TRK) produce oncogenic fusions in a wide variety of cancers in adults and children. In this manuscript, TRK fusions were screened for in 7,311 patients with a variety of hematologic malignancies. Overall, 8 TRK-fusions were identified including 1 ETV6-NTRK2 fusion in a patient with acute myeloid leukemia (AML) Treatment with TRK-Inhibitor larotrectinib led to a partial Response in an AML patient with ETV6-NTRK2 fusion after sucessful xenograft studies. 29920189 PubMed Taylor et al., 2018, J. Clin. Invest. 4 accepted 6396 2396 3984 Somatic 2020-03-24 22:58:17 UTC https://civicdb.org/links/evidence_items/6396 https://civicdb.org/links/variants/2396 https://civicdb.org/links/genes/3984 false BRAF 673 intron 10 rearrangement Melanoma 1909 Vemurafenib,Dabrafenib Substitutes Predictive Supports B Resistance In a retrospective study of 44 relapsed melanoma patients harboring BRAF V600E or V600K (known BRAF inhibitor sensitizing mutations), MAPK pathway reactivation mechanisms were implicated in acquired resistance to BRAF inhibitor (vemurafenib or dabrafenib) monotherapy. The following MAPK pathway variants were found in progressive tumors with patient matched baseline tumors (some patients donated samples from multiple geographically/temporally distinct progressive tumors): NRAS mutations (G12D, G12R, G13R, Q61K, Q61R, Q61L) in 13/71 (18%) of progressive tumors, KRAS mutations (G12C, G12R, Q61H) in 5/71 (7%) of progressive tumors, mutant BRAF amplification (2-15 fold or 4-75 copies) in 11/57 (19%) of progressive tumors, mutant BRAF alternative splice variants (novel exon boundaries between 1/9, 1/11, 3/9) in 6/48 (13%) of progressive tumor RNA. 24265155 PubMed Shi et al., 2014, Cancer Discov 3 accepted 6400 2226 5 Somatic 2018-07-19 23:10:17 UTC https://civicdb.org/links/evidence_items/6400 https://civicdb.org/links/variants/2226 https://civicdb.org/links/genes/5 false BRAF 673 intron 9 rearrangement Melanoma 1909 Vemurafenib,Dabrafenib Substitutes Predictive Supports B Resistance In a retrospective study of 44 relapsed melanoma patients harboring BRAF V600E or V600K (known BRAF inhibitor sensitizing mutations), MAPK pathway reactivation mechanisms were implicated in acquired resistance to BRAF inhibitor (vemurafenib or dabrafenib) monotherapy. The following MAPK pathway variants were found in progressive tumors with patient matched baseline tumors (some patients donated samples from multiple geographically/temporally distinct progressive tumors): NRAS mutations (G12D, G12R, G13R, Q61K, Q61R, Q61L) in 13/71 (18%) of progressive tumors, KRAS mutations (G12C, G12R, Q61H) in 5/71 (7%) of progressive tumors, mutant BRAF amplification (2-15 fold or 4-75 copies) in 11/57 (19%) of progressive tumors, mutant BRAF alternative splice variants (novel exon boundaries between 1/9, 1/11, 3/9) in 6/48 (13%) of progressive tumor RNA. 24265155 PubMed Shi et al., 2014, Cancer Discov 3 accepted 6401 2225 5 Somatic 2018-07-19 23:10:50 UTC https://civicdb.org/links/evidence_items/6401 https://civicdb.org/links/variants/2225 https://civicdb.org/links/genes/5 false BRAF 673 D594K Colorectal Cancer 9256 Irinotecan Predictive Supports B Resistance The presence of BRAF V600E or D594K was associated with reduced progression-free survival in 5 patients with metastatic colorectal cancer treated with irinotecan-based first line therapy (3.5mo vs. 12.8mo, HR:4.1, 95%CI:1.5-11.3, P=0.006) when compared to 39 patients with wildtype BRAF. 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6402 2398 5 Somatic 2018-07-19 22:55:12 UTC https://civicdb.org/links/evidence_items/6402 https://civicdb.org/links/variants/2398 https://civicdb.org/links/genes/5 false BRAF 673 D594K Colorectal Cancer 9256 Oxaliplatin Predictive Supports B Resistance Of 100 metastatic colorectal cancer patients treated with oxaliplatin-based first-line therapy, the 6 patients with either BRAF V600E or D594K had reduced progression-free survival compared to 94 patients with wildtype BRAF (5.0mo vs. 11.7mo, HR:6.4, 95%CI:2.6-15.6, P<0.0001). 19603024 PubMed Souglakos et al., 2009, Br. J. Cancer 3 accepted 6403 2398 5 Somatic 2018-07-19 23:01:48 UTC https://civicdb.org/links/evidence_items/6403 https://civicdb.org/links/variants/2398 https://civicdb.org/links/genes/5 false FGFR3 2261 V555M Myeloid Neoplasm 0070004 FGFR Inhibitor AZD4547,AZ12908010,PD173074 Substitutes Predictive Supports D Resistance Preclinical study of FGFR Inhibitors AZ12908010, PD173074 and AZD4547 in cancer cell lines. Cell lines with aberrant FGFR signalling were more sensitive to FGFR Inhibition. Sequencing of a myeloma cell line KMS-11R with acquired resistance to FGFR inhibition revealed a FGFR3 V555M Mutation. These cells were cross-resistant to AZD4547 and PD173074. 22869148 PubMed Chell et al., 2013, Oncogene 2 accepted 6408 2400 23 4 1807494 1807494 G A ENST00000440486.8 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. Somatic 2022-07-22 20:25:18 UTC https://civicdb.org/links/evidence_items/6408 https://civicdb.org/links/variants/2400 https://civicdb.org/links/genes/23 false FGFR3 2261 FGFR3::TACC3 Transitional Cell Carcinoma 2671 Infigratinib Predictive Supports C Sensitivity/Response In this one-arm study, 67 patients with metastastic urothelial carcinoma and diverse FGFR3 alterations were treated with pan-FGFR Inhibitor BGJ398. The majority of patients (70.1%) had received two or more prior antineoplastic therapies. An overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization. No clear differences between type of FGFR3 aberration and response could be seen. Four of five patients with FGFR3-TACC3 fusions had response data, with three achieving stable disease and one having a complete response. The authors conclude that BGJ398 appears to have moderate anticancer activity in patients with metastatic urothelial carcinoma, that response rates and disease control rate exceed outcomes with most agents in this setting, and that enriching for patients with activating FGFR3 mutations together with the high specificity of BGJ398 for FGFR3 likely explains this improved response. 29848605 PubMed Pal et al., 2018, Cancer Discov 3 accepted 6409 830 23 4 1795039 1808661 ENST00000340107.4 4 1741429 1746898 ENST00000313288.4 75 GRCh37 Somatic 2021-05-05 05:52:18 UTC https://civicdb.org/links/evidence_items/6409 https://civicdb.org/links/variants/830 https://civicdb.org/links/genes/23 false VHL 7428 R167W (c.499C>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and six patients with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 4 accepted 6416 1747 58 3 10191506 10191506 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6416 https://civicdb.org/links/variants/1747 https://civicdb.org/links/genes/58 false VHL 7428 A122I (c.364_365GC>AT) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This mutation was found in the VHL gene and one patient with pheochromocytoma. 12000816 PubMed Neumann et al., 2002, N. Engl. J. Med. 3 accepted 6417 2028 58 3 10188221 10188222 GC AT ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6417 https://civicdb.org/links/variants/2028 https://civicdb.org/links/genes/58 false IDH1 3417 R132 Intrahepatic Cholangiocarcinoma 4928 Dasatinib Predictive Supports D Sensitivity/Response Through a high-throughput drug screen of a large panel of cancer cell lines, including 17 biliary tract cancers, this work found that IDH mutant (IDHm) ICC cells demonstrate a striking response to the multikinase inhibitor dasatinib, identifying SRC as a critical dasatinib target in IDHm ICC. Dasatinib-treated IDHm xenografts exhibited pronounced apoptosis and tumor regression. 27231123 PubMed Saha et al., 2016, Cancer Discov 4 accepted 6439 58 26 2 209113111 209113113 ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes, IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2019-11-27 20:47:59 UTC https://civicdb.org/links/evidence_items/6439 https://civicdb.org/links/variants/58 https://civicdb.org/links/genes/26 false STK11 6794 Mutation Lung Adenocarcinoma 3910 Atezolizumab,Pembrolizumab,Nivolumab Substitutes Predictive Supports B Resistance In a retrospective analysis in two separate datasets (Stand Up To Cancer 2 Cohort and Checkmate-057), patients with concomitant KRAS and STK11 mutations had significantly worse response rates, PFS and OS compares to KRAS only and KRAS-TP53 Mutant Patients. This work identifies STK11/LKB1 alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD-L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets. 29773717 PubMed Skoulidis et al., 2018, Cancer Discov 4 accepted 6441 715 5534 19 1205740 1223074 ENST00000326873.7 75 GRCh37 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/6441 https://civicdb.org/links/variants/715 https://civicdb.org/links/genes/5534 false SDHB 6390 p.193_196dupSTSC (c.577_588dupAGCACCAGCTGC) Paraganglioma 0050773 Predisposing Supports C Uncertain Significance An in-frame duplication of 12 nucleotides resulting in the insertion of 4 amino acids within exon 6 of the SDHB gene was found in a single female case (a 13-year-old) with confirmed paraganglioma. The patient also exhibited refractory hypertension, sweating and headaches, and elevated norepinephrine concentrations in plasma and urine. The same mutation was in four other family members with no evidence of disease. 20193854 PubMed Musil et al., 2010, Cancer Genet. Cytogenet. 2 accepted 6442 2411 5177 1 17350521 17350522 GCAGCTGGTGCT ENST00000375499.3 75 GRCh37 ClinGen Canonical Allele Identifier: CA658820851 Rare Germline 2019-08-08 16:31:43 UTC https://civicdb.org/links/evidence_items/6442 https://civicdb.org/links/variants/2411 https://civicdb.org/links/genes/5177 false SMAD4 4089 R361C Juvenile Polyposis Syndrome 0050787 Predisposing N/A C N/A The goal of this study was to find out if there was a link between the mutation of SMAD4 and Juvenile polyposis syndrome (JPS). Eight families of JPS were analyzed and there was no evidence of linkage to SMAD4. The eight families and an additional 13 JPS cases were then tested for germline mutations. A single familial JPS patient had the missense mutation R361C in the MH2 domain of SMAD4, with potentially profound effects on protein function. No samples from family members of the patient were available for sequencing. Also, this mutation was not found in 50 control individuals or the other JPS patients in the study. ACMG evidence codes: 'PM1' based on R361 being a hotspot. 9811934 PubMed Houlston et al., 1998, Hum. Mol. Genet. 1 accepted 6446 2851 77 Rare Germline 2021-05-20 16:31:26 UTC https://civicdb.org/links/evidence_items/6446 https://civicdb.org/links/variants/2851 https://civicdb.org/links/genes/77 false H3-3A 3020 K28M Diffuse Midline Glioma, H3 K27M-mutant 0080684 Diagnostic Supports B Positive Wu et al analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs) by whole genome, whole exome, and/or transcriptome sequencing. In addition to ACVR1, they identified 41 recurrent K27M mutations in H3F3A (H3.3, 41/112 = 36.6%), and in 14 HIST1H3B (H3.1, 14/112, 12.5%) in NBS-HGGs and DIPGs. The authors focus on ACVR1 mutations, as H3F3A and HIST1H3A mutations in pediatric gliomas have previously been reported. However, this evidence helps confirm potential diagnostic utility of H3F3A K27M mutations. 24705251 PubMed Wu et al., 2014, Nat. Genet. 3 accepted 6450 2416 2537 1 226064434 226064434 A T ENST00000366813.1 105 GRCh38 K28M is a highly recurrent mutation in this gene in multiple cancer types but particularly well known in brain cancers. In amino acid position 27 of H3F3A there is an arginine (R). The medically relevant Lysine (K) is in position 28. Also UNIPROT records the lysine in position 28. However, K27M is common in the literature so is included as a synonym. Somatic 2020-03-20 18:39:05 UTC https://civicdb.org/links/evidence_items/6450 https://civicdb.org/links/variants/2416 https://civicdb.org/links/genes/2537 false H3-3A 3020 K28M Diffuse Midline Glioma, H3 K27M-mutant 0080684 Diagnostic Supports B Positive Whole genome sequencing (WGS) was performed on the diffuse intrinsic pontine gliomas (DIPGs) and matched germline DNA of 7 pediatric patients. Targeted sequencing was performed on an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). Authors identified K27M mutations in 30/50 (60%) of pediatric DIPGs (including 4/7 WGS samples) and 7/36 (19%) pediatric non-brainstem glioblastomas. The authors comment that the K27M mutation appeared exclusive to pediatric high grade gliomas, with H3F3A p.K27M mutation in one of 9 pediatric anaplastic astrocytomas (Grade III), but no histone H3 mutations found in any other pediatric brain tumors including 7 low-grade brainstem gliomas, 15 low-grade non-brainstem gliomas, 38 medulloblastomas, and 22 ependymomas. H3 K27M was not found in an additional 170 non-central nervous system pediatric tumors. 22286216 PubMed Wu et al., 2012, Nat. Genet. 3 accepted 6453 2416 2537 1 226064434 226064434 A T ENST00000366813.1 105 GRCh38 K28M is a highly recurrent mutation in this gene in multiple cancer types but particularly well known in brain cancers. In amino acid position 27 of H3F3A there is an arginine (R). The medically relevant Lysine (K) is in position 28. Also UNIPROT records the lysine in position 28. However, K27M is common in the literature so is included as a synonym. Somatic 2021-01-29 01:29:49 UTC https://civicdb.org/links/evidence_items/6453 https://civicdb.org/links/variants/2416 https://civicdb.org/links/genes/2537 false H3-3B 3021 K36M Chondroblastoma 2649 Diagnostic Supports B Positive Behjati et al identified K36M mutations in a set of 77 chondroblastomas. Chondroblastoma is a typically a pediatric or early adult cancer. Of the 77, 5 had K36M mutations in H3F3A, 68 had K36M in H3F3B and 4 were WT. Of the 77, 65 of the cases were 25 years old or less. Of those, 3 had K36M in H3F3A and 59 had K36M in H3F3B with 3 being WT (See Supplementary Table 1). Thus, 59/65 (90.7%) cases at age 25 or less had K36M mutations in H3F3B. Behjati et al screened over 268 other bone and cartilage tumor types, and identified only 1 K36M H3F3B mutation (a clear cell chondrosarcoma). The authors conclude discussing the remarkable specificity of these mutations and implications for immediate diagnostic utility. 24162739 PubMed Behjati et al., 2013, Nat. Genet. 4 accepted 6463 2420 2538 Somatic 2019-11-20 00:04:30 UTC https://civicdb.org/links/evidence_items/6463 https://civicdb.org/links/variants/2420 https://civicdb.org/links/genes/2538 false VHL 7428 S65W (c.194C>G) Von Hippel-Lindau Disease 14175 Epididymal cyst,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance A 33 year old Asian male patient presented with advanced bilateral multicentric renal carcinoma. Genetic testing confirmed a de novo missense variant at c.194C>G of the VHL gene. The patient was diagnosed with an epididymal cyst at age 23, bilateral retinal angiomatosis at age 26, and bilateral clear cell renal cell carcinoma at age 33. ACMG codes:PM1; PM5; and PP4. 26622630 PubMed Zhang et al., 2015, Oncol Lett 3 accepted 6468 1787 58 3 10183725 10183725 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6468 https://civicdb.org/links/variants/1787 https://civicdb.org/links/genes/58 false H3-3A 3020 G34W Bone Giant Cell Tumor 4305 Diagnostic Supports B Positive Behjati et al queried 53 samples of giant cell tumors of bone, which is a cancer typically identified in young adults, for histone gene variants. They identified 92% (49/53) with histone 3.3 variants exclusively in H3F3A (which were G34W or, in one case, G34L). Of the 53 samples, 12 were aged 25 or less. The authors queried these mutations in 268 other bone and cartilage cancers and did not identify G34W variant in any, although one G34R was identified in an osteosarcoma. The authors discuss these results as having diagnostic utility. Keyword: pediatric 24162739 PubMed Behjati et al., 2013, Nat. Genet. 4 accepted 6469 2421 2537 Somatic 2019-11-20 00:00:48 UTC https://civicdb.org/links/evidence_items/6469 https://civicdb.org/links/variants/2421 https://civicdb.org/links/genes/2537 false NTRK3 4916 ETV6::NTRK3 Congenital Fibrosarcoma 8418 Larotrectinib Predictive Supports C Sensitivity/Response Nagasubramanian et al reports on a case of refractory infantile fibrosarcoma (IFS) with constitutive activation of the tropomyosin‐related kinase (TRK) signaling pathway from an ETS variant gene 6–neurotrophin 3 receptor gene (ETV6–NTRK3) gene fusion. The patient was diagnosed with IFS at 6 months of age. At 16 months the patient enrolled in a pediatric Phase 1 trial of LOXO‐101 (Larotrectinib, ARRY-470), an experimental, highly selective inhibitor of TRK. The patient experienced a rapid, radiographic response, demonstrating the potential for LOXO‐101 to provide benefit for IFS harboring NTRK gene fusions. 27093299 PubMed Nagasubramanian et al., 2016, Pediatr Blood Cancer 2 accepted 6473 801 3985 12 11802788 12022903 ENST00000396373.4 15 88483984 88418230 ENST00000394480.2 75 GRCh37 Somatic 2020-06-12 15:55:10 UTC https://civicdb.org/links/evidence_items/6473 https://civicdb.org/links/variants/801 https://civicdb.org/links/genes/3985 false NTRK3 4916 ETV6::NTRK3 Thyroid Gland Papillary Carcinoma 3969 Prognostic Supports B Poor Outcome Prasad et al queried the histopathology of 28 Papillary Thyroid Carcinomas (PTCs) from patients ages 6-18 years (20 females, 8 males). None had significant exposure to radiation. 5 / 27 PTCs (18.5%) had NTRK3-ETV6 fusion oncogenes. The authors compare NTRK3-ETV6 (and include 2 other NTRK fusion samples) to PTCs with BRAF(V) (600E) and find they are associated with large size (mean, 2.2 cm vs 1.5 cm, respectively; P = .05), solid and diffuse variants (11 of 13 vs 0 of 13 tumors, respectively; P < .001), and lymphovascular invasion (12 of 13 vs 6 of 13 tumors, respectively; P = .02); The authors conclude that NTRK fusion oncogene PTC presents with more extensive disease and aggressive pathology than BRAF(V) (600E) PTC in the pediatric population. 26784937 PubMed Prasad et al., 2016, Cancer 3 accepted 6474 801 3985 12 11802788 12022903 ENST00000396373.4 15 88483984 88418230 ENST00000394480.2 75 GRCh37 Somatic 2018-08-21 15:27:42 UTC https://civicdb.org/links/evidence_items/6474 https://civicdb.org/links/variants/801 https://civicdb.org/links/genes/3985 false NTRK3 4916 ETV6::NTRK3 Breast Secretory Carcinoma 4922 Larotrectinib Substitutes Predictive Supports C Sensitivity/Response Shukla et al report on a remarkable case study of a 14 year old pediatric patient with refractory secretory breast carcinoma first presenting as a fibroadenoma at 8 yo. Over the next years, she experienced recurrence, multiple rounds of chemotherapy and metastasis -- until her case was presented at a virtual multidisciplinary tumor board organized by the Global Cancer Institute which recommended testing for ETV6-NTRK3 fusion. This fusion was confirmed by RNA-seq, targeted DNA and WGS sequencing as well as immunohistochemistry staining with a TRK antibody. The patient was treated with LOXO-101 (larotrectinib) in a single patient use protocol. Within two months, she experienced near complete resolution of a 10.4 × 8.5 cm fungating chest mass with multiple satellite lesions (See Figure 2). The authors note that TERT promoter mutation and a reciprocal inversion including CDKN2A were also identified, but given what is known about LOXO-101 and ETV6-NTRK3, they infer ETV6-NTRK3 fusion as the primary mitogenic driver in this patient. 29623306 PubMed Shukla et al., 2017, JCO Precis Oncol 3 accepted 6475 801 3985 12 11802788 12022903 ENST00000396373.4 15 88483984 88418230 ENST00000394480.2 75 GRCh37 Somatic 2018-08-21 15:25:38 UTC https://civicdb.org/links/evidence_items/6475 https://civicdb.org/links/variants/801 https://civicdb.org/links/genes/3985 false VHL 7428 E70K (c.208G>A) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient age 20Y at the last follow-up had retinal hemangioblastoma and a germline c.208G>A (p.Glu70Lys) mutation in the VHL gene. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 2 accepted 6503 1956 58 3 10183739 10183739 G A ENST00000256474.2 75 GRCh37 The VHL gene has a low rate of benign missense variation and is known to be definitively associated with VHL disease. The E70K missense mutation, located in the Beta-domain of VHL, is rare in open-source genome databases (0.00001489 allele frequency in ExAC, 4.365e-6 allele frequency in gnomAD) and was identified in several individuals with VHL disease symptoms (see evidence statements). Thus, this variant could be assigned ACMG code 'PP2' - Missense mutation in a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. Although this variant is registered once in ExAC and gnomAD, 'PM2' could be applied (Absent from controls in ESP, 1000 Genomes or ExAC) because VHL manifestations sometimes emerge later in adulthood. Thus, the allele may have been detected in a proband who was not yet affected by symptoms. Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/6503 https://civicdb.org/links/variants/1956 https://civicdb.org/links/genes/58 false VHL 7428 c.−213− ?_463 ?del Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Pancreatic endocrine tumor,Multiple renal cysts,Retinal capillary hemangioma,Spinal hemangioblastoma,Cerebellar hemangioblastoma,Pancreatic cysts Predisposing Supports C Uncertain Significance Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. Four patients were found with this deletion in the VHL gene. Their age at last follow-up was presented as a range, 38Y-48Y and their phenotypes were grouped together: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumour, renal cysts, pancreatic cysts. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6504 2431 58 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6504 https://civicdb.org/links/variants/2431 https://civicdb.org/links/genes/58 false VHL 7428 P81S (c.241C>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma,Multiple renal cysts,Pancreatic endocrine tumor,Cerebellar hemangioblastoma,Retinal capillary hemangioma,Renal cell carcinoma Predisposing N/A C N/A Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. Two patients were found with this missense mutation in the VHL gene. One patient was 34Y and the other was 59Y at last follow-up. Their phenotypes were grouped together: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumour, pheochromocytoma, and renal cysts. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6505 1837 58 3 10183772 10183772 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/6505 https://civicdb.org/links/variants/1837 https://civicdb.org/links/genes/58 false VHL 7428 V87fs (c.259_260insA) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Cerebellar hemangioblastoma,Multiple renal cysts,Spinal hemangioblastoma,Retinal capillary hemangioma,Renal cell carcinoma Predisposing Supports C Uncertain Significance Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this insertion in the VHL gene. The patient was 42Y at the last follow-up and presented with: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, renal cysts and pancreatic cysts. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6506 2432 58 3 10183790 10183791 A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6506 https://civicdb.org/links/variants/2432 https://civicdb.org/links/genes/58 false VHL 7428 G93S (c.277G>A) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Retinal capillary hemangioma,Pheochromocytoma,Spinal hemangioblastoma,Multiple renal cysts Predisposing Supports C Uncertain Significance Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. Two patients were found with this missense mutation in the VHL gene. One patient was 35Y and the other was 60Y at last follow-up. Their phenotypes were grouped together: retinal hemangioblastoma, spinal cord hemangioblastoma, pheochromocytoma, renal cysts, and pancreatic cysts. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6507 1859 58 3 10183808 10183808 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6507 https://civicdb.org/links/variants/1859 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.340+1G>A) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma,Pancreatic cysts,Spinal hemangioblastoma,Multiple renal cysts,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this splice varaint in the VHL gene. The patient was 32Y at the last follow-up and presented with: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, renal cysts and pancreatic cysts. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6509 2114 58 3 10183872 10183872 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6509 https://civicdb.org/links/variants/2114 https://civicdb.org/links/genes/58 false VHL 7428 c.341-59_341-14del Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Multiple renal cysts,Pancreatic cysts,Pheochromocytoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. Two patients were found with this deletion in the VHL gene. One patient was 33Y and the other was 67Y at the last follow-up. The phenotypes of the patients were presented together: retinal hemangioblastoma, cerebellar hemangioblastoma, renal cell carcinoma, pheochromocytoma, renal cysts and pancreatic cysts. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6510 2435 58 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6510 https://civicdb.org/links/variants/2435 https://civicdb.org/links/genes/58 false VHL 7428 R120G (c.358A>G) Von Hippel-Lindau Disease 14175 Spinal hemangioblastoma Predisposing Supports C Uncertain Significance Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this missense varaint in the VHL gene. The patient was 15Y at the last follow-up and presented with: spinal cord hemangioblastoma. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6511 1914 58 3 10188215 10188215 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6511 https://civicdb.org/links/variants/1914 https://civicdb.org/links/genes/58 false VHL 7428 F136S (c.407T>C) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Pancreatic cysts,Multiple renal cysts,Spinal hemangioblastoma,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this missense varaint in the VHL gene. The patient was 41Y at the last follow-up and presented with: cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, renal cysts and pancreatic cysts. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6512 1801 58 3 10188264 10188264 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6512 https://civicdb.org/links/variants/1801 https://civicdb.org/links/genes/58 false VHL 7428 P154= (c.462A>C) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Multiple renal cysts,Pheochromocytoma Predisposing Supports C Uncertain Significance Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this missense varaint in the VHL gene. The patient was 71Y at the last follow-up and presented with: cerebellar hemangioblastoma, pheochromocytoma, and renal cysts. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6513 1962 58 3 10188319 10188319 A C ENST00000256474.2 75 GRCh37 Note that there is a different variant reported at this amino acid position of VHL in ClinVar: NM_000551.3(VHL):c.462A>G (p.Pro154=).(https://www.ncbi.nlm.nih.gov/clinvar/variation/411977/) Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6513 https://civicdb.org/links/variants/1962 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.463+2T>C) Von Hippel-Lindau Disease 14175 Spinal hemangioblastoma,Retinal capillary hemangioma,Renal cell carcinoma,Multiple renal cysts,Cerebellar hemangioblastoma Predisposing Supports C Uncertain Significance Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this splice varaint in the VHL gene. The patient was 31Y at the last follow-up and presented with: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, and renal cysts. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6514 2075 58 3 10188322 10188322 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6514 https://civicdb.org/links/variants/2075 https://civicdb.org/links/genes/58 false VHL 7428 Y156C (c.467A>G) Von Hippel-Lindau Disease 14175 Pheochromocytoma,Multiple renal cysts Predisposing N/A C N/A Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. Seven patients were found with this missense varaint in the VHL gene. The ages of the patients was represented as a range 7-88 (mean 45). Phenotypes were grouped together: phenochromocytoma and renal cysts, although it is unclear if only one of the seven patients had renal cysts. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6516 1946 58 3 10191474 10191474 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6516 https://civicdb.org/links/variants/1946 https://civicdb.org/links/genes/58 false VHL 7428 V166A (c.497T>C) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor,Pheochromocytoma Predisposing Supports C Uncertain Significance Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this missense varaint in the VHL gene. The patient was 27Y at the last follow-up and presented with: pancreatic neuroendocrine tumour and pheochromocytoma. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6518 2437 58 3 10191504 10191504 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6518 https://civicdb.org/links/variants/2437 https://civicdb.org/links/genes/58 false VHL 7428 R167W (c.499C>T) Von Hippel-Lindau Disease 14175 Spinal hemangioblastoma,Pheochromocytoma,Multiple renal cysts,Renal cell carcinoma,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this missense varaint in the VHL gene. The patient was 43Y at the last follow-up and presented with: retinal hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, pheochromocytoma, and renal cysts. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6519 1747 58 3 10191506 10191506 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6519 https://civicdb.org/links/variants/1747 https://civicdb.org/links/genes/58 false VHL 7428 R167Q (c.500G>A) Von Hippel-Lindau Disease 14175 Spinal hemangioblastoma,Pancreatic endocrine tumor,Retinal capillary hemangioma,Cerebellar hemangioblastoma,Renal cell carcinoma,Multiple renal cysts,Pheochromocytoma,Pancreatic cysts Predisposing Supports C Uncertain Significance Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. Eleven patients were found with this missense varaint in the VHL gene. The ages of the patient was represented as a range, 21-65Y. The phenotypes were presented together: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumour, phenchromocytoma, renal cysts, and pancreatic cysts. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6520 1739 58 3 10191507 10191507 G A ENST00000256474.2 75 GRCh37 R167Q is the most common point mutation in hereditary Von Hippel-Lindau (VHL) disease and disrupts the VHL genes binding to elongin C reducing the levels of the VHL-elongin B-elongin C (VBC) E3 ligase complex and inhibiting the ability of VHL to regulate HIF2α. This partial function in turn leads to an increased risk of tumorgenesis. VHL derived clear cell renal cell carcinoma models however have shown the proteasome inhibitors bortezomib and carfilzomib can act to stabilize mutant VHL-R167Q leading to downregulation of HIF2α and suprressed tumorgenesis. Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6520 https://civicdb.org/links/variants/1739 https://civicdb.org/links/genes/58 false VHL 7428 V170D (c.509T>A) Von Hippel-Lindau Disease 14175 Multiple renal cysts,Spinal hemangioblastoma,Renal cell carcinoma,Pancreatic endocrine tumor,Pancreatic cysts,Retinal capillary hemangioma,Cerebellar hemangioblastoma,Pheochromocytoma Predisposing N/A C N/A Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. 15 patients were found with this missense varaint in the VHL gene. The ages of the patients were represented as a range, 16-71Y (mean 45). The phenotypes were presented together: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumour, phenchromocytoma, renal cysts, and pancreatic cysts. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6522 1826 58 3 10191516 10191516 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6522 https://civicdb.org/links/variants/1826 https://civicdb.org/links/genes/58 false VHL 7428 E189fs (c.565del) Von Hippel-Lindau Disease 14175 Multiple renal cysts,Cerebellar hemangioblastoma Predisposing N/A C N/A Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this frameshift mutation in the VHL gene. The patient was 30Y at the last follow-up and presented with: cerebellar hemangioblastoma and renal cysts. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6523 1869 58 3 10191572 10191572 G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/6523 https://civicdb.org/links/variants/1869 https://civicdb.org/links/genes/58 false VHL 7428 Rearrangement Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma,Multiple renal cysts,Pancreatic cysts,Spinal hemangioblastoma,Retinal capillary hemangioma Predisposing N/A C N/A Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with a VHL rearrangment determined by a southern blot. The patient was 25Y at the last follow-up and presented with: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cysts and pancreatic cysts. Family history was not described. 24132471 PubMed Kruizinga et al., 2014, Endocr. Relat. Cancer 3 accepted 6525 2439 58 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6525 https://civicdb.org/links/variants/2439 https://civicdb.org/links/genes/58 false VHL 7428 V66Gfs*89 (c.197_209del) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. 25867206 PubMed Bausch et al., 2016, Head Neck 2 accepted 6546 2447 58 Rare Germline 2022-01-12 17:35:44 UTC https://civicdb.org/links/evidence_items/6546 https://civicdb.org/links/variants/2447 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation (p.Phe76del), which was found in 4 individuals from Germany or France. 25867206 PubMed Bausch et al., 2016, Head Neck 2 accepted 6547 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6547 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false VHL 7428 N78S (c.233A>G) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation (p.Asn78Ser), which was found in 2 individuals, one from Germany and the other from Japan. 25867206 PubMed Bausch et al., 2016, Head Neck 2 accepted 6548 1755 58 3 10183764 10183764 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:44 UTC https://civicdb.org/links/evidence_items/6548 https://civicdb.org/links/variants/1755 https://civicdb.org/links/genes/58 false VHL 7428 R79_S80del (c.236_241delGCAGTC) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Germany. 25867206 PubMed Bausch et al., 2016, Head Neck 2 accepted 6549 2448 58 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6549 https://civicdb.org/links/variants/2448 https://civicdb.org/links/genes/58 false VHL 7428 P86A (c.256C>G) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Italy. 25867206 PubMed Bausch et al., 2016, Head Neck 2 accepted 6550 1759 58 3 10183787 10183787 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6550 https://civicdb.org/links/variants/1759 https://civicdb.org/links/genes/58 false VHL 7428 P86S (c.256C>T) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. 25867206 PubMed Bausch et al., 2016, Head Neck 2 accepted 6551 1902 58 3 10183787 10183787 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6551 https://civicdb.org/links/variants/1902 https://civicdb.org/links/genes/58 false VHL 7428 L89P (c.266T>C) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. 25867206 PubMed Bausch et al., 2016, Head Neck 2 accepted 6552 1793 58 3 10183797 10183797 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:44 UTC https://civicdb.org/links/evidence_items/6552 https://civicdb.org/links/variants/1793 https://civicdb.org/links/genes/58 false VHL 7428 D92G (c.275A>G) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. 25867206 PubMed Bausch et al., 2016, Head Neck 2 accepted 6553 2449 58 3 10183806 10183806 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6553 https://civicdb.org/links/variants/2449 https://civicdb.org/links/genes/58 false VHL 7428 Y98H (c.292T>C) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Germany. 25867206 PubMed Bausch et al., 2016, Head Neck 2 accepted 6554 1741 58 3 10183823 10183823 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6554 https://civicdb.org/links/variants/1741 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. An in-frame deletion (TCT) at nucleotide 227 was present in 1 individual of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6557 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:42 UTC https://civicdb.org/links/evidence_items/6557 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false NTRK1 4914 Fusion Solid Tumor Larotrectinib Predictive Supports A Sensitivity/Response This was a Phase 1/2 study of 55 patients from 4 months to 76 years old with TRK-fusion positive tumors given NTRK inhibitor Larotrectinib. Patients had 17 unique NTRK fusion types. Patient overall response rate was 75% according to independent review and 80% according to investigator assessment. Authors state that Larotrectinib had durable anti tumor activity regardless of age or tumor type. 17/23 patients with NTRK1-fusion showed maximum percent change in tumor size between -30% and -100%. 29466156 PubMed Drilon et al., 2018, N. Engl. J. Med. NCT02576431,NCT02122913,NCT02637687 4 accepted 6567 419 3983 1 156844175 156851434 ENST00000524377.1 75 GRCh37 Somatic 2022-07-21 22:49:09 UTC https://civicdb.org/links/evidence_items/6567 https://civicdb.org/links/variants/419 https://civicdb.org/links/genes/3983 false NTRK3 4916 Fusion Solid Tumor Larotrectinib Predictive Supports A Sensitivity/Response This was a Phase 1/2 study of 55 patients from 4 months to 76 years old with TRK-fusion positive tumors given NTRK inhibitor Larotrectinib. Patients had 17 unique NTRK fusion types. Patient overall response rate was 75% according to independent review and 80% according to investigator assessment. Authors state that Larotrectinib had durable anti tumor activity regardless of age or tumor type. 26/27 patients with NTRK3-fusion showed maximum percent change in tumor size between -30% and -100%. 29466156 PubMed Drilon et al., 2018, N. Engl. J. Med. NCT02576431,NCT02122913,NCT02637687 4 accepted 6568 1277 3985 Somatic 2021-08-04 14:06:30 UTC https://civicdb.org/links/evidence_items/6568 https://civicdb.org/links/variants/1277 https://civicdb.org/links/genes/3985 false NTRK1 4914 Fusion Sarcoma 1115 Larotrectinib Predictive Supports B Sensitivity/Response In a Phase 1/2 study involving 15 pediatric patients with infantile fibrosarcoma or soft tissue sarcoma, 8 patients had NTRK1 fusions. The patients were administered Larotrectinib, and 7 out of 8 patients showed objective response, with 2 complete and 5 partial responses. The patient without objective response had soft tissue sarcoma, and showed stable disease. 29606586 PubMed Laetsch et al., 2018, Lancet Oncol. NCT02637687 4 accepted 6569 419 3983 1 156844175 156851434 ENST00000524377.1 75 GRCh37 Somatic 2020-12-03 03:54:04 UTC https://civicdb.org/links/evidence_items/6569 https://civicdb.org/links/variants/419 https://civicdb.org/links/genes/3983 false VHL 7428 F136S (c.407T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 2 individuals of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6573 1801 58 3 10188264 10188264 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6573 https://civicdb.org/links/variants/1801 https://civicdb.org/links/genes/58 false VHL 7428 P138T (c.412C>A) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 5 individuals of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 2 accepted 6574 1928 58 3 10188269 10188269 C A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6574 https://civicdb.org/links/variants/1928 https://civicdb.org/links/genes/58 false VHL 7428 L153P (c.458T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 1 individual of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6576 1923 58 3 10188315 10188315 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6576 https://civicdb.org/links/variants/1923 https://civicdb.org/links/genes/58 false VHL 7428 P154= (c.462A>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 2 individuals of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6577 1962 58 3 10188319 10188319 A C ENST00000256474.2 75 GRCh37 Note that there is a different variant reported at this amino acid position of VHL in ClinVar: NM_000551.3(VHL):c.462A>G (p.Pro154=).(https://www.ncbi.nlm.nih.gov/clinvar/variation/411977/) Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6577 https://civicdb.org/links/variants/1962 https://civicdb.org/links/genes/58 false VHL 7428 V155G (c.464T>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 2 individuals of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6579 1934 58 3 10191471 10191471 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6579 https://civicdb.org/links/variants/1934 https://civicdb.org/links/genes/58 false VHL 7428 T157I (c.470C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 2 individuals of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6581 1745 58 3 10191477 10191477 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:35 UTC https://civicdb.org/links/evidence_items/6581 https://civicdb.org/links/variants/1745 https://civicdb.org/links/genes/58 false VHL 7428 R161G (c.481C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 2 individuals of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6582 1915 58 3 10191488 10191488 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6582 https://civicdb.org/links/variants/1915 https://civicdb.org/links/genes/58 false VHL 7428 R161* (c.481C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 2 individuals of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6583 1804 58 3 10191488 10191488 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:38 UTC https://civicdb.org/links/evidence_items/6583 https://civicdb.org/links/variants/1804 https://civicdb.org/links/genes/58 false VHL 7428 C162F (c.485G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 1 individual of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6584 1773 58 3 10191492 10191492 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:37 UTC https://civicdb.org/links/evidence_items/6584 https://civicdb.org/links/variants/1773 https://civicdb.org/links/genes/58 false VHL 7428 C162W (c.486C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 1 individual of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6585 1774 58 3 10191493 10191493 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6585 https://civicdb.org/links/variants/1774 https://civicdb.org/links/genes/58 false VHL 7428 R167Q (c.500G>A) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 9 individuals of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 2 accepted 6587 1739 58 3 10191507 10191507 G A ENST00000256474.2 75 GRCh37 R167Q is the most common point mutation in hereditary Von Hippel-Lindau (VHL) disease and disrupts the VHL genes binding to elongin C reducing the levels of the VHL-elongin B-elongin C (VBC) E3 ligase complex and inhibiting the ability of VHL to regulate HIF2α. This partial function in turn leads to an increased risk of tumorgenesis. VHL derived clear cell renal cell carcinoma models however have shown the proteasome inhibitors bortezomib and carfilzomib can act to stabilize mutant VHL-R167Q leading to downregulation of HIF2α and suprressed tumorgenesis. Rare Germline 2022-01-12 17:35:36 UTC https://civicdb.org/links/evidence_items/6587 https://civicdb.org/links/variants/1739 https://civicdb.org/links/genes/58 false VHL 7428 R167L (c.500G>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. The c.500 G>T mutation was present in 3 individuas of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6588 1916 58 3 10191507 10191507 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6588 https://civicdb.org/links/variants/1916 https://civicdb.org/links/genes/58 false VHL 7428 L169P (c.506T>C) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. The c.506 T>C mutation was present in 1 individual of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6589 1887 58 3 10191513 10191513 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6589 https://civicdb.org/links/variants/1887 https://civicdb.org/links/genes/58 false VHL 7428 V170G (c.509T>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations presented. The c.509 T>G mutation was present in 3 individuals of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6590 1935 58 3 10191516 10191516 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6590 https://civicdb.org/links/variants/1935 https://civicdb.org/links/genes/58 false VHL 7428 S183* (c.548C>A) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. The c.548 C>A mutation was present in 3 individuals of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6592 1784 58 3 10191555 10191555 C A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6592 https://civicdb.org/links/variants/1784 https://civicdb.org/links/genes/58 false VHL 7428 L184R (c.551T>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. The c.551 T>G mutation was present in 1 individual of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6593 1808 58 3 10191558 10191558 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6593 https://civicdb.org/links/variants/1808 https://civicdb.org/links/genes/58 false VHL 7428 L188R (c.563T>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. The c.563 T>G mutation was present in 3 individuals of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6595 1924 58 3 10191570 10191570 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6595 https://civicdb.org/links/variants/1924 https://civicdb.org/links/genes/58 false VHL 7428 Q195* (c.583C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. The c.583 C>T mutation was present in 2 individuals of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6596 1810 58 3 10191590 10191590 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6596 https://civicdb.org/links/variants/1810 https://civicdb.org/links/genes/58 false VHL 7428 Deletion Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. A complete deletion was present in 13 individuals of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 2 accepted 6597 2932 58 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6597 https://civicdb.org/links/variants/2932 https://civicdb.org/links/genes/58 false VHL 7428 Rearrangement Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. A rearrangement mutation was present in 4 individuals of the 122 total number of variants captured in this population. 26763786 PubMed Feletti et al., 2016, Neuro-oncology 1 accepted 6599 2439 58 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6599 https://civicdb.org/links/variants/2439 https://civicdb.org/links/genes/58 false VHL 7428 S111C (c.331A>T) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing N/A C N/A Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Statistics of the VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6600 2045 58 3 10183862 10183862 A T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/6600 https://civicdb.org/links/variants/2045 https://civicdb.org/links/genes/58 false VHL 7428 S111N (c.332G>A) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing N/A C N/A Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Statistics of the VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 2 individuals from the UK. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6601 1763 58 3 10183863 10183863 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6601 https://civicdb.org/links/variants/1763 https://civicdb.org/links/genes/58 false VHL 7428 R113* (c.337C>T) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6602 1796 58 3 10183868 10183868 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6602 https://civicdb.org/links/variants/1796 https://civicdb.org/links/genes/58 false VHL 7428 G114Vfs*45 (c.339delA) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing N/A C N/A Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Statistics of the VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Germany. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6603 2455 58 Rare Germline 2022-01-12 17:35:44 UTC https://civicdb.org/links/evidence_items/6603 https://civicdb.org/links/variants/2455 https://civicdb.org/links/genes/58 false VHL 7428 H115Q (c.345C>G) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing N/A C N/A Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. The statistics of the VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6604 1957 58 3 10188202 10188202 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:44 UTC https://civicdb.org/links/evidence_items/6604 https://civicdb.org/links/variants/1957 https://civicdb.org/links/genes/58 false VHL 7428 R120G (c.358A>G) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Italy. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6605 1914 58 3 10188215 10188215 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6605 https://civicdb.org/links/variants/1914 https://civicdb.org/links/genes/58 false VHL 7428 N131T (c.392A>C) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Germany. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6606 2580 58 3 10188249 10188249 A C ENST00000256474.2 75 GRCh37 A similar but distinct variant the same position has been reported in ClinVar (c.392A>G (p.Asn131Ser); https://www.ncbi.nlm.nih.gov/clinvar/variation/496062/). It involves the same base position but a different nucleotide change leading to a different amino acid change. Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6606 https://civicdb.org/links/variants/2580 https://civicdb.org/links/genes/58 false VHL 7428 T133fs (c.397del) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6607 1843 58 3 10188252 10188252 A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6607 https://civicdb.org/links/variants/1843 https://civicdb.org/links/genes/58 false VHL 7428 L135* (c.404T>A) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs in the VHL registries of the participating centers in Europe were identified and included in the International Endolymphatic Sac Tumor Registry. The statistics of this registry is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. Only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Spain. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6608 1769 58 3 10188261 10188261 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6608 https://civicdb.org/links/variants/1769 https://civicdb.org/links/genes/58 false VHL 7428 P154L (c.461C>T) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 2 individuals from Germany. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6609 1782 58 3 10188318 10188318 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6609 https://civicdb.org/links/variants/1782 https://civicdb.org/links/genes/58 false VHL 7428 Splice Site (c.463+2T>C) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 2 individuals from Germany. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6610 2075 58 3 10188322 10188322 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6610 https://civicdb.org/links/variants/2075 https://civicdb.org/links/genes/58 false VHL 7428 T157I (c.470C>T) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs in the VHL registries of the participating centers in Europe were identified and included in the International Endolymphatic Sac Tumor Registry. The statistics of this registry is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. Only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Italy. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6612 1745 58 3 10191477 10191477 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6612 https://civicdb.org/links/variants/1745 https://civicdb.org/links/genes/58 false VHL 7428 L158P (c.473T>C) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs in the VHL registries of the participating centers in Europe were identified and included in the International Endolymphatic Sac Tumor Registry. The statistics of this registry is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. Only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6613 1738 58 3 10191480 10191480 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:44 UTC https://civicdb.org/links/evidence_items/6613 https://civicdb.org/links/variants/1738 https://civicdb.org/links/genes/58 false VHL 7428 R161* (c.481C>T) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 3 individuals from France or Argentina. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6614 1804 58 3 10191488 10191488 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6614 https://civicdb.org/links/variants/1804 https://civicdb.org/links/genes/58 false VHL 7428 C162Y (c.485G>A) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6615 1824 58 3 10191492 10191492 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6615 https://civicdb.org/links/variants/1824 https://civicdb.org/links/genes/58 false VHL 7428 C162W (c.486C>G) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation (p.Cys162Trp), which was found in 2 individuals from France. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6616 1774 58 3 10191493 10191493 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6616 https://civicdb.org/links/variants/1774 https://civicdb.org/links/genes/58 false VHL 7428 Q164L (c.491A>T) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Germany. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6617 2079 58 3 10191498 10191498 A T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6617 https://civicdb.org/links/variants/2079 https://civicdb.org/links/genes/58 false VHL 7428 R167W (c.499C>T) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 3 individuals each from France, UK, and Germany. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6618 1747 58 3 10191506 10191506 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6618 https://civicdb.org/links/variants/1747 https://civicdb.org/links/genes/58 false VHL 7428 R167Q (c.500G>A) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 4 individuals from France or Italy. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6619 1739 58 3 10191507 10191507 G A ENST00000256474.2 75 GRCh37 R167Q is the most common point mutation in hereditary Von Hippel-Lindau (VHL) disease and disrupts the VHL genes binding to elongin C reducing the levels of the VHL-elongin B-elongin C (VBC) E3 ligase complex and inhibiting the ability of VHL to regulate HIF2α. This partial function in turn leads to an increased risk of tumorgenesis. VHL derived clear cell renal cell carcinoma models however have shown the proteasome inhibitors bortezomib and carfilzomib can act to stabilize mutant VHL-R167Q leading to downregulation of HIF2α and suprressed tumorgenesis. Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6619 https://civicdb.org/links/variants/1739 https://civicdb.org/links/genes/58 false VHL 7428 R167P (c.500G>C) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6620 2458 58 3 10191507 10191507 G C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:44 UTC https://civicdb.org/links/evidence_items/6620 https://civicdb.org/links/variants/2458 https://civicdb.org/links/genes/58 false VHL 7428 Y175* (c.525C>A) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. 25867206 PubMed Bausch et al., 2016, Head Neck 2 accepted 6621 1932 58 3 10191532 10191532 C A ENST00000256474.2 75 GRCh37 Note that there is a different variant reported at this amino acid position of VHL in ClinVar, which produces the same protein change. NM_000551.3(VHL):c.525C>G (p.Tyr175Ter), https://www-ncbi-nlm-nih-gov/clinvar/variation/182974/ Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6621 https://civicdb.org/links/variants/1932 https://civicdb.org/links/genes/58 false VHL 7428 L178P (c.532C>T) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing N/A C N/A Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Statistics of the VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6622 2459 58 Rare Germline 2020-12-18 19:39:29 UTC https://civicdb.org/links/evidence_items/6622 https://civicdb.org/links/variants/2459 https://civicdb.org/links/genes/58 true VHL 7428 Q195* (c.583C>T) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 2 individuals from France. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6623 1810 58 3 10191590 10191590 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6623 https://civicdb.org/links/variants/1810 https://civicdb.org/links/genes/58 false VHL 7428 Exon 1 Deletion Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from the Netherlands. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6624 844 58 3 10183532 10183871 ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6624 https://civicdb.org/links/variants/844 https://civicdb.org/links/genes/58 false VHL 7428 Exon 2 Deletion Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6625 1938 58 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6625 https://civicdb.org/links/variants/1938 https://civicdb.org/links/genes/58 false VHL 7428 Exon 3 Deletion Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing N/A C N/A Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Statistics of the VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 4 individuals from France, Germany, or Italy. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6626 1939 58 3 10191471 10193904 ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:44 UTC https://civicdb.org/links/evidence_items/6626 https://civicdb.org/links/variants/1939 https://civicdb.org/links/genes/58 false VHL 7428 EXON 2-3 DELETION Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Germany. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6627 1940 58 Rare Germline 2022-01-12 17:35:44 UTC https://civicdb.org/links/evidence_items/6627 https://civicdb.org/links/variants/1940 https://civicdb.org/links/genes/58 false VHL 7428 Exon 1-3 Deletion Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing N/A C N/A Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Statistics of the VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 6 individuals from France, Germany, the Netherlands, or Spain. 25867206 PubMed Bausch et al., 2016, Head Neck 3 accepted 6628 843 58 3 10183532 10191649 ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:44 UTC https://civicdb.org/links/evidence_items/6628 https://civicdb.org/links/variants/843 https://civicdb.org/links/genes/58 false VHL 7428 S65L (c.194C>T) Von Hippel-Lindau Disease 14175 Cerebellar hemangioblastoma Predisposing N/A C N/A Thirty-two surgically resected HB specimens from 28 patients treated at the University of Tokyo Hospital between 1995 and 2012 were analyzed retrospectively. Of the 32 specimens, 11 were VHL-related HBs from 7 patients, and 21 were sporadic HBs from 21 patients. One of the 7 VHL patients was a female patient with a c.194C>T (p.Ser65Leu) mutation in the VHL gene. She developed a CNS hemangioblastoma in the cerebellum at 19Y. It is unclear whether she had germline testing. However, the patient met clinical criteria for VHL (Losner et al., 2003). Interestingly, the HB from this patient was noted to have LOH of chromosome 3p. No other phenotypic information was available. 28379443 PubMed Takayanagi et al., 2017, Neuro-oncology 2 accepted 6644 1788 58 3 10183725 10183725 C T ENST00000256474.2 75 GRCh37 Unknown 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/6644 https://civicdb.org/links/variants/1788 https://civicdb.org/links/genes/58 false PRKCB 5579 D427N Adult T-cell Leukemia/lymphoma 0050523 Diagnostic Supports D Positive PRKCB was mutated in 33% of ATLL cases. 93% of these mutations were within the catalytic domain at Asp427. This gene has not been reported to be significantly mutated in any other cancers. Indeed this is the first known example in any cancer that appears to involve activation by the PKC gene family. Nearly all occurrences of this mutation in COSMIC correspond to ATLL. 26437031 PubMed Kataoka et al., 2015, Nat. Genet. 3 accepted 6654 2468 4517 Somatic 2018-08-25 01:59:41 UTC https://civicdb.org/links/evidence_items/6654 https://civicdb.org/links/variants/2468 https://civicdb.org/links/genes/4517 false VHL 7428 S65W (c.194C>G) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance The national cohort study describes how the rate of new tumor development varies through the lifetimes of VHL patients and how it is influenced by age and genotype. This study included 52 VHL mutation carriers who were retrospectively followed for a total of 799 person-years. From birth to current age, 581 manifestations were diagnosed during 2,583 examinations in the study subjects. Genetic testing confirmed a germline variant at c.194C>G of the VHL gene in two patients. Detailed phenotype, demographic, and family history information was not available for the 2 patients. 25834951 PubMed Binderup et al., 2016, Genet. Med. 3 accepted 6661 1787 58 3 10183725 10183725 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:39 UTC https://civicdb.org/links/evidence_items/6661 https://civicdb.org/links/variants/1787 https://civicdb.org/links/genes/58 false VHL 7428 S65L (c.194C>T) Von Hippel-Lindau Disease 14175 Predisposing Supports C Uncertain Significance This retrospective study of 52 Danish patients with genetically confirmed VHL mutations analyzed the results of each individual's VHL-related examinations and manifestations diagnosed up to the time of study inclusion. All patients were enrolled in the Danish vHL surveillance program. Data was collected through detailed interviews and subsequent evaluation of each subject’s clinical, radiographic, and histological records. Genetic testing confirmed a germline VHL mutation at c.194C>T in four patients. Associated phenotypes, demographic, and family history is unknown. 25834951 PubMed Binderup et al., 2016, Genet. Med. 2 accepted 6662 1788 58 3 10183725 10183725 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6662 https://civicdb.org/links/variants/1788 https://civicdb.org/links/genes/58 false VHL 7428 I151T (c.452T>C) Von Hippel-Lindau Disease 14175 Renal cyst,Epididymal cyst,Hemangioblastoma,Renal cell carcinoma,Pancreatic cysts Predisposing N/A C N/A A retrospective medical chart review was performed on patients referred to the genetics service. Two unrelated probands were genetically confirmed with a non-familial mutation at c.452T>C of the VHL gene. The first, a 30 year old male, presented with central nervous system hemangioblastoma, renal cell carcinoma, and a pancreatic cyst. The second, a 37 year old male, presented with central nervous system hemangioblastoma, renal cyst, pancreatic cyst, and epididymal cyst. Family histories are both negative. 28469506 PubMed Sriphrapradang et al., 2017, Clin Med Insights Endocrinol Diabetes 3 accepted 6696 1871 58 3 10188309 10188309 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/6696 https://civicdb.org/links/variants/1871 https://civicdb.org/links/genes/58 false VHL 7428 S65L (c.194C>T) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Renal cell carcinoma,Hemangioblastoma Predisposing Supports C Uncertain Significance A retrospective study reviewed cases of 23 patients with advanced and complicated VHL eye disease who underwent pars plana vitrectomy in the years 1999 to 2012. These inidiviuals were part of 223 VHL patients consulted at the International Hereditary Cancer Center and Polish VHL Registry. 22/23 patients received genetic molecular testing to identify germline mutations in the VHL gene. 24 eyes from 23 patients were studied. Patient #6 (35 years old) had the p.Ser65Leu (c.194C>T) mutation and a previous history of HbCNS and RCC. Patient # 16 (44 year old) also had this mutation, and had a previous history of HbCNS and RCC. Patient # 17 (20 year old) had this mutation, and had a previous history of HbCNS. Since patients were listed 'by eye' it is impossible to determine whether the three patients listed above actually represent 2 or 3 unique patients. 26308528 PubMed Krzystolik et al., 2016, Retina (Philadelphia, Pa.) 3 accepted 6710 1788 58 3 10183725 10183725 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6710 https://civicdb.org/links/variants/1788 https://civicdb.org/links/genes/58 false VHL 7428 *214G (c.640T>G) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing N/A C N/A A 49 year old female (Patient 3) from Europe presented with a unilateral adrenal pheochromocytoma. Genetic testing confirmed germline missense mutation found at c.640T>G in the VHL gene (reported as T852G in the paper). Family history and patient demographic is unknown. This patient underwent surgical resection. 12673678 PubMed Dannenberg et al., 2003, Int. J. Cancer 2 accepted 6723 2488 58 3 10191647 10191647 T G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/6723 https://civicdb.org/links/variants/2488 https://civicdb.org/links/genes/58 false VHL 7428 *214C (c.641_642insC) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing N/A C N/A A female of unknown age (Patient 8) from Europe presented with a unilateral adrenal pheochromocytoma. Genetic testing confirmed a germline frameshift mutation found at c.641insC in the VHL gene. Family history and patient demographic is unknown. This patient underwent surgical resection. 12673678 PubMed Dannenberg et al., 2003, Int. J. Cancer 2 accepted 6724 2489 58 3 10191648 10191649 C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/6724 https://civicdb.org/links/variants/2489 https://civicdb.org/links/genes/58 false VHL 7428 S65L (c.194C>T) Von Hippel-Lindau Disease 14175 Clear cell renal cell carcinoma Predisposing Supports C Uncertain Significance 240 ccRCC specimens were genetically analyzed. 3 specimens (ccRCC-58, ccRCC-154, ccRCC-238) from 3 different patients were confirmed to carry the p.Ser65Leu; c.194C>T mutation. The mutation was found to be germline in one male patient, age 27, who had contralateral kidney cancer. Family history and patient demographics are unknown. This patient was the source of ccRCC-238. This evidence supports AMCG code 'PM2' - Absent from controls (i.e. gnomAD). 23797736 PubMed Sato et al., 2013, Nat. Genet. 2 accepted 6728 1788 58 3 10183725 10183725 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6728 https://civicdb.org/links/variants/1788 https://civicdb.org/links/genes/58 false VHL 7428 E70K (c.208G>A) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Hemangioblastoma Predisposing Supports C Uncertain Significance Thirteen unrelated Korean subjects and their family members were tested for VHL mutations with direct sequencing and multiplex ligation dependent probe amplification. Clinical manifestations and family histories were recorded for each subject. Genetic testing confirmed a c.208G>A missense mutation in members of family #2,3,4. Family #2; A 25-year-old male Korean proband presented with a central nervous system hemangioblastoma. This patient had no family history of VHL. Family #3; A 46-year-old female Korean proband presented with bilateral retinal hemangioblastomas. The patient's 19-year-old son was found to share her mutation, but did not exhibit and VHL symptoms at the time of the study. The proband had a sister with retinal hemangioblastoma, but she did not receive genetic testing. Family #4; A 20-year-old female Korean proband presented with bilateral retinal hemangioblastomas. The patient has a mother who had received treatment for retinal hemangioblastoma, but refused to undergo genetic analysis. No other VHL symptoms were observed in the proband or her mother. Suggested ACMG Code: 'PP4' because the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. 27439424 PubMed Lee et al., 2016, BMC Med. Genet. 3 accepted 6742 1956 58 3 10183739 10183739 G A ENST00000256474.2 75 GRCh37 The VHL gene has a low rate of benign missense variation and is known to be definitively associated with VHL disease. The E70K missense mutation, located in the Beta-domain of VHL, is rare in open-source genome databases (0.00001489 allele frequency in ExAC, 4.365e-6 allele frequency in gnomAD) and was identified in several individuals with VHL disease symptoms (see evidence statements). Thus, this variant could be assigned ACMG code 'PP2' - Missense mutation in a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. Although this variant is registered once in ExAC and gnomAD, 'PM2' could be applied (Absent from controls in ESP, 1000 Genomes or ExAC) because VHL manifestations sometimes emerge later in adulthood. Thus, the allele may have been detected in a proband who was not yet affected by symptoms. Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6742 https://civicdb.org/links/variants/1956 https://civicdb.org/links/genes/58 false VHL 7428 S65W (c.194C>G) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Pancreatic cysts,Hemangioblastoma Predisposing Supports C Uncertain Significance A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. The c.194C>G (p.Ser65Trp) variant was found in a 48Y patient with RCC and multiple pancreatic cysts or tumours, and his son who had a CNS hemangioblastoma at 22Y. The patient's mother and brother had CNS hemangioblastomas at age 61 and 33 respectively, although genotypic confirmation was not available. This variant was also found in an unrelated woman with CNS hemangioblastoma diagnosed at age 34Y, and renal cell carcinoma and multiple pancreatic cysts or tumours diagnosed at age 37Y. ACMG codes: PM2 -absent from controls in GnomAD; PP4 - patient's phenotype or FHx is highly specific for a disease with a single genetic etiology. 28388566 PubMed Peng et al., 2017, Oncotarget 3 accepted 6789 1787 58 3 10183725 10183725 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6789 https://civicdb.org/links/variants/1787 https://civicdb.org/links/genes/58 false VHL 7428 S65L (c.194C>T) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Hemangioblastoma,Pheochromocytoma,Pancreatic cysts,Retinal capillary hemangioma Predisposing Supports C Uncertain Significance A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. A mutation c.194C>T (p.Ser65Leu) was found in 3 families (#4, #5, #6) with 11 genetically confirmed patients and 13 affected members in total. From family #4: one male patient presented with renal cell carcinoma at 33Y and pancreatic cysts or tumors at 33Y (mutation confirmed). From family #5: male proband with CNS haemangioblastoma at 21Y and multpile pancreatic cysts or tumours at 30Y (mutation confirmed), grandfather with CNS haemangioblastoma at 30Y (mutation status unknown), father with CNS haemangioblastoma at 36Y (mutation status unknown), and uncle with CNS haemangioblastoma at 33Y (mutation status unknown). From family #6: female proband with RCC at 36Y who then developed PCT at 37Y (mutation confirmed); daughter confirmed with the mutation but no manifestations and age unknown; mother with CNS hemangioblastoma diagnosed at 59Y (mutation confirmed); uncle 1 with CNS hemangioblastoma at 45Y, renal cell carcinoma at 59Y, and multiple pancreatic cysts or tumours at 65Y (mutation confirmed); son of uncle 1 with CNS hemangioblastoma at 22Y (mutation status unknown); Uncle 2 with CNS hemangioblastoma at 51Y, renal cell carcinoma at 51Y, and pancreatic cysts or tumours at 51Y (mutation status unknown); 1st son of uncle 2 with CNS hemangioblastoma at 22Y, renal cell carcinoma at 30Y, and pancreatic cysts or tumours at 31Y (mutation confirmed); 2nd son of uncle 2 with mutation confirmed but no manifestations and age unknown; granddaughter of uncle 2 with mutation confirmed but no manifestations and age unknown; Uncle 3 with multiple pancreatic cysts or tumours at 49Y (mutation confirmed); Aunt with CNS hemangioblastoma at 53Y and retinal angioma at 53Y (mutation confirmed). This evidence supports the following ACMG Codes: PP4 - the patient's phenotype and family history are highly specific for a disease with single genetic etiology, PP1- Co-segregation with disease in multiple affected family members (.e. family #6), PM2 - Absent from controls (i.e. gnomAD) 28388566 PubMed Peng et al., 2017, Oncotarget 3 accepted 6791 1788 58 3 10183725 10183725 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6791 https://civicdb.org/links/variants/1788 https://civicdb.org/links/genes/58 false VHL 7428 E70K (c.208G>A) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Hemangioblastoma Predisposing Supports C Uncertain Significance Medical records of 26 patients with germline mutations of the VHL gene who had been diagnosed with VHL disease in Severance Hospital (Seoul, Republic of Korea) and Samsung Medical Center (Seoul, Republic of Korea) between 2003 and 2012 were reviewed. 9 unrelated patients diagnosed with Type 1 VHL disease shared the same VHL germline missense mutation (c.208G>A; p.Glu70Lys). The patients' phenotypes were as follows: 55 year old male with multiple CNS hemangioblastomas (patient 3), 55Y male with multiple CNS hemangioblastomas (Patient 4), 43Y male with multiple CNS hemangioblastomas (other phenotypic data not available, Patient 5), 11Y male with bilateral retinal hemangioblastoma (patient 6), 48Y female with CNS hemangioblastoma (Patient 7) , 64Y female with CNS hemangioblastoma (patient 8), 16Y F with retinal hemangioblastoma (Patient 9), 41Y female with CNS hemangioblastoma (patient 10). One patient has concurrent missense and splicing mutations (208G>A and IVS1+5G>C). 52 year old male with retinal hemangioblstoma. ACMG codes as follows: PM1 Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. 25078357 PubMed Hwang et al., 2014, J. Hum. Genet. 3 accepted 6860 1956 58 3 10183739 10183739 G A ENST00000256474.2 75 GRCh37 The VHL gene has a low rate of benign missense variation and is known to be definitively associated with VHL disease. The E70K missense mutation, located in the Beta-domain of VHL, is rare in open-source genome databases (0.00001489 allele frequency in ExAC, 4.365e-6 allele frequency in gnomAD) and was identified in several individuals with VHL disease symptoms (see evidence statements). Thus, this variant could be assigned ACMG code 'PP2' - Missense mutation in a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. Although this variant is registered once in ExAC and gnomAD, 'PM2' could be applied (Absent from controls in ESP, 1000 Genomes or ExAC) because VHL manifestations sometimes emerge later in adulthood. Thus, the allele may have been detected in a proband who was not yet affected by symptoms. Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6860 https://civicdb.org/links/variants/1956 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.224_226delTCT) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Hemangioblastoma Predisposing Supports C Uncertain Significance Medical records of 26 patients diagnosed with VHL disease in two Korean hospitals between 2003-2012 and harboring germline VHL mutations were retrospectively reviewed. One male patient diagnosed with Type 1 VHL disease at 23Y (Patient 14) presented with renal cell carcinoma, multiple CNS hemangioblastomas and other manifestations. He had a germline inframe deletion in the VHL gene (c.227delTCT) and a negative family history of VHL disease. 25078357 PubMed Hwang et al., 2014, J. Hum. Genet. 3 accepted 6862 2088 58 3 10183755 10183757 TCT ENST00000256474.2 75 GRCh37 Note that this variant occurs within a short TCT repeat and there are several variant notations that resolve to the same sequence when they are shifted or justified. Each results in the same in-frame single amino acid deletion (Phe76del aka F76del). Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/6862 https://civicdb.org/links/variants/2088 https://civicdb.org/links/genes/58 false VHL 7428 S65L (c.194C>T) Renal Carcinoma 4451 Clear cell renal cell carcinoma,Sporadic Oncogenic N/A C N/A Tumors from 110 patients with sporadic renal carcinoma were analyzed for VHL mutations and loss of heterozygosity. 56 of the 98 samples from sporadic, clear cell renal carcinoma patients were identified with VHL somatic mutations; Loss of heterozygosity was observed in 97% of those samples. This missense mutation was found in one of the clear cell renal carcinoma cell lines (sample UOK164). No phenotype described. 7915601 PubMed Gnarra et al., 1994, Nat. Genet. 1 accepted 6890 1788 58 3 10183725 10183725 C T ENST00000256474.2 75 GRCh37 Somatic 2021-06-04 18:46:56 UTC https://civicdb.org/links/evidence_items/6890 https://civicdb.org/links/variants/1788 https://civicdb.org/links/genes/58 false VHL 7428 L118P (c.353T>C) Clear Cell Renal Cell Carcinoma 4467 Clear cell renal cell carcinoma Oncogenic N/A C N/A Tumors from 98 patients with sporadic clear cell renal carcinoma (ccRC) were analyzed for VHL mutations and loss of heterozygosity (LOH). Somatic VHL variants were observed in 56 patients, and VHL LOH was observed in 98% of samples with VHL variants. VHL L118P (c.353T>C) was found in a granular ccRC (sample T36, variant location indicated at c.566 because of differences in reference transcript). Authors noted that VHL variants were highly specific to ccRC and not found in the 12 other tumor types examined. 7915601 PubMed Gnarra et al., 1994, Nat. Genet. 1 accepted 6905 1798 58 3 10188210 10188210 T C ENST00000256474.2 75 GRCh37 Somatic 2021-04-16 02:26:24 UTC https://civicdb.org/links/evidence_items/6905 https://civicdb.org/links/variants/1798 https://civicdb.org/links/genes/58 false VHL 7428 D121_A122del (c.361_366del) Clear Cell Renal Cell Carcinoma 4467 Clear cell renal cell carcinoma Oncogenic N/A C N/A Tumors from 98 patients with sporadic clear cell renal carcinoma (ccRC) were analyzed for VHL mutations and loss of heterozygosity (LOH). Somatic VHL variants were observed in 56 patients, and VHL LOH was observed in 98% of samples with VHL variants. VHL D121_A122del (c.361_366del) was found in a granular ccRC (sample UOK142, variant noted as 6 NT deletion, NT 574 because of differences in reference transcript). Authors noted that VHL variants were highly specific to ccRC and not found in the 12 other tumor types examined. 7915601 PubMed Gnarra et al., 1994, Nat. Genet. 1 accepted 6907 2553 58 Somatic 2021-04-15 21:20:19 UTC https://civicdb.org/links/evidence_items/6907 https://civicdb.org/links/variants/2553 https://civicdb.org/links/genes/58 false VHL 7428 P138R (c.413C>G) Clear Cell Renal Cell Carcinoma 4467 Clear cell renal cell carcinoma Oncogenic N/A C N/A Tumors from 98 patients with sporadic clear cell renal carcinoma (ccRC) were analyzed for VHL mutations and loss of heterozygosity (LOH). Somatic VHL variants were observed in 56 patients, and VHL LOH was observed in 98% of samples with VHL variants. P138R (c.413C>G) was found in a granular ccRC (sample UOK102, variant location indicated at NT 626 because of differences in reference transcript). Authors noted that VHL variants were highly specific to ccRC and not found in the 12 other tumor types examined. 7915601 PubMed Gnarra et al., 1994, Nat. Genet. 1 accepted 6915 2440 58 3 10188270 10188270 C G ENST00000256474.2 75 GRCh37 Somatic 2021-04-15 21:18:58 UTC https://civicdb.org/links/evidence_items/6915 https://civicdb.org/links/variants/2440 https://civicdb.org/links/genes/58 false VHL 7428 N150fs (c.447del) Renal Carcinoma 4451 Clear cell renal cell carcinoma Oncogenic N/A C N/A Tumors from 98 patients with sporadic clear cell renal carcinoma (ccRC) were analyzed for VHL mutations and loss of heterozygosity (LOH). Somatic VHL variants were observed in 56 patients, and VHL LOH was observed in 98% of samples with VHL variants. VHL N150fs (c.447del) was found in a ccRC (sample T683, variant noted as c.659del because of differences in reference transcript). Authors noted that VHL variants were highly specific to ccRC and not found in the 12 other tumor types examined. 7915601 PubMed Gnarra et al., 1994, Nat. Genet. 1 accepted 6918 2561 58 3 10188303 10188303 C ENST00000256474.2 75 GRCh37 Somatic 2021-04-15 21:22:15 UTC https://civicdb.org/links/evidence_items/6918 https://civicdb.org/links/variants/2561 https://civicdb.org/links/genes/58 false VHL 7428 Q164* (c.490C>T) Clear Cell Renal Cell Carcinoma 4467 Clear cell renal cell carcinoma Oncogenic N/A C N/A Tumors from 98 patients with sporadic clear cell renal cell carcinoma (ccRCC) were analyzed for VHL mutations and loss of heterozygosity (LOH). Somatic VHL variants were observed in 56 patients, and VHL LOH was observed in 98% of samples with VHL variants. VHL Q164* (c.490C>T) was found in a granular ccRC (sample UOK161, variant location indicated as c.703 because of differences in reference transcript). Authors noted that VHL variants were highly specific to ccRC and not found in the 12 other tumor types examined. 7915601 PubMed Gnarra et al., 1994, Nat. Genet. 1 accepted 6925 1845 58 3 10191497 10191497 C T ENST00000256474.2 75 GRCh37 Somatic 2021-04-16 02:30:20 UTC https://civicdb.org/links/evidence_items/6925 https://civicdb.org/links/variants/1845 https://civicdb.org/links/genes/58 false NTRK3 4916 ETV6::NTRK3 B-lymphoblastic Leukemia/lymphoma 0080630 Young adult onset Larotrectinib Predictive Supports D Sensitivity/Response Both in vivo and in vitro models demonstrated Larotrectinib was an effective treatment against cells harboring ETV6-NTRK3. In YFP-luciferase PDX mice from a 16-year-old with Ph-like B-ALL, flow cytometry indicated the absence of leukemic cells in the bone marrow (p<.0001), peripheral blood (p=.0018), and spleen (p=.0001) after 6 weeks of Larotrectinib (n=10) compared to vehicle treated mice (n=10). Treated mice also had lower splenic weight (p<.001) and the absence of leukemia burden in the bone marrow and central nervous system as determined by histopathology. In 2 mice, leukemic burden increased while Larotrectinib was paused from weeks 6-25. Upon the reintroduction of treatment for 4 weeks, leukemic burden was lowered. Conditional knock-in Etv6-NTRK CD19-Cre cells isolated from bone marrow and cultured ex vivo were highly sensitive to serial dilutions of Larotrectinib. After 48 hours of Larotrectinib exposure, Ba/F3 cells stably expressing ETV6-NTRK3 demonstrated a response with an IC50 of 17.0nM (viability measured by CellTiter blue). Finally, Larotrectinib was 1000x more potent against 3 human cancer cell lines with an NTRK fusion versus the 76 with other alterations. The most sensitive was an AML cell line (M0-91) with an ETV6-NTRK3 fusion. 29880614 PubMed Roberts et al., 2018, Blood 4 accepted 6930 801 3985 12 11802788 12022903 ENST00000396373.4 15 88483984 88418230 ENST00000394480.2 75 GRCh37 Somatic 2021-07-24 02:21:27 UTC https://civicdb.org/links/evidence_items/6930 https://civicdb.org/links/variants/801 https://civicdb.org/links/genes/3985 false TERT 7015 Promoter Mutation Glioblastoma 3068 Prognostic Supports B Poor Outcome In 50 patients with primary glioblastomas, patients without TERT promoter mutations (N=13, median 27 mo) survived longer than those harboring mutations (N=37, 14 mo; P = 0.01 by the log rank test; HR 0.38, 95% CI [0.18, 0.81]). 23530248 PubMed Killela et al., 2013, Proc. Natl. Acad. Sci. U.S.A. 3 accepted 6933 220 79 5 1295161 1295373 ENST00000310581.5 75 GRCh37 TERT promoter mutations are activating and commonly found at two hotspots within the TERT promoter region which occur 124 and 146 base pairs (hg19) upstream of the translation start site. These hotspots, termed C228T and C250T are observed in many cancer types and have a particularly high prevalence in glioblastoma (83%), melanoma (71%), bladder cancer (66%) and hepatocelluar carcinoma (HCC) (47%). The two mutations are usually heterozygous and mutually exclusive and result in an increased similarity to an ETS binding domain and may act as a binding site to an ETS transcription factor. These mutations are thought to be early events in tumorgenesis and aid in cellular immortality. Decreased overall survival in patients with these mutations have been observed in medulloblastoma, thyroid cancer, urogenital cancer, melanoma, and laryngeal tumors. The presence of these mutations has also been shown to be predictive of malignant/premalignant nodules in HCC and meningiomas. Somatic 2020-04-28 23:02:41 UTC https://civicdb.org/links/evidence_items/6933 https://civicdb.org/links/variants/220 https://civicdb.org/links/genes/79 false BRAF 673 V600 Melanoma 1909 Trametinib,Dabrafenib Combination Predictive Supports B Sensitivity/Response In this Phase III trial (NCT01584648 COMBI-d), 423 previously untreated patients with unresectable stage IIIC or IV BRAF V600E or V600K mutant melanoma received dabrafenib and trametinib or dabrafenib alone with primary endpoint of progression free survival with secondary endpoints including disease response. The hazard ratio for progression or death in the dabrafenib–trametinib group was 0.75 (95% confidence interval, 0.57 to 0.99; P=0.03). Of 210 patients in the dabrafenib + trametinib group, 67% of patients had a response, which was 16 percentage points higher than in the dabrafenib-alone group (95% CI, 6 to 25; P=0.002). 25265492 PubMed Long et al., 2014, N. Engl. J. Med. NCT01584648 5 accepted 6937 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2021-01-06 01:44:31 UTC https://civicdb.org/links/evidence_items/6937 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false BRAF 673 V600E Melanoma 1909 Trametinib,Dabrafenib Combination Predictive Supports B Sensitivity/Response In this Phase III trial (NCT01584648 COMBI-d), previously untreated patients with unresectable stage IIIC or IV melanoma with BRAF V600E (359 patients) or V600K (61 patients) received dabrafenib and trametinib or dabrafenib alone with primary endpoint of progression free survival and secondary endpoints including disease response. The hazard ratio for progression or death in the V600E group was 0.81 for dabrafenib-trametinib vs dabrafenib-alone. Of 179 V600E patients in the dabrafenib-trametinib group, 68% of patients had a response, which was 15 percentage points higher than in the dabrafenib-alone group (95% CI, 4 to 24; P=0.006). 25265492 PubMed Long et al., 2014, N. Engl. J. Med. NCT01584648 5 accepted 6938 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-11-08 17:54:34 UTC https://civicdb.org/links/evidence_items/6938 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Melanoma 1909 Dabrafenib,Trametinib Combination Predictive Supports B Sensitivity/Response In this Phase I and II study (NCT01072175) patients with metastatic melanoma were given dabrafenib and trametinib combination therapy vs. dabrafenib monotherapy. From V600E patients, 45 received monotherapy and 92 received combination therapy. Hazard ratio for progression or death was 0.43 (95% CI, 0.27-0.71). Both patients with the BRAF V600E and V600K mutation showed significant improvement in progression-free survival. 23020132 PubMed Flaherty et al., 2012, N. Engl. J. Med. NCT01072175 4 accepted 6940 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2018-11-08 17:18:57 UTC https://civicdb.org/links/evidence_items/6940 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false ACVR1 90 G328V Diffuse Midline Glioma, H3 K27M-mutant 0080684 Diagnostic Supports B Positive In a study sequencing 61 patients (median age 6.3) with diffuse intrinsic pontine glioma (DIPG), 12 variants affecting ACVR1 were observed. Five patients had G328V within the kinase domain. The ACVR1 G328V mutation was expressed using the pCDH511b vector in immortalized normal human astrocytes (iNHAs) where it activated downstream BMP signaling and enhanced cell growth. Activating ACVR1 mutations are recurrent and support diagnosis of high grade glioma. PEDIATRIC 24705254 PubMed Buczkowicz et al., 2014, Nat. Genet. 3 accepted 6955 1686 154 2 158622516 158622516 C A ENST00000434821.1 75 GRCh37 Somatic 2018-10-15 23:09:14 UTC https://civicdb.org/links/evidence_items/6955 https://civicdb.org/links/variants/1686 https://civicdb.org/links/genes/154 false NRAS 4893 Q61 Thyroid Gland Follicular Carcinoma 3962 Prognostic Does Not Support B Poor Outcome Follicular thyroid cancers harboring RAS mutations have limited aggressiveness in the absence of TERT mutations. 2/2 follicular thyroid cancer patients with co-mutations in NRAS (10 Q61R and 1 Q61K) or HRAS (2 Q61R and 1 Q61K) and TERT promoter mutations had persistent or recurrent disease compared to 1/11 patients with only a RAS mutation (100% vs 8%, P=0.03). 25448848 PubMed Muzza et al., 2015, Mol. Cell. Endocrinol. 2 accepted 6959 94 36 1 115256528 115256530 ENST00000369535.4 75 GRCh37 NRAS Q61 mutations have been found in multiple myeloma, gastrointestinal stromal tumors, melanoma, and others. Two melanoma patients, each harboring mutations at this locus (Q61L and Q61R), responded to treatment with the akylating agent temozolomide. However, in colorectal cancer patients, mutations at this locus have been shown to confer resistance to cetuximab. The prognostic impact of mutations at this locus is currently under study. Somatic 2019-02-10 01:56:04 UTC https://civicdb.org/links/evidence_items/6959 https://civicdb.org/links/variants/94 https://civicdb.org/links/genes/36 false HRAS 3265 Q61 Thyroid Gland Follicular Carcinoma 3962 Prognostic Does Not Support B Poor Outcome Follicular thyroid cancers harboring RAS mutations have limited aggressiveness in the absence of TERT mutations. 2/2 follicular thyroid cancer patients with co-mutations in NRAS (10 Q61R and 1 Q61K) or HRAS (2 Q61R and 1 Q61K) and TERT promoter mutations had persistent or recurrent disease compared to 1/11 patients with only a RAS mutation (100% vs 8%, P=0.03). 25448848 PubMed Muzza et al., 2015, Mol. Cell. Endocrinol. 2 accepted 6960 2570 2747 Somatic 2019-02-10 01:56:19 UTC https://civicdb.org/links/evidence_items/6960 https://civicdb.org/links/variants/2570 https://civicdb.org/links/genes/2747 false BRAF 673 V600K Melanoma 1909 Trametinib,Dabrafenib Combination Predictive Supports B Sensitivity/Response In this Phase III trial (coBRIM, NCT01689519) of 495 V600 mutant melanoma patients, 56 had V600K mutation. 32 patients were treated with vemurafenib and placebo, and 24 were treated with vemurafenib and cobimetinib and tested for progression free survival. 17 of 32 monotherapy group patients had an event with median progression free survival of 5.3 months. In the combination group 4 of 24 patients had an event with median progression-free survival not met, however, when in combination with other V600 mutations median progression-free survival was 9.9 months with combination treatment. Median time to followup for the whole cohort was 7.3 months. Hazard Ratio for progression or death was 0.27 (0.09-0.81). 25265494 PubMed Larkin et al., 2014, N. Engl. J. Med. NCT01689519 4 accepted 6965 563 5 7 140453136 140453137 AC TT ENST00000288602.6 75 GRCh37 Somatic 2018-11-08 16:57:28 UTC https://civicdb.org/links/evidence_items/6965 https://civicdb.org/links/variants/563 https://civicdb.org/links/genes/5 false BRAF 673 V600 Melanoma 1909 Vemurafenib,Cobimetinib Combination Predictive Supports B Sensitivity/Response In this Phase 1b study, 129 patients with unresectable or metastatic melanoma were verified for BRAF V600 mutation using the cobas 4800 mutation test were selected who had progressed on vemurafenib (66 patients) or never received BRAF inhibitor (63 patients). The combination of vemurafenib and cobimetinib was deemed safe and tolerable. Confirmed objective responses were seen in 15% of vemurafenib progressed patients and median progression-free survival was 2.8 months (95% CI 2·6–3·4). Confirmed objective responses were seen in 87% of patients who had never received BRAF inhibitor, including 10% with complete response. Median progression-free survival was 13.7 months (95% CI 10·1–17·5). The majority of patients had BRAF V600E mutation. Post-hoc sequencing of 94 tumor samples indicated seven tumors with a mutation other than BRAF V600E. 25037139 PubMed Ribas et al., 2014, Lancet Oncol. NCT01271803 3 accepted 6966 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2018-11-08 16:33:34 UTC https://civicdb.org/links/evidence_items/6966 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false ABL1 25 ETV6::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Dasatinib Predictive Supports C Sensitivity/Response An adult patient (82 yo) who presented with B-ALL (initial WBC of 183,000) with ETV6-ABL1 fusion was treated with dasatinib as a single agent after his chemotherapy had to be stopped due to toxicity. This resulted in morphological and cytogenetic remission after 2 weeks of treatment. Patient continued dasatinib daily plus 2 cycles of prednisolone (50 mg orally daily) for 4 weeks each. He remained in cytogenetic remission after 8 months of maintenance dasatinib. (See Supplementary Appendix 2, Page 11). 25207766 PubMed Roberts et al., 2014, N. Engl. J. Med. 2 accepted 6969 2575 4 Somatic 2020-11-20 16:21:28 UTC https://civicdb.org/links/evidence_items/6969 https://civicdb.org/links/variants/2575 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359V Chronic Myeloid Leukemia 8552 Nilotinib,Imatinib Mesylate Substitutes Predictive Supports C Resistance In this open-label, phase II registration trial, patients that were imatinib-resistant or intolerant underwent nilotinib monotherapy. Within 12 months of nilotinib therapy, there was no significant difference in response to nilotinib treatment between patients with mutations in the Abl1 kinase domain versus without. However, the authors identify Y253H, E255K/V, and F359C/V variants as resistant as they had an IC50 of >150nM. In patients with F359C and/or F359V mutations prior to nilotinib treatment, complete hematological responses were achieved in 3 of 10 patients, a major cytogenetic response in 1 of 11 patients, a complete cytogenetic response in 0 of 11 patients, and major molecular response in 0 of 10 patients. After a median follow-up of 15.5 months, 9 of 11 patients with this mutation progressed or died. The F359C mutation was present in 1 patient at baseline and newly emerged in 1 patient at progression. The F359V mutation was present in 4 patients at baseline and newly emerged in 1 patient at progression. 19652056 PubMed Hughes et al., 2009, J. Clin. Oncol. 3 accepted 6970 892 4 9 133748414 133748414 T G ENST00000318560.5 75 GRCh37 Somatic 2018-11-05 22:44:52 UTC https://civicdb.org/links/evidence_items/6970 https://civicdb.org/links/variants/892 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255V Chronic Myeloid Leukemia 8552 Nilotinib,Imatinib Mesylate Substitutes Predictive Supports C Resistance In this open-label, phase II registration trial, patients that were imatinib resistant or intolerant underwent nilotinib monotherapy. Within 12 months of nilotinib therapy, there was no significant difference in response to nilotinib treatment between patients with mutations in the Abl1 kinase domain versus without. However, the authors identify Y253H, E255K/V, and F359C/V variants as resistant as they had an IC50 greater than 150 nM. In patients with E255K and/or E255V mutations prior to nilotinib treatment, complete hematological responses were achieved in 5 of 7 patients, major cytogenetic responses in 3 of 7 patients, complete cytogenetic responses in 0 of 7 patients, and a major molecular response in 1 of 7 patients. After a median follow-up of 15.5 months, 6 of 7 patients with this mutation progressed or died. The E255K mutation was present in 6 patients at baseline and newly emerged in 4 patients at progression. The E255V mutation was present in 0 patients at baseline and newly emerged in 3 patients at progression. 19652056 PubMed Hughes et al., 2009, J. Clin. Oncol. 3 accepted 6971 1173 4 9 133738364 133738364 A T ENST00000318560.5 75 GRCh37 Somatic 2018-11-05 22:45:12 UTC https://civicdb.org/links/evidence_items/6971 https://civicdb.org/links/variants/1173 https://civicdb.org/links/genes/4 false BRAF 673 V600E Thyroid Gland Anaplastic Carcinoma 0080522 Trametinib,Dabrafenib Combination Predictive Supports B Sensitivity/Response Interim analysis of a basket trial evaluating the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in previously treated V600E-mutated patients showed 11/16 patients with anaplastic thyroid carcinoma responded to treatment (overall response rate 69%; 95% CI, 41% to 89%). Seven patients had ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached after 120 weeks. 29072975 PubMed Subbiah et al., 2018, J. Clin. Oncol. NCT02034110 4 accepted 6975 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-12-11 07:18:39 UTC https://civicdb.org/links/evidence_items/6975 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false PDGFRB 5159 EBF1::PDGFRB Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Young adult onset Imatinib Predictive Supports C Sensitivity/Response A 16-year-old boy with B-cell acute lymphoblastic leukemia refractory to conventional chemotherapy and harboring an IKZF1 deletion (delta 2-7) and a 5q33 microdeletion resulting in an EBF1-PDGFRB fusion responded to continuous imatinib (400 mg/d) during consolidation. Following consolidation therapy that included dexamethasone, vincristine, etoposide, cytarabine, and high-dose methotrexate, MRD declined to 10^-5 and the patient underwent bone marrow transplant. MRD performed at 105 days post-BMT found no detectable blasts with a sensitivity of 10^-5. 24186319 PubMed Lengline et al., 2013, Haematologica 3 accepted 6976 535 4176 5 158134987 158526769 ENST00000517373.1 5 149493400 149505140 ENST00000261799.4 75 GRCh37 EBF1-PDGFRB fusions are associated with Ph-like acute lymphoblastic leukemia lacking the BCR-ABL fusion. Case reports have shown positive responses to imatinib treatment. Somatic 2021-07-20 20:15:13 UTC https://civicdb.org/links/evidence_items/6976 https://civicdb.org/links/variants/535 https://civicdb.org/links/genes/4176 false ABL1 25 C475V Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, C475V was seen in a single imatinib resistant patient that was also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 6977 1639 4 9 ENST00000318560.5 GRCh37 Somatic 2018-11-16 21:44:26 UTC https://civicdb.org/links/evidence_items/6977 https://civicdb.org/links/variants/1639 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, F317L was seen in 8 imatinib resistant patients that were also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 3 accepted 6978 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2018-12-21 20:01:20 UTC https://civicdb.org/links/evidence_items/6978 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL N336S Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, N336S was seen in a single imatinib-resistant patient that was also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 6979 1640 4 9 133748346 133748346 A G ENST00000318560.5 75 GRCh37 Somatic 2019-01-14 19:18:23 UTC https://civicdb.org/links/evidence_items/6979 https://civicdb.org/links/variants/1640 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E453A Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, E453A was seen in a single imatinib-resistant patient that was also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 6980 1536 4 9 133753889 133753889 A C ENST00000318560.5 75 GRCh37 Somatic 2019-01-14 20:19:44 UTC https://civicdb.org/links/evidence_items/6980 https://civicdb.org/links/variants/1536 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L387F Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, L387F was seen in a single imatinib-resistant patient that was also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 6981 1232 4 9 133750330 133750330 G C ENST00000318560.5 75 GRCh37 Somatic 2019-01-14 19:20:48 UTC https://civicdb.org/links/evidence_items/6981 https://civicdb.org/links/variants/1232 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL V299L Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports B Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, V299L was seen in two imatinib-resistant patients that were also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 6982 1231 4 9 133747588 133747588 G C ENST00000318560.5 75 GRCh37 Somatic 2019-01-14 20:20:58 UTC https://civicdb.org/links/evidence_items/6982 https://civicdb.org/links/variants/1231 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Q300R Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, Q300R was seen in a single imatinib-resistant patient that was also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 6983 1527 4 9 133747592 133747592 A G ENST00000318560.5 75 GRCh37 Somatic 2019-01-14 20:22:11 UTC https://civicdb.org/links/evidence_items/6983 https://civicdb.org/links/variants/1527 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359I Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, F359I was seen in two imatinib-resistant patients that were also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 6984 1523 4 9 133748414 133748414 T A ENST00000318560.5 75 GRCh37 Somatic 2019-01-14 20:23:12 UTC https://civicdb.org/links/evidence_items/6984 https://civicdb.org/links/variants/1523 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359C Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, F359C was seen in two imatinib-resistant patients that were also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 6985 1184 4 9 133748415 133748415 T G ENST00000318560.5 75 GRCh37 Somatic 2019-01-14 20:24:01 UTC https://civicdb.org/links/evidence_items/6985 https://civicdb.org/links/variants/1184 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255V Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, E255V was seen in a single imatinib-resistant patient that was also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 6986 1173 4 9 133738364 133738364 A T ENST00000318560.5 75 GRCh37 Somatic 2019-01-14 20:25:31 UTC https://civicdb.org/links/evidence_items/6986 https://civicdb.org/links/variants/1173 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F486S Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, F486S was seen in a single imatinib-resistant patient that was also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 6987 1152 4 9 133755488 133755488 T C ENST00000318560.5 75 GRCh37 Somatic 2019-01-14 20:28:06 UTC https://civicdb.org/links/evidence_items/6987 https://civicdb.org/links/variants/1152 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL H396R Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, H396R was seen in a single imatinib-resistant patient that was also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 6988 1030 4 9 133750356 133750356 A G ENST00000318560.5 75 GRCh37 Somatic 2019-01-14 20:29:05 UTC https://civicdb.org/links/evidence_items/6988 https://civicdb.org/links/variants/1030 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M351T Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, M351T was seen in a single imatinib-resistant patient that was also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 6989 1029 4 9 133748391 133748391 T C ENST00000318560.5 75 GRCh37 Somatic 2019-01-14 20:30:24 UTC https://civicdb.org/links/evidence_items/6989 https://civicdb.org/links/variants/1029 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, T315I was seen in 7 imatinib-resistant patients that were also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 3 accepted 6990 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2019-01-14 20:37:39 UTC https://civicdb.org/links/evidence_items/6990 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, E255K was seen in a single imatinib-resistant patient that was also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 6991 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2019-01-14 20:38:32 UTC https://civicdb.org/links/evidence_items/6991 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253H Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, Y253H was seen in 6 imatinib-resistant patients that were also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 3 accepted 6992 1025 4 9 133738357 133738357 T C ENST00000318560.5 75 GRCh37 Somatic 2019-01-14 20:40:05 UTC https://civicdb.org/links/evidence_items/6992 https://civicdb.org/links/variants/1025 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G250E Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, G250E was seen in 6 imatinib-resistant patients that were also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 3 accepted 6993 1023 4 9 133738349 133738349 G A ENST00000318560.5 75 GRCh37 Somatic 2019-01-14 20:41:04 UTC https://civicdb.org/links/evidence_items/6993 https://civicdb.org/links/variants/1023 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M244V Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, M244V was seen in 3 imatinib-resistant patients that were also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 2 accepted 6994 1021 4 9 133738330 133738330 A G ENST00000318560.5 75 GRCh37 Somatic 2019-01-14 20:42:24 UTC https://civicdb.org/links/evidence_items/6994 https://civicdb.org/links/variants/1021 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359V Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a study of 39 chronic phase CML patients with BCR-ABL variants, C475V was seen in one imatinib-resistant patient that was also resistant or intolerant to dasatinib and/or nilotinib treatment. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occurring. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 1 accepted 6995 892 4 9 133748414 133748414 T G ENST00000318560.5 75 GRCh37 Somatic 2019-01-14 21:20:29 UTC https://civicdb.org/links/evidence_items/6995 https://civicdb.org/links/variants/892 https://civicdb.org/links/genes/4 false ABL1 25 TKD MUTATION Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support B Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Among 39 patients with mutational analysis at baseline, subsets were evaluated for complete hematologic response (CHR) and major cytogenetic response (MCyR). Both were comparable for patients with Abl1 mutation versus without [CHR = 26/39 (67%) vs. 34/44 (77%); MCyR = 11/35 (31%) vs. 15/43 (35%)]. The authors observe responses with bosutanib monotherapy across many BCR-ABL mutations with the notable exception of T315I. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 3 accepted 6996 2371 4 Somatic 2018-12-21 19:56:19 UTC https://civicdb.org/links/evidence_items/6996 https://civicdb.org/links/variants/2371 https://civicdb.org/links/genes/4 false ABL1 25 P-Loop Mutation Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support B Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Among 39 patients with mutational analysis at baseline, subsets were evaluated for complete hematologic response (CHR) and major cytogenetic response (MCyR). Both were comparable for patients with P-loop mutations versus patients without Abl1 mutations [ CHR = 9/14 (64%) vs. 34/44 (77%); MCyR = 4/13 (31%) vs. 15/43 (35%)]. The authors observe responses with bosutanib monotherapy across many BCR-ABL mutations with the notable exception of T315I. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 2 accepted 6997 2375 4 Somatic 2018-12-21 19:53:01 UTC https://civicdb.org/links/evidence_items/6997 https://civicdb.org/links/variants/2375 https://civicdb.org/links/genes/4 false ABL1 25 Non-P-Loop Mutation Chronic Myeloid Leukemia 8552 Bosutinib Predictive Does Not Support B Resistance This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Among 39 patients with mutational analysis at baseline, subsets were evaluated for complete hematologic response (CHR) and major cytogenetic response (MCyR). Both were comparable for patients with non-P-loop mutations versus patient without Abl1 mutations [ CHR = 18/29 (62%) vs. 34/44 (77%); MCyR = 9/26 (35%) vs. 15/43 (35%)]. The authors observe responses with bosutanib monotherapy across many BCR-ABL mutations with the notable exception of T315I. 22371878 PubMed Khoury et al., 2012, Blood NCT00261846 3 accepted 6998 2376 4 Somatic 2018-12-21 19:54:32 UTC https://civicdb.org/links/evidence_items/6998 https://civicdb.org/links/variants/2376 https://civicdb.org/links/genes/4 false VHL 7428 L178P (c.533T>C) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. 25867206 PubMed Bausch et al., 2016, Head Neck 2 accepted 7004 1748 58 3 10191540 10191540 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/7004 https://civicdb.org/links/variants/1748 https://civicdb.org/links/genes/58 false VHL 7428 Y175* (c.525C>G) Von Hippel-Lindau Disease 14175 Endolymphatic sac tumor Predisposing Supports C Uncertain Significance Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. 25867206 PubMed Bausch et al., 2016, Head Neck 2 accepted 7005 1969 58 3 10191532 10191532 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/7005 https://civicdb.org/links/variants/1969 https://civicdb.org/links/genes/58 false JAK2 3717 GOLGA5::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Ph-positive acute lymphoblastic leukemia Ruxolitinib Predictive Supports C Sensitivity/Response A 10-year-old Caucasian boy with high risk B-cell acute lymphoblastic leukemia failed induction therapy. The patient had a complex karyotype and microarray revealed a 9p duplication involving JAK2 and deletions of IKZF1, PAX5, and CDKN2A. RNA studies demonstrated a Ph-like ALL expression signature but did not identify the underlying kinase fusion. Research level RNA sequencing identified a GOLGA5-JAK2 fusion which was confirmed by other methods and patient cells were introduced to patient-derived xenograft models that demonstrated a response to ruxolitinib. Therefore, 40mg/m2 ruxolitinib was added to the patient’s multiagent chemotherapy regiment. The treatment was well tolerated and the patient demonstrated significant clinical response by the end of consolidation, though MRD ≥ 0.01% was detected by flow cytometry. The patient received CART therapy and achieved MRD negative remission, then underwent HSCT, and remained in remission with full donor chimerism at 2-months post-HSCT. 29773603 PubMed Ding et al., 2018, Haematologica 3 accepted 7007 3214 28 The GOLGA5-JAK2 fusion is composed of part of the GOLGA5 (Golgin A5) gene at the 5’ end (N-terminus of the fusion protein), and part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 10 of GOLGA5 to exon 12 of JAK2 (GOLGA5-JAK2 10-12). The fusion is predicted to result from a reciprocal translocation t(9;14)(p24;q32), and has been identified in one patient by RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the coiled coil domain from GOLGA5 and an aberrantly activated JH1 kinase domain from JAK2, which is thought to upregulate the pathway shared with signal transducers and activators of transcription (STATs). The inclusion of the JH1 domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The novel GOLGA5-JAK2 fusion has been documented in one 10-year-old boy with BCR-ABL1-like B-lymphoblastic leukemia with complex karyotype. The clinical details of this case could predict response to treatment with JAK2 inhibitors. A xenograft model created from the patient's malignant cells demonstrated clearance of the leukemic clone in murine peripheral blood upon exposure to ruxolitinib. Moreover, this drug was added to the child's treatment regimen, resulting in nearly undetectable levels of the GOLGA5-JAK2 fusion measured after 64 days of therapy. The patient has reportedly remained in remission 20 months after CAR T-cell infusion and allogeneic hematopoietic stem cell transplantation. This child was included in the currently ongoing prospective clinical trial evaluating the efficacy of JAK2 inhibitors in treating pediatric B-lymphoblastic leukemia with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2020-10-19 20:19:12 UTC https://civicdb.org/links/evidence_items/7007 https://civicdb.org/links/variants/3214 https://civicdb.org/links/genes/28 false NCOA2 10499 HEY1::NCOA2 Mesenchymal Chondrosarcoma 4545 Diagnostic Supports B Positive A HEY1-NCOA2 fusion joining exon 4 of HEY1 to exon 13 of NCOA2 was identified in 10 mesenchymal chondrosarcomas but was absent from all other sarcoma types tested including other chondrosarcoma subtypes suggesting this fusion is diagnostic for mesenchymal chondrosarcomas. 22034177 PubMed Wang et al., 2012, Genes Chromosomes Cancer 4 accepted 7008 2581 8368 8 80 80 ENST00000337919.9 8 71 71 ENST00000452400.6 94 GRCh37 HEY1-NCOA2 is a specific and recurrent translocation in mesenchymal chondrosarcoma. The resulting chimeric transcription factor consists of the HEY1 DNA binding domain (exons 1-4) and two activating domains and a histone methyltransferase-interacting domain from NCOA2 (exon 13-23). Somatic 2019-02-19 20:00:12 UTC https://civicdb.org/links/evidence_items/7008 https://civicdb.org/links/variants/2581 https://civicdb.org/links/genes/8368 false FOXO1 2308 PAX3::FOXO1 Alveolar Rhabdomyosarcoma 4051 Diagnostic Supports B Positive In a cohort of 171 uniformly treated pediatric rhabdomyosarcoma (RMS) patients, 78 patients had alveolar rhabdomyosarcoma (ARMS). Of ARMS patients, 55% harbored a PAX3-FOXO1 fusion, 22% harbored a PAX7-FOXO1 fusion, and 23% were fusion negative. In contrast, all of the embryonal RMS or undifferentiated sarcoma patients (n=93) were fusion-negative. The authors concluded that PAX7-FOXO1 and PAX2-FOXO1 fusions are ARMS tumor specific. 12039929 PubMed Sorensen et al., 2002, J. Clin. Oncol. 4 accepted 7009 2582 1925 Somatic 2020-10-01 22:36:51 UTC https://civicdb.org/links/evidence_items/7009 https://civicdb.org/links/variants/2582 https://civicdb.org/links/genes/1925 false FOXO1 2308 PAX7::FOXO1 Alveolar Rhabdomyosarcoma 4051 Diagnostic Supports B Positive In a cohort of 171 uniformly treated pediatric rhabdomyosarcoma (RMS) patients, 78 patients had alveolar rhabdomyosarcoma (ARMS). Of ARMS patients, 55% harbored a PAX3-FOXO1 fusion, 22% harbored a PAX7-FOXO1 fusion, and 23% were fusion negative. In contrast, all of the embryonal RMS or undifferentiated sarcoma patients (n=93) were fusion-negative. The authors concluded that PAX7-FOXO1 and PAX3-FOXO1 fusions are ARMS tumor specific. 12039929 PubMed Sorensen et al., 2002, J. Clin. Oncol. 4 accepted 7010 2583 1925 Somatic 2020-10-01 22:40:36 UTC https://civicdb.org/links/evidence_items/7010 https://civicdb.org/links/variants/2583 https://civicdb.org/links/genes/1925 false FOXO1 2308 PAX3::FOXO1 Alveolar Rhabdomyosarcoma 4051 BET Inhibitor Predictive Supports D Sensitivity/Response 5 PAX3-FOXO1 fusion positive rhabdomyosarcoma cell lines exhibited greater sensitivity to BET bromodomain inhibitors than fusion negative lines and introduction of the PAX3-FOXO1 fusion to fibroblasts was sufficient to drive an 11 fold increase in sensitivity. The BET inhibitor JQ1 was efficacious in a PAX3-FOXO1 xenograft model. 28446439 PubMed Gryder et al., 2017, Cancer Discov 3 accepted 7011 2582 1925 Somatic 2021-01-15 21:36:20 UTC https://civicdb.org/links/evidence_items/7011 https://civicdb.org/links/variants/2582 https://civicdb.org/links/genes/1925 false PARP1 142 OVEREXPRESSION Malignant Peripheral Nerve Sheath Tumor 5940 Olaparib Predictive Supports D Sensitivity/Response The majority of MPNST samples were positive for PARP staining. Overall, moderate to high expression of PARP1 and PARP2 was observed (Table 1)....Overall, treatment continued for 60 d at which point 5 out of 7 mice in the AZD2281 treatment group were alive versus 0 out of 7 mice in the control group (Fig. 4). These results indicated that treatment with AZD2281 significantly increased the survival of mice with metastatic disease. 26650448 PubMed Kivlin et al., 2016, Cancer Biol. Ther. 3 accepted 7016 2586 199 N/A 2019-12-16 22:01:45 UTC https://civicdb.org/links/evidence_items/7016 https://civicdb.org/links/variants/2586 https://civicdb.org/links/genes/199 false NCOA2 10499 HEY1::NCOA2 Mesenchymal Chondrosarcoma 4545 Diagnostic Supports B Positive 6 of 6 patients with mesenchymal chondrosarcoma and sufficient tissue tested positive for NCOA2 rearrangments by FISH supporting that NCOA2 rearrangements (presumably HEY1-NCOA2 translocations) are prevalent in this disease. 26146478 PubMed Bishop et al., 2015, Sarcoma 2 accepted 7017 2581 8368 8 80 80 ENST00000337919.9 8 71 71 ENST00000452400.6 94 GRCh37 HEY1-NCOA2 is a specific and recurrent translocation in mesenchymal chondrosarcoma. The resulting chimeric transcription factor consists of the HEY1 DNA binding domain (exons 1-4) and two activating domains and a histone methyltransferase-interacting domain from NCOA2 (exon 13-23). Somatic 2019-02-19 20:00:45 UTC https://civicdb.org/links/evidence_items/7017 https://civicdb.org/links/variants/2581 https://civicdb.org/links/genes/8368 false BRD4 23476 BRD4::NUTM1 NUT Midline Carcinoma 0060463 Birabresib Predictive Supports C Sensitivity/Response In the clinic, compassionate use of the BET inhibitor birabresib (also known as OTX015 or MK-8628) induced rapid tumor regression in 2 of 4 patients with confirmed BRD4-NUTM1 fusions and significant disease stabilization in a third patient. This study provides the first clinical evidence that a BET inhibitor can induce impressive and rapid antitumor activity in this rare and exceptionally aggressive disease. 26976114 PubMed Stathis et al., 2016, Cancer Discov 3 accepted 7018 719 9588 Somatic 2019-12-16 02:45:44 UTC https://civicdb.org/links/evidence_items/7018 https://civicdb.org/links/variants/719 https://civicdb.org/links/genes/9588 false BRD4 23476 BRD4::NUTM1 NUT Midline Carcinoma 0060463 Diagnostic Supports B Positive 5 of 28 cases of undifferentiated carcinomas of the upper aerodigestive tract (UCUAT) not associated with EBV infection were found to have NUTM1 rearrangements suggesting NUT midline carcinoma may be underdiagnosed and more prevalent than previously thought. 18391746 PubMed Stelow et al., 2008, Am. J. Surg. Pathol. 3 accepted 7019 719 9588 Somatic 2019-12-16 02:49:57 UTC https://civicdb.org/links/evidence_items/7019 https://civicdb.org/links/variants/719 https://civicdb.org/links/genes/9588 false PDGFRA 5156 FIP1L1::PDGFRA T674I Myeloid And Lymphoid Neoplasms With Eosinophilia And Abnormalities Of PDGFRA, PDGFRB, And FGFR1 0080164 Imatinib Predictive Supports C Resistance One patient with FIP1L1/PDGFRA-positive CEL was identified as developing secondary resistance to imatinib. A PDGFRA T674I mutation was identified in the tyrosine kinase domain. Salvage therapy with nilotinib and sorafenib each failed in this patient, who was eventually transplanted with an HLA-matched sibling donor. 21818111 PubMed Metzgeroth et al., 2012, Leukemia 3 accepted 7020 577 38 4 55144547 55144547 C T ENST00000257290.5 75 GRCh37 A case study of relapsed myeloproliferative hypereosinophilic syndrome suggests that a T674I mutation in the PDGFRA split kinase domain of FIP1L1-PDGFRA fusions may confer resistance to imatinib. Somatic 2018-12-28 16:03:51 UTC https://civicdb.org/links/evidence_items/7020 https://civicdb.org/links/variants/577 https://civicdb.org/links/genes/38 false JAK2 3717 F694L Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Acute lymphoblastic leukemia Ruxolitinib Predictive Supports C Sensitivity/Response A 17-year-old Native American female with B-ALL had persistent MRD at the end of induction. In addition to a complex karyotype, sequencing revealed a novel F694L mutation in JAK2, a p.Cys119_Ile121delinsTrpGlyLeu in IKZF1, and a IGH-CRLF2 translocation, all consistent with BCR-ABL1 like B-ALL. In addition to conventional cytotoxic therapy, the patient was started on 40 mg/m2/day ruxolitinib TKI BID for 2 weeks on, 2 weeks off, and MRD diminished to <0.01% prior to allogeneic transplant. The patient was in remission with 100% engraftment from a full match sibling at day 100 post-transplant. 27860260 PubMed Mayfield et al., 2017, Pediatr Blood Cancer 2 accepted 7021 2587 28 Somatic 2020-10-08 19:59:46 UTC https://civicdb.org/links/evidence_items/7021 https://civicdb.org/links/variants/2587 https://civicdb.org/links/genes/28 false EGFR 1956 Mutation Lung Non-small Cell Carcinoma 3908 Erlotinib Predictive Supports B Sensitivity/Response In this open-label, randomised, phase 3 trial at 22 centres in China, patients with stage IIIB or IV NSCLC who had exon 19 deletion or exon 21 L858R point mutation, and who had not received previous systemic anticancer therapy, were administered tyrosine kinase inhibitor erlotinib (83 patients) or gemcitabine plus carboplatin (82 patients). Median progression-free survival was found to be significantly longer with erlotinib than in patients on chemotherapy (13.1 [95% CI 10.58–16.53] vs 4.6 [4.21–5.42] months; hazard ratio 0.16, 95% CI 0.10–0.26; p<0.0001). Chemotherapy was also associated with more grade 3 or 4 toxic effects. Authors conclude that in patients with advanced EGFR mutant NSCLC, erlotinib offers an improved first line treatment option. 21783417 PubMed Zhou et al., 2011, Lancet Oncol. NCT00874419 4 accepted 7024 442 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2019-11-04 16:47:54 UTC https://civicdb.org/links/evidence_items/7024 https://civicdb.org/links/variants/442 https://civicdb.org/links/genes/19 false PDGFRB 5159 EBF1::PDGFRB Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Imatinib Predictive Supports C Sensitivity/Response Two patients with EBF1-PDGFRB positive pediatric B-ALL were treated with induction/post-induction therapy and Imatinib. Neither patient experienced disease relapse. One patient died of an undefined encephalopathy at 6 mos post-transplant and the other patient was alive in clinical remission at 10 months after diagnosis. 26872634 PubMed Schwab et al., 2016, Blood 2 accepted 7028 535 4176 5 158134987 158526769 ENST00000517373.1 5 149493400 149505140 ENST00000261799.4 75 GRCh37 EBF1-PDGFRB fusions are associated with Ph-like acute lymphoblastic leukemia lacking the BCR-ABL fusion. Case reports have shown positive responses to imatinib treatment. Somatic 2020-11-20 15:58:07 UTC https://civicdb.org/links/evidence_items/7028 https://civicdb.org/links/variants/535 https://civicdb.org/links/genes/4176 false ABL1 25 BCR::ABL L248V Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance In this phase II multinational study, 60 imatinib-resistantpatients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with L248V, 3/3 had MaHRs and 1/3 had MCyRs which were comparable to response rates among wild type patients. 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 7029 1022 4 9 133738342 133738342 C G ENST00000318560.5 75 GRCh37 Somatic 2020-04-26 21:42:01 UTC https://civicdb.org/links/evidence_items/7029 https://civicdb.org/links/variants/1022 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports C Reduced Sensitivity In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with F317L, 4/4 had MaHRs which was higher than response rates among wild type patients, and 0/4 had MCyRs which was lower than response rates among wild type patients. 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 7030 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2020-04-26 21:28:26 UTC https://civicdb.org/links/evidence_items/7030 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E459K Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with E459K, 1/3 had MaHRs which was lower than response rates among wild type patients, and 3/3 had MCyRs which was higher than response rates among wild type patients. 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 7031 2370 4 9 133753906 133753906 G A ENST00000318560.5 75 GRCh37 Somatic 2020-04-26 21:29:23 UTC https://civicdb.org/links/evidence_items/7031 https://civicdb.org/links/variants/2370 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL V379I Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a phase II study of 60 imatinib-resistant patients with BCR-ABL mutations, 4 had V379I mutations 17264298 PubMed Guilhot et al., 2007, Blood 3 accepted 7033 1609 4 9 133750304 133750304 G A ENST00000318560.5 75 GRCh37 Somatic 2021-11-12 17:41:43 UTC https://civicdb.org/links/evidence_items/7033 https://civicdb.org/links/variants/1609 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL A397P Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a phase II study of 60 imatinib-resistant patients with BCR-ABL mutations, 2 had A397P mutations. Both patients with A397P mutation achieved major hematologic response, and one also had major cytogenetic response. 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 7034 1612 4 9 133750358 133750358 G C ENST00000318560.5 75 GRCh37 Somatic 2020-09-29 04:55:29 UTC https://civicdb.org/links/evidence_items/7034 https://civicdb.org/links/variants/1612 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359C Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a phase II study of 60 imatinib-resistant patients with BCR-ABL mutations, 2 had F359C mutations 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 7035 1184 4 9 133748415 133748415 T G ENST00000318560.5 75 GRCh37 Somatic 2019-01-31 10:18:56 UTC https://civicdb.org/links/evidence_items/7035 https://civicdb.org/links/variants/1184 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E355G Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a phase II study of 60 imatinib-resistant patients with BCR-ABL mutations, 4 had E355G mutations 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 7036 1487 4 9 133748403 133748403 A G ENST00000318560.5 75 GRCh37 Somatic 2019-01-31 10:19:35 UTC https://civicdb.org/links/evidence_items/7036 https://civicdb.org/links/variants/1487 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M351T Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a phase II study of 60 imatinib-resistant patients with BCR-ABL mutations, 6 had M351T mutations 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 7037 1029 4 9 133748391 133748391 T C ENST00000318560.5 75 GRCh37 Somatic 2019-01-31 10:20:36 UTC https://civicdb.org/links/evidence_items/7037 https://civicdb.org/links/variants/1029 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a phase II study of 60 imatinib-resistant patients with BCR-ABL mutations, 5 had T315I mutations 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 7038 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2019-01-31 10:20:58 UTC https://civicdb.org/links/evidence_items/7038 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a phase II study of 60 imatinib-resistant patients with BCR-ABL mutations, 6 had E255K mutations 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 7039 3 4 9 133738363 133738363 G A ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation E255K has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and nilotinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2019-01-31 10:27:01 UTC https://civicdb.org/links/evidence_items/7039 https://civicdb.org/links/variants/3 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253H Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports B Resistance In a phase II study of 60 imatinib-resistant patients with BCR-ABL mutations, 6 had Y253H mutations 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 7040 1025 4 9 133738357 133738357 T C ENST00000318560.5 75 GRCh37 Somatic 2019-01-31 10:28:21 UTC https://civicdb.org/links/evidence_items/7040 https://civicdb.org/links/variants/1025 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G250E Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports B Resistance In a phase II study of 60 imatinib-resistant patients with BCR-ABL mutations, 9 had G250E mutations 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 7041 1023 4 9 133738349 133738349 G A ENST00000318560.5 75 GRCh37 Somatic 2019-01-31 10:28:49 UTC https://civicdb.org/links/evidence_items/7041 https://civicdb.org/links/variants/1023 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M244V Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a phase II study of 60 imatinib-resistant patients with BCR-ABL mutations, 5 had M244V mutations 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 7042 1021 4 9 133738330 133738330 A G ENST00000318560.5 75 GRCh37 Somatic 2019-01-31 10:29:17 UTC https://civicdb.org/links/evidence_items/7042 https://civicdb.org/links/variants/1021 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F359V Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a phase II study of 60 imatinib-resistant patients with BCR-ABL mutations, 7 had F359V mutations 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 7043 892 4 9 133748414 133748414 T G ENST00000318560.5 75 GRCh37 Somatic 2019-01-31 10:29:41 UTC https://civicdb.org/links/evidence_items/7043 https://civicdb.org/links/variants/892 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L248V Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a phase II study of 60 imatinib-resistant patients with BCR-ABL mutations, 3 had L248V mutations 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 7044 1022 4 9 133738342 133738342 C G ENST00000318560.5 75 GRCh37 Somatic 2019-01-31 10:30:09 UTC https://civicdb.org/links/evidence_items/7044 https://civicdb.org/links/variants/1022 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a phase II study of 60 imatinib-resistant patients with BCR-ABL mutations, 4 had F317L mutations 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 7045 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2019-01-31 10:30:57 UTC https://civicdb.org/links/evidence_items/7045 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E459K Chronic Myeloid Leukemia 8552 Imatinib Mesylate Predictive Supports C Resistance In a phase II study of 60 imatinib-resistant patients with BCR-ABL mutations, 3 had E459K mutations 17264298 PubMed Guilhot et al., 2007, Blood 1 accepted 7046 2370 4 9 133753906 133753906 G A ENST00000318560.5 75 GRCh37 Somatic 2019-01-31 10:31:48 UTC https://civicdb.org/links/evidence_items/7046 https://civicdb.org/links/variants/2370 https://civicdb.org/links/genes/4 false RET 5979 Overexpression Lung Adenocarcinoma 3910 Prognostic Supports B Poor Outcome ASCL1 and RET mRNA levels were examined by microarray analysis in lung cancer samples. High expression of RET (RET-high) correlated with shorter overall survival compared to the RET-low group in patients with ASCL1 expression in stage I (P=0.007, N=15 vs 38) and all adenocarcinoma (P=0.037, N=31 vs 58). However, expression of RET did not affect survival in the ASCL1- tumors. 24037524 PubMed Kosari et al., 2014, Oncogene 3 accepted 7056 597 42 10 43572475 43625799 ENST00000355710.3 75 GRCh37 N/A 2021-01-29 05:54:24 UTC https://civicdb.org/links/evidence_items/7056 https://civicdb.org/links/variants/597 https://civicdb.org/links/genes/42 false RET 5979 Fusion Lung Non-small Cell Carcinoma 3908 Selpercatinib Predictive Supports B Sensitivity/Response In this phase 1 trial, 57 patients with RET fusion- or mutation positive cancers were treated in 7 dose levels. Among patients with RET-Fusion positive NSCLC, objective response rates were 65% (n = 17/26). Responses occurred independent of fusion partner (9/13 KIF5B vs 7/9 non-KIF5B) and included 3 pts w/ baseline brain metastases. 161573 ASCO 102 Alexander E. Drilon, 2018, ASCO Annual Meeting, Abstract 102 NCT03157128 4 accepted 7066 1687 42 Somatic 2020-09-18 19:41:52 UTC https://civicdb.org/links/evidence_items/7066 https://civicdb.org/links/variants/1687 https://civicdb.org/links/genes/42 false EGFR 1956 V441F Colorectal Cancer 9256 Panitumumab,Cetuximab Substitutes Predictive Supports E Resistance Next-generation sequencing data of cfDNA from 1,397 patients with colorectal cancer identified a novel cluster of extracellular domain (ECD). EGFR V441G/D/F mutations were found in 19% (n=8) of patients with EGFR ECD domain III (location of cetuximab and panitumumab binding epitope) mutations. V441D and V441G were more common than V441F. Resistance of V441G to cetuximab was modeled in silico, and authors predicted that it destroys a critical hydrophobic node. In vitro, V441G/D transduced NIH3T3 cells had significantly reduced binding to panitumumab and cetuximab compared to EGFR wt NH3T3 cells (p<0.01 for all comparisons to wt). Authors inferred that EGFR domain III (ECD) mutations, including V441F, may be responsible for secondary resistance to EGFR blockade. 29196463 PubMed Strickler et al., 2018, Cancer Discov 2 accepted 7096 2613 19 7 55227854 55227854 G T ENST00000275493.2 75 GRCh37 Somatic 2020-12-07 17:59:04 UTC https://civicdb.org/links/evidence_items/7096 https://civicdb.org/links/variants/2613 https://civicdb.org/links/genes/19 false NCOA2 10499 HEY1::NCOA2 Mesenchymal Chondrosarcoma 4545 Diagnostic Supports B Positive FISH was used to detect HEY1-NCOA2 fusions in 10 paraffin embedded samples from patients diagnosed with mesenchymal chondrosarcoma. HEY1 and NCOA2 are located on the same chromosome but generate distinct FISH signals, whereas the HEY1-NCOA2 fusion appears as a single fused dot. Specimens were considered positive for fusion when FISH showed overlapping signals of HEY1 and NCOA2 in greater than 20% of the cells. Overlap signal of over 20% was seen in 8/10 patients. The two patients with no overlap signal were also negative for FISH staining, suggesting insufficient or damaged material for FISH. 23252872 PubMed Nakayama et al., 2012, Pathol. Int. 4 accepted 7124 2581 8368 8 80 80 ENST00000337919.9 8 71 71 ENST00000452400.6 94 GRCh37 HEY1-NCOA2 is a specific and recurrent translocation in mesenchymal chondrosarcoma. The resulting chimeric transcription factor consists of the HEY1 DNA binding domain (exons 1-4) and two activating domains and a histone methyltransferase-interacting domain from NCOA2 (exon 13-23). Somatic 2019-09-26 21:01:50 UTC https://civicdb.org/links/evidence_items/7124 https://civicdb.org/links/variants/2581 https://civicdb.org/links/genes/8368 false NCOA2 10499 HEY1::NCOA2 Mesenchymal Chondrosarcoma 4545 Diagnostic Supports B Positive Meningeal hemangiopericytoma (HPC) and mesenchymal chondrosarcoma (MC) are aggressive neoplasms with overlapping clinical presentations and morphology. Thirteen FFPE samples of MC (9 females, 4 males) from ages 19 to 54 and Eighteen cases of meningeal HPC (8 females, 10 males) from ages from 24 to 73 years were tested using RT-PCR for the presence of HEY1-NCOA2 fusion. Of cases with evaluable RNA, 6/6 MC cases were positive for the fusion, but 0/11 meningeal HPC cases were fusion positive. 24124145 PubMed Fritchie et al., 2013, Am. J. Clin. Pathol. 4 accepted 7125 2581 8368 8 80 80 ENST00000337919.9 8 71 71 ENST00000452400.6 94 GRCh37 HEY1-NCOA2 is a specific and recurrent translocation in mesenchymal chondrosarcoma. The resulting chimeric transcription factor consists of the HEY1 DNA binding domain (exons 1-4) and two activating domains and a histone methyltransferase-interacting domain from NCOA2 (exon 13-23). Somatic 2019-09-26 21:01:22 UTC https://civicdb.org/links/evidence_items/7125 https://civicdb.org/links/variants/2581 https://civicdb.org/links/genes/8368 false PDGFRB 5159 EBF1::PDGFRB Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Imatinib,Dasatinib Substitutes Predictive Supports C Sensitivity/Response The EBF1-PDGFRB fusion was detected in leukemia cells of a 7 year old Latino boy who presented with B-ALL and initial WBC of 600,000. He failed to enter remission with 4 drug induction (90% blasts at day 23), and showed testicular involvement. SNP array showed deletion of IKZF1 deletion and gains in 5q32 and 5q33.3 that interrupted the PDGFRB and EBF1 loci, respectively. FISH studies demonstrated an extra PDGFRB signal with suspect EBF1-PDGFRB that needs molecular confirmation. Imatinib, cyclophosphamide and etoposide were commenced with MRD 4.3% after 1 month. Imatinib dose was increased with MRD 0.44% after additional month of treatment. MRD was 0.0226% after two months of dasatinib treatment, and the patient proceeded to matched unrelated donor hematopoietic stem cell transplantation. 25207766 PubMed Roberts et al., 2014, N. Engl. J. Med. 2 accepted 7128 535 4176 5 158134987 158526769 ENST00000517373.1 5 149493400 149505140 ENST00000261799.4 75 GRCh37 EBF1-PDGFRB fusions are associated with Ph-like acute lymphoblastic leukemia lacking the BCR-ABL fusion. Case reports have shown positive responses to imatinib treatment. Somatic 2020-04-29 03:32:36 UTC https://civicdb.org/links/evidence_items/7128 https://civicdb.org/links/variants/535 https://civicdb.org/links/genes/4176 false VHL 7428 G104V (c.311G>T) Von Hippel-Lindau Disease 14175 Paraganglioma,Hypertension,Hemangioblastoma Predisposing N/A C N/A A healthy 21 year old woman presented with high blood pressure. She noted palpitations ongoing for 6 months prior. Her adrenal galnds were found to be normal via CT scan. A 2cm x 1.8cm x 1.5cm lesion close to costovertebral angle of third right thoracic vertebra was found via PET scan were histological findings found this to be consistent with paraganglioma. Blood samples for genomic DNA analysis were taken and screening for mutations in SDHA, SDHB, SDHC, SDHD, RET, SDHAF2, TMEM127, MAX, NF1, FH, MDH2, and EPAS1 genes was negative but she was positive for a heterozygous mutation in the VHL gene, c.311G > T (p.Gly104Val). This same variant was found in her 17 year-old sister and her mother but not in her father. Her mother refused a complete staging. The probands sister presented with a small retinal hemangioblastoma at this time. ACMG evidence codes: 'PM2' since this variant is absent from controls (gnomAD), 'PP1' since there is cosegregation with disease in multiple affected family members, 'PP2' since we have a missense variant in a gene where missense variants are a common mechanism of disease, 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology. 29789510 PubMed Bahougne et al., 2018, J Clin Med 3 accepted 7134 2428 58 3 10183842 10183842 G T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/7134 https://civicdb.org/links/variants/2428 https://civicdb.org/links/genes/58 false VHL 7428 R161Q (c.482G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing N/A C N/A A 12 year old Japanese female confirmed with the germline VHL mutation (c.482G>A) presented with pheochromocytoma. It was found that neither of her parents harboured this variation, confirming that she had a de novo mutation. The paper concluded that weight loss could be indicative of pheochromocytoma. 29662268 PubMed Igaki et al., 2018, Clin Pediatr Endocrinol 3 accepted 7141 1746 58 3 10191489 10191489 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/7141 https://civicdb.org/links/variants/1746 https://civicdb.org/links/genes/58 false BRAF 673 KIAA1549::BRAF Pilocytic Astrocytoma 4851 Diagnostic Supports B Positive Genetic alterations in pilocytic astrocytoma (PA) were evaluated. Whole-genome sequencing of normal (blood) and tumor samples (n=96) was performed along with corresponding RNA-Seq (n=73) and mate-pair (MP) sequencing (n=68). Several known events activating the MAPK pathway were identified with KIAA1549-BRAF fusion being the most frequent variants (70 of 96 cases, 73%). Importantly, all but one of the cerebellar PA harbored a BRAF fusion (47 of 48 samples, 98%) with this one exception having a KRAS alteration. 23817572 PubMed Jones et al., 2013, Nat. Genet. 5 accepted 7148 618 5 7 138545885 138666064 ENST00000440172.1 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2019-02-26 05:24:14 UTC https://civicdb.org/links/evidence_items/7148 https://civicdb.org/links/variants/618 https://civicdb.org/links/genes/5 false SMARCA4 6597 Loss Lung Non-small Cell Carcinoma 3908 Palbociclib,Abemaciclib Substitutes Predictive Supports D Sensitivity/Response Preclinical evidence showing that SMARCA4 inactivation results in downregulation of Cyclin D1 in NSCLC cells and confers sensitivity of such to CDK4/6 inhibitors. SMARCA4 loss is synthetic letha with CDK4/6 inhibition. 30718506 PubMed Xue et al., 2019, Nat Commun 4 accepted 7155 2644 78 N/A 2020-08-19 19:32:33 UTC https://civicdb.org/links/evidence_items/7155 https://civicdb.org/links/variants/2644 https://civicdb.org/links/genes/78 false BRAF 673 V600E Colorectal Cancer 9256 Prognostic Supports B Poor Outcome Patients with completely resected colorectal adenocarcinoma (Stage II-III) were treated with fluorouracil and leucovorin +/- ironotecan. Of the 1,307 FFPE samples tested, V600E was observed in 31 Stage II samples (7.6%) and 72 Stage III samples (7.9%). V600E was prognostic for overall survival, but not for relapse-free survival, in patients with stages II and III combined, and in stage III alone. For all MSI low and stable tumors, BRAF V600E positive samples had a hazard ratio (HR) of 2.19 (95% CI, 1.43 to 3.37, P=0.00034). For all samples in the cohort (MSI-H and MSI-L) BRAF V600E positive samples had a 1.66 HR (95% CI, 1.15 to 2.40, P=0.0069). The authors note prognostic value for BRAF V600E, especially in non-MSI high tumors. 20008640 PubMed Roth et al., 2010, J. Clin. Oncol. 4 accepted 7156 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2019-02-28 18:46:30 UTC https://civicdb.org/links/evidence_items/7156 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Prognostic Supports B Poor Outcome The CRYSTAL Phase III Trial evaluated efficacy of irinotecan, fluorouracil, and leucovorin (FOLFIRI) with or without Cetuximab for colorectal cancer patients who presented with unresectable metastatic disease. BRAF mutation status (V600E) was analyzed via LightMix BRAF V600E Kit. V600E mutations were detected in 60/999 tumor samples (6%), 59 of which were wild-type for KRAS. When comparing patients with wildtype KRAS (n=625), BRAF V600E tumors had worse outcomes relative to BRAF wildtype. For patients with BRAF V600E tumors (n=566), median overall survival (OS) was 25.1 months with cetuximab and 21.6 months without cetuximab. For patients with wildtype BRAF (n=59), median OS was 14.1 months with cetuximab and 10.3 months without cetuximab. 21502544 PubMed Van Cutsem et al., 2011, J. Clin. Oncol. 4 accepted 7157 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2019-02-28 18:42:15 UTC https://civicdb.org/links/evidence_items/7157 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 Mutation Colorectal Cancer 9256 Prognostic Supports B Poor Outcome In the Medical Research Council (MRC) COIN trial, ISRCTN27286448, patients who presented with advanced colorectal cancer were randomly assigned to chemotherapy (oxaliplatin and fluoropyrimidine; arm A), or chemotherapy plus cetuximab (arm B). Median overall survival was found to differ by mutation, regardless of treatment. Median overall survival was 8.8 months (IQR 4.5-27) for patients with BRAF variants, 14.4 months (IQR 8.5-24.0) for patients with KRAS variants, and 20.1 months (IQR 11.5-31.7) for wildtype patients. BRAF mutations were found in 102/1291 samples (7.90%), and of these, 12 were D594G and 90 V600E. 21641636 PubMed Maughan et al., 2011, Lancet 4 accepted 7158 399 5 7 140453136 140481403 ENST00000288602.6 75 GRCh37 Somatic 2019-02-28 18:43:01 UTC https://civicdb.org/links/evidence_items/7158 https://civicdb.org/links/variants/399 https://civicdb.org/links/genes/5 false BRAF 673 Mutation Colorectal Cancer 9256 Prognostic Supports B Poor Outcome A meta analysis was performed using data from 21 published studies (n = 9885 patients) to assess prognostic value of BRAF mutations in colorectal cancer. When evaluating 14 studies (n = 7778 patients), the odds ratio (OR) of a proximal lesion, which is associated with greater mortality in colon cancer, was increased for patients with BRAF mutations (OR 5.222, 95% CI 3.801–7.174, P < 0.001). When evaluating 4 studies (n = 1526 patients), the odds ratio of T4 tumors, which indicates tumor growth past bowel lining, was increased for patients with BRAF mutations (OR 1.761, 95% CI 1.164–2.663, P = 0.007). When evaluating 8 studies (n = 2786 patients), the odds ratio of poor tumor differentiation was increased in patients with BRAF mutations (OR 3.816, 95% CI 2.714–5.365, P < 0.001). These results support that BRAF mutations indicate poor prognosis for patients with colorectal cancer. 24112392 PubMed Clancy et al., 2013, Colorectal Dis 4 accepted 7159 399 5 7 140453136 140481403 ENST00000288602.6 75 GRCh37 Somatic 2019-02-28 18:05:03 UTC https://civicdb.org/links/evidence_items/7159 https://civicdb.org/links/variants/399 https://civicdb.org/links/genes/5 false TP53 7157 R248Q Lymphoma 0060058 Predisposing Supports D Likely Pathogenic In mouse models, the R248Q variant had accelerated onset of all tumor types and accelerated death rate. Endogenous R248Q proteins are devoid of several important wildtype tp53 tumor-suppressor functions including transcription of cell cycle arrest genes, replicative senescence and irradiation-induced apoptosis. Patients with germline R248Q/+ genotype showed a drastically younger median age until first tumor onset compared with patients with a null/+ genotype (19.5 vs 30 years, P=0.023). 23538418 PubMed Hanel et al., 2013, Cell Death Differ. 4 accepted 7161 117 45 17 7577538 7577538 C T ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R248 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, R248 mutations have been shown to confer worse overall survival. The R248Q mutation has also shown an increased invasive behavior in cell lines. This is specific to the 248Q variant. Rare Germline 2019-04-25 19:04:09 UTC https://civicdb.org/links/evidence_items/7161 https://civicdb.org/links/variants/117 https://civicdb.org/links/genes/45 false TP53 7157 C238Y Breast Cancer 1612 Prognostic Supports E Poor Outcome Cys-238 was directly bound to zinc molecule. Patients with missense mutations affecting amino acids directly involved in DNA or zinc binding displayed a very aggressive clinical phenotype. 11051239 PubMed Alsner et al., 2000, Clin. Cancer Res. 3 accepted 7173 2648 45 17 7577568 7577568 C T ENST00000269305.4 75 GRCh37 Somatic 2020-03-31 18:23:51 UTC https://civicdb.org/links/evidence_items/7173 https://civicdb.org/links/variants/2648 https://civicdb.org/links/genes/45 false PIK3CA 5290 Mutation Head And Neck Squamous Cell Carcinoma 5520 Celecoxib,Sulindac,Aspirin Substitutes Predictive Supports B Sensitivity/Response In this retrospective study, the impact of nonsteroidal anti-inflammatory drugs (NSAID) on survival in PIK3CA-altered HNSCC patients (N=266) was assessed. Among patients with a PIK3CA Mutation or amplification, regular NSAID use was significantly associated with disease-specific (HR 0.23, p=0.0032) and overall survival (HR 0.31, p=0.0043). These findings were recreated in a panel of six patient-derived xenograft models, where treatment with NSAIDs (sulindac, Celecoxib or Aspirin) significantly reduced growth rates in PIK3CA mutant, but not wild-type models. 30683736 PubMed Hedberg et al., 2019, J. Exp. Med. 3 accepted 7185 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2021-12-09 18:14:03 UTC https://civicdb.org/links/evidence_items/7185 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PIK3CA 5290 Amplification Head And Neck Squamous Cell Carcinoma 5520 Sulindac,Aspirin,Ibuprofen Substitutes Predictive Supports B Sensitivity/Response In this retrospective study, the impact of nonsteroidal anti-inflammatory drugs (NSAID) on survival in PIK3CA-altered HNSCC patients (N=266) was assessed. Among patients with a PIK3CA Mutation or amplification, regular NSAID use was significantly associated with disease-specific (HR 0.23, p=0.0032) and overall survival (HR 0.31, p=0.0043). These findings were recreated in a panel of six patient-derived xenograft models, where treatment with NSAIDs (sulindac, Celecoxib or Aspirin) significantly reduced growth rates in PIK3CA mutant, but not wild-type models. 30683736 PubMed Hedberg et al., 2019, J. Exp. Med. 3 accepted 7186 212 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 N/A 2021-12-09 18:15:04 UTC https://civicdb.org/links/evidence_items/7186 https://civicdb.org/links/variants/212 https://civicdb.org/links/genes/37 false TERT 7015 Promoter Mutation Childhood Low-grade Glioma 0080830 Pediatric onset,Early young adult onset Prognostic Supports C Poor Outcome The aim of this Chinese study was to identify prognostic biomarkers for pediatric low-grade gliomas (PLGG). Approximately 300 patients were included. Using Sanger sequencing, mutations at TERT promoter (TERTp) regions were identified (C228T: 3/278; C250T: 4/278). The median age of patients with TERTp mutations was 15 years. There were 5 males and 2 females. Six patients had diffuse astrocytoma and one had pilocytic astrocytoma. Tumors were found in the midline of four patients, the hemisphere of two, and the cerebellum of one. Kaplan-Meier survival analysis showed that TERTp mutations were associated with shorter progression-free survival and overall survival [mt (n=6) vs wt (n=205); p<0.0001 for both OS and PFS]. However, the association of TERTp mutations with OS and PFS was no longer statistically significant after adjusting for age, grade, histology, tumor location, and extent of resection in multivariate analysis. 29948154 PubMed Yang et al., 2018, Acta Neuropathol. 4 accepted 7188 220 79 5 1295161 1295373 ENST00000310581.5 75 GRCh37 TERT promoter mutations are activating and commonly found at two hotspots within the TERT promoter region which occur 124 and 146 base pairs (hg19) upstream of the translation start site. These hotspots, termed C228T and C250T are observed in many cancer types and have a particularly high prevalence in glioblastoma (83%), melanoma (71%), bladder cancer (66%) and hepatocelluar carcinoma (HCC) (47%). The two mutations are usually heterozygous and mutually exclusive and result in an increased similarity to an ETS binding domain and may act as a binding site to an ETS transcription factor. These mutations are thought to be early events in tumorgenesis and aid in cellular immortality. Decreased overall survival in patients with these mutations have been observed in medulloblastoma, thyroid cancer, urogenital cancer, melanoma, and laryngeal tumors. The presence of these mutations has also been shown to be predictive of malignant/premalignant nodules in HCC and meningiomas. Somatic 2022-03-02 21:49:49 UTC https://civicdb.org/links/evidence_items/7188 https://civicdb.org/links/variants/220 https://civicdb.org/links/genes/79 false H3-3A 3020 MUTATION Childhood Low-grade Glioma 0080830 Early young adult onset,Pediatric onset Prognostic Supports B Poor Outcome Using Sanger sequencing, H3F3A mutations in patients with pediatric low-grade gliomas (PLGGs) were identified (K27M: 13/280; G34R: 5/280). Kaplan-Meier survival analysis showed that H3F3A mutations were associated with shorter progression-free survival (PFS) and overall survival (OS) [15 cases with H3F3A mutation (n=15) vs wt (n=197); p<0.0001 for both OS and PFS]. A further multivariate analysis indicated H3F3A mutation as an independent, unfavorable prognosis marker for both PFS [HR 2.76 (95% CI 1.10–6.94); p = 0.031] and OS [HR 3.96 (95% CI 1.36–11.53); p = 0.012]. 29948154 PubMed Yang et al., 2018, Acta Neuropathol. 4 accepted 7189 2652 2537 Somatic 2021-10-07 19:14:52 UTC https://civicdb.org/links/evidence_items/7189 https://civicdb.org/links/variants/2652 https://civicdb.org/links/genes/2537 false ATRX 546 Underexpression Childhood Low-grade Glioma 0080830 Pediatric onset,Early young adult onset Prognostic Supports B Poor Outcome Loss of ATRX was identified in 12 of 247 patients with PLGGs using immunohistochemistry. Survival analysis showed that ATRX loss was associated with adverse overall survival (p<0.0001) and progression-free survival (p=0.0002) [mt (n=10) vs wt (n=175)]. In a multivariate analysis taking into account age, grade, histology, tumour location, and extent of resection, ATRX was still an independent prognosticator of PFS [HR 3.85 (95% CI 1.27–11.65); p = 0.017], and OS [HR 3.53 (95% CI 1.02–12.24); p = 0.047]. 29948154 PubMed Yang et al., 2018, Acta Neuropathol. 4 accepted 7190 648 525 X 76760356 77041702 ENST00000373344.5 75 GRCh37 Somatic 2021-01-08 22:12:51 UTC https://civicdb.org/links/evidence_items/7190 https://civicdb.org/links/variants/648 https://civicdb.org/links/genes/525 false BRAF 673 V600E Childhood Low-grade Glioma 0080830 Early young adult onset,Pediatric onset Prognostic Supports B Poor Outcome Using Sanger sequencing, BRAFV600E mutations were identified in 21 of 285 patients with PLGGs (7.4%). This mutation was enriched in hemispheric tumors (p<0.007) and was associated with shorter progression-free survival (p=0.011) and overall survival (p=0.032) [mt (n=18) vs wt (n=166)]. 29948154 PubMed Yang et al., 2018, Acta Neuropathol. 4 accepted 7191 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-12-10 20:17:35 UTC https://civicdb.org/links/evidence_items/7191 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false CDKN2A 1029 Deletion Childhood Low-grade Glioma 0080830 Early young adult onset,Pediatric onset Prognostic Supports B Poor Outcome CDKN2A deletion was identified in 24 of 273 patients with PLGGs using FISH analysis. An association between this alteration and BRAFV600E was detected (p=0.0001). Hemispheric tumors with CDKN2A deletion were associated with shorter progression-free survival (p=0.0073) but did not affect overall survival (p=0.5) [mt (n=10) vs wt (n=59)]. CDKN2A deletion remained an independent prognostic factor in multivariate analysis for PFS [HR 4.38 (95% CI 1.05–18.23); p = 0.043]. CDKN2A deletion was not a prognostic factor in midline or cerebellar tumors. 29948154 PubMed Yang et al., 2018, Acta Neuropathol. 4 accepted 7192 2654 14 Somatic 2020-12-10 20:12:45 UTC https://civicdb.org/links/evidence_items/7192 https://civicdb.org/links/variants/2654 https://civicdb.org/links/genes/14 false BRAF 673 KIAA1549::BRAF Childhood Low-grade Glioma 0080830 Pediatric onset,Early young adult onset Prognostic Supports B Better Outcome KIAA1549-BRAF fusion was identified in 87 of 272 patients with PLGGs using Fluorescence In situ hybridization (FISH) analysis. This mutation was strongly associated with a greater progression-free survival (p=0.0017) and overall survival (p=0.0029) [fusion-positive (n=64) vs fusion-negative (n=141)]. 29948154 PubMed Yang et al., 2018, Acta Neuropathol. 4 accepted 7193 618 5 7 138545885 138666064 ENST00000440172.1 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2020-12-10 20:17:48 UTC https://civicdb.org/links/evidence_items/7193 https://civicdb.org/links/variants/618 https://civicdb.org/links/genes/5 false MYB 4602 AMPLIFICATION Childhood Low-grade Glioma 0080830 Pediatric onset,Early young adult onset Prognostic Supports B Better Outcome MYB amplification was detected in 28 of 263 patients with PLGGs using Fluorescence In situ hybridization (FISH) analysis. The amplification of MYB was strongly associated with greater progression-free survival (p=0.04) but did not affect overall survival (p=0.13) [amplified (n=19) vs not amplified (n=177)]. MYB amplification was not an independent prognostic factor in multivariate analysis. 29948154 PubMed Yang et al., 2018, Acta Neuropathol. 4 accepted 7194 2655 3730 Somatic 2020-12-11 16:14:07 UTC https://civicdb.org/links/evidence_items/7194 https://civicdb.org/links/variants/2655 https://civicdb.org/links/genes/3730 false BRAF 673 KIAA1549::BRAF Childhood Low-grade Glioma 0080830 Everolimus,Trametinib Combination Predictive Supports D Sensitivity/Response This preclinical study proposed to use a combination therapy of an MEK inhibitor (e.g. trametinib) and an mTOR inhibitor (e.g. everolimus) for the treatment of pediatric low-grade gliomas (PLGGs) with BRAF fusions to evade acquired resistance to MEK targeted therapy. The PI3K/Akt/mTOR pathway was identified as a resistance mechanism to MEKi treatment based on RNASeq and GSEA analysis. Using flank xenograft model, mice were injected with NIH3T3 cells expressing KIAA1549-BRAF fusions and treated daily with trametinib, everolimus either alone or combined with each other (n=~10 for each treatment arm). Combination therapy (Trametinib 1mg/kg+ Everolimus 10mg/kg) resulted in better suppression in tumor growth than single-agent treatment. Similarly, combination treatment strongly reduced colony formation as well as pERK and pS6 levels, showing on target effects. 29156677 PubMed Jain et al., 2017, Oncotarget 2 accepted 7199 618 5 7 138545885 138666064 ENST00000440172.1 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2020-12-11 07:09:17 UTC https://civicdb.org/links/evidence_items/7199 https://civicdb.org/links/variants/618 https://civicdb.org/links/genes/5 false BRAF 673 KIAA1549::BRAF Childhood Low-grade Glioma 0080830 Prognostic Supports B Better Outcome Hawkins et al. (2011) retrospectively studied 70 consecutive patient with incompletely resected pediatric low-grade astrocytomas (PLGA). KIAA1549-BRAF fusion was identified in 60% of cases in this cohort. Multi-variant analysis suggested that KIAA1549-BRAF fusion was the most significant favorable prognosis factor in incompletely resected PLGA and was independent of location, pathology, and age. Five-year PFS of fusion positive and fusion negative patients were 61% +/- 8% and 18% +/- 8% (P=0.0004), respectively. These results suggested that KIAA1549-BRAF fusion confers a less aggressive clinical phenotype on PLGA and may explain their tendency to growth arrest. 21610142 PubMed Hawkins et al., 2011, Clin. Cancer Res. 4 accepted 7200 618 5 7 138545885 138666064 ENST00000440172.1 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2020-12-11 16:14:07 UTC https://civicdb.org/links/evidence_items/7200 https://civicdb.org/links/variants/618 https://civicdb.org/links/genes/5 false FGFR1 2260 Internal Duplication Childhood Low-grade Glioma 0080830 Early young adult onset,Pediatric onset Diagnostic Supports B Positive This GWAS study identified a structural variant of FGFR1. Duplication of the tyrosine kinase domain (TKD) of FGFR1 was found in 11 of 149 patients (13/151 tumor samples, including 2 recurrent tumors) with pediatric low-grade gliomas (PLGGs) and related low-grade glioneuronal tumors (LGGNTs). This alteration resulted in autophosphorylation of FGFR1 and subsequent activation of downstream PI3K and MAPK/ERK pathways. Also, transfection of Tp53-null astrocytes with TDK duplicated FGFR1 and implantation into the brains of nude mice results in high-grade astrocytic tumours with short latency and complete penetrance. Of note, this variant was present in 24% (8 of 34) of grade II diffuse cerebral gliomas. 23583981 PubMed Zhang et al., 2013, Nat. Genet. 4 accepted 7203 2659 1885 Somatic 2020-12-11 16:14:07 UTC https://civicdb.org/links/evidence_items/7203 https://civicdb.org/links/variants/2659 https://civicdb.org/links/genes/1885 false ABL1 25 NUP214::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Juvenile onset Dasatinib,Dexamethasone,Vincristine Combination Predictive Supports C Sensitivity/Response A 15-year-old girl with B-cell precursor ALL was placed into the very high risk group after showing corticoid resistance on treatment day 8, and induction failure on day 35 (MRD >0.01). The patient received a successful bone marrow transplant and at day 100 showed a complete remission (CR). The patient relapsed 6 months later, and second line therapy was unsuccessful. During this relapse, SNP microarray was performed on the diagnostic sample and identified amplification of 9q34 flanked by the NUP214 and ABL1 genes. Follow-up molecular studies confirmed a NUP214-ABL1 fusion gene. The patient was then started on dasatinib in combination with vincristine and dexamethasone. The patient achieved a second CR, and continued on dasatinib until her disease relapsed 2 months later. 26681761 PubMed Duployez et al., 2016, Haematologica 2 accepted 7208 2660 4 9 134000948 134106156 ENST00000359428.5 9 133730188 133763062 ENST00000318560.5 75 GRCh37 The NUP214 -ABL1 fusion is composed of part of the NUP214 (Nucleoporin 214) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 34 of NUP214 to exon 2 of ABL1 (NUP214-ABL1 34-2). In T-ALL, the fusion is typically expressed from amplified extrachromosomal bodies (episomes) that arise when the genomic region from ABL1 to NUP214 circularizes to generate the NUP214-ABL1 fusion. In B-ALL, the fusion commonly results from an intrachromosomal duplication involving chromosome 9, with breakpoints within the NUP214 and ABL1 genes. The fusion has been identified in 6% of cases of T-lymphoblastic leukemia and rare cases of B-lymphoblastic leukemia by multiplex ligation-dependent probe amplification, single nucleotide polymorphism array, real-time polymerase chain reaction, and fluorescence in situ hybridization targeting the ABL1 gene. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the WD40 repeat and coiled-coil domains of NUP214 and the SH2, tyrosine kinase, and F actin binding domains of ABL1, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and MAPK and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The case report that illustrates the clinical significance of the NUP214-ABL1 fusion describes a 6-year-old boy and a 15-year-old girl with BCR-ABL1-like B-lymphoblastic leukemia with normal karyotype. Both patients demonstrated minimal residual disease after induction chemotherapy, and later experienced relapse after either consolidation therapy or bone marrow transplant. Dasatinib was then prescribed and follow-up information is available for the older child, who successfully achieved a complete response for three months before succumbing to the disease. The clinical details of this case could predict response to treatment with tyrosine kinase inhibitors and is the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-06-24 14:47:30 UTC https://civicdb.org/links/evidence_items/7208 https://civicdb.org/links/variants/2660 https://civicdb.org/links/genes/4 false CRLF2 64109 IGH::CRLF2 B-cell Adult Acute Lymphocytic Leukemia 0060592 Prognostic Supports B Poor Outcome CRLF2 overexpression was examined in 90 adult B-ALL patients with demographic data that lacked characteristic rearrangements and identified overexpression in 15/90 (16.67%). Disease-free survival was significantly shorter among patients with CRLF2 overexpression (median 17.8 mo vs. 37.8 mo; P<0.03). 20018760 PubMed Yoda et al., 2010, Proc. Natl. Acad. Sci. U.S.A. 4 accepted 7212 2663 14303 Somatic 2021-03-02 19:53:00 UTC https://civicdb.org/links/evidence_items/7212 https://civicdb.org/links/variants/2663 https://civicdb.org/links/genes/14303 false TP53 7157 C238Y Li-Fraumeni Syndrome 3012 Functional Supports D Dominant Negative This study evaluated the dominant negative potential of 103 p53 germline mutations contained in the IRAC database. The C238Y variant was considered severely deficient as cotransformation with empty vector resulted in poor transactivation of luciferase expression in 4 yeast strains compared to the p53 wildtype control vector (mean residual activity <25% of wildtype control). Cotransformation of C238Y and wildtype vectors led to the hinderance of luciferase expression below 90% compared to wildtype alone in all 4 yeast strains, which based on the authors criteria qualified the C238Y variant as dominant negative. 21343334 PubMed Monti et al., 2011, Mol. Cancer Res. 2 accepted 7215 2648 45 17 7577568 7577568 C T ENST00000269305.4 75 GRCh37 Rare Germline 2022-01-12 17:35:49 UTC https://civicdb.org/links/evidence_items/7215 https://civicdb.org/links/variants/2648 https://civicdb.org/links/genes/45 false PIK3CA 5290 Exon 10 or Exon 21 Mutation Rectum Cancer 1993 Neoplasm of the rectum Prognostic Supports B Poor Outcome This study examined outcomes of 240 rectum cancer patients treated with total mesorectal excision therapy. Tumor samples were obtained at the time of surgery and genotyped for PIK3CA mutations in exons 10 and 21 (listed as exons 9 and 20 in the source, as it was common to exclude non-coding exon 1). PIK3CA mutations were identified in 19 cases (12 in exon 10 and 7 in exon 21). PIK3CA mutations were associated with a 3-fold increase in risk of recurrence of rectal tumors (5-year risk: 27.8% vs 9.4%, p = 0.008). Furthermore, patients with PIK3CA mutations experienced a shorter time to recurrence compared to those with WT PIK3CA (median: 7.9 vs 19.6 months, p = 0.07). Patients with concomitant PIK3CA and KRAS mutations had a similar local reoccurrence rate to patients with PIK3CA mutations only. In multivariate analysis, PIK3A mutation was an independent predictor for the development of local recurrences (HR: 3.4, P =0.017). 19903786 PubMed He et al., 2009, Clin. Cancer Res. 3 accepted 7220 3311 37 Somatic 2021-04-09 21:12:04 UTC https://civicdb.org/links/evidence_items/7220 https://civicdb.org/links/variants/3311 https://civicdb.org/links/genes/37 false CDKN1A 1026 rs1801270 Retinoblastoma 768 Predisposing N/A B N/A This study examined two CDKN1A polymorphisms (rs1801270 and rs1059234) in 141 carriers of RB1 variants and 120 unrelated healthy individuals. Authors found that RB1 carriers were more likely to have the non-wildtype CA genotype for rs1801270 than healthy controls (p=0.0117), and the chance of developing retinoblastoma increased 1.98 fold with the CA genotype compared to the wildtype CC genotype (OR: 1.98, 95% CI: 1.16-3.37). 24045412 PubMed Carvalho et al., 2013, Carcinogenesis 3 accepted 7227 2671 913 Common Germline 2021-04-14 20:08:35 UTC https://civicdb.org/links/evidence_items/7227 https://civicdb.org/links/variants/2671 https://civicdb.org/links/genes/913 false ABL1 25 SNX2::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Juvenile onset Dasatinib Predictive Supports C Resistance A 7-yr-old boy with B-cell precursor acute lymphoblastic leukemia was found to harbor the SNX2-ABL1 fusion gene. Gene expression analysis showed enrichment for BCR-ABL1+ ALL using GSEA. After first relapse (15 months after diagnosis) the patient was given imatinib at a dose of 240 mg/m2/d once daily and his disease stabilized for 2 months. The patient received dasatinib (80 mg/m2/d once daily) after an umbilical cord blood transplant and did not respond to treatment. Patient was put back on imatinib at a dose of 600 mg/m2/d once daily which rapidly decreased the number of blast cells. However, 6 months after transplant he had bone marrow relapse and did not again achieve remission by the time of reporting. 24215620 PubMed Masuzawa et al., 2014, Eur. J. Haematol. 2 accepted 7241 2678 4 5 122110691 122135550 ENST00000379516.2 9 133738150 133763062 ENST00000372348.2 75 GRCh37 The SNX2-ABL1 fusion is composed of part of the SNX2 (Sorting Nexin 2) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 3 of SNX2 to exon 4 of ABL1 (SNX2-ABL1 3-4). The fusion is the result of a reciprocal translocation t(5;9)(p23.2;q34.12) and has been identified by RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the sorting nexin, N-terminal domain of SNX2 and the SH2, tyrosine kinase, and F actin binding domains of ABL1, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The SNX2-ABL1 fusion has been documented in six young men between the ages of 7 and 29 years with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. Two patients had tyrosine kinase inhibitors (imatinib and dasatinib + imatinib) added to their chemotherapy regimens that, while producing initially encouraging results, ultimately did not prevent these individuals from succumbing to their disease. The clinical details of these cases may predict response to treatment with tyrosine kinase inhibitors and is the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-06-14 17:15:09 UTC https://civicdb.org/links/evidence_items/7241 https://civicdb.org/links/variants/2678 https://civicdb.org/links/genes/4 false FGFR1 2260 Amplification Breast Cancer 1612 Pazopanib Predictive Supports C Sensitivity/Response Case report in a HR positive, Her2/neu negative breast cancer patient harboring an FGFR1 amplification. The patient responded to treatment to Pazopanib - including a near CR of brain metastases. Duration of Treatment or median PFS was not reported at the time of publication. 29223982 PubMed Cheng et al., 2017, J Natl Compr Canc Netw 2 accepted 7246 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). Somatic 2020-01-10 19:25:36 UTC https://civicdb.org/links/evidence_items/7246 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false ABL1 25 RCSD1::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Juvenile onset Imatinib Predictive Supports C Sensitivity/Response The RCSD1-ABL1 fusion was identified in a 6 yo boy with Ph-like B-ALL (expression signature verified by low density gene expression array) and hyperleukocytosis. Following standard induction therapy the patient had an MRD of 16.4% in bone marrow, indicating a poor response. Addition of imatinib decreased MRD to 2% at day 29. In addition, this study reports that expression of the RCSD1-ABL1 fusion protein in murine Ba/F3 cells promotes cytokine-independent proliferation and that viable cells were reduced following exposure to dasatinib. 25207766 PubMed Roberts et al., 2014, N. Engl. J. Med. 3 accepted 7248 2681 4 The RCSD1-ABL1 fusion is composed of part of the RCSD1 (RCS Domain Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 2 or, more frequently, exon 3 of RCSD1 to exon 4 of ABL1 (RCSD1-ABL1 3-4). The fusion is the result of a reciprocal translocation t(1;9)(q24.2;q34.12) and has been identified by FISH/karyotype, RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the ABL1 SH2, actin binding domain, and tyrosine kinase domain, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The RCSD1-ABL1 fusion has been documented in greater than fifteen pediatric and adult patients with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. The majority that that were exposed to tyrosine kinase inhibitors (TKIs: imatinib, dasatinib, or ponatinib) experienced durable remissions until the TKIs were discontinued. The clinical details of these cases may predict response to treatment with TKIs and are the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-07-09 13:45:39 UTC https://civicdb.org/links/evidence_items/7248 https://civicdb.org/links/variants/2681 https://civicdb.org/links/genes/4 false ABL1 25 RCSD1::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Juvenile onset Dasatinib Predictive Supports D Sensitivity/Response The ABL1-RCSD1 fusion was identified in a 6 yo boy with Ph-like B-ALL and hyperleukocytosis. Following standard induction therapy the patient had an MRD of 16.4% in bone marrow, indicating a poor response. Addition of imatinib decreased MRD to 2% at day 29. In addition, this study reports that expression of the ABL1-RCSD1 fusion protein in murine Ba/F3 cells promotes cytokine-independent proliferation and that viable cells were reduced following exposure to dasatinib. 25207766 PubMed Roberts et al., 2014, N. Engl. J. Med. 3 accepted 7249 2681 4 The RCSD1-ABL1 fusion is composed of part of the RCSD1 (RCS Domain Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 2 or, more frequently, exon 3 of RCSD1 to exon 4 of ABL1 (RCSD1-ABL1 3-4). The fusion is the result of a reciprocal translocation t(1;9)(q24.2;q34.12) and has been identified by FISH/karyotype, RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the ABL1 SH2, actin binding domain, and tyrosine kinase domain, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The RCSD1-ABL1 fusion has been documented in greater than fifteen pediatric and adult patients with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. The majority that that were exposed to tyrosine kinase inhibitors (TKIs: imatinib, dasatinib, or ponatinib) experienced durable remissions until the TKIs were discontinued. The clinical details of these cases may predict response to treatment with TKIs and are the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-08-19 13:57:42 UTC https://civicdb.org/links/evidence_items/7249 https://civicdb.org/links/variants/2681 https://civicdb.org/links/genes/4 false ABL2 27 Fusion B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Dasatinib Predictive Supports D Sensitivity/Response The ABL2-RCSD1 fusion was identified in a 5 yo boy with Ph-like B-ALL and Klinefelter syndrome. Following standard induction therapy the patient had an MRD of 1.2% in bone marrow, and continued to be MRD positive at 6 months off therapy (0.029%). He received imatinib and a bone marrow performed 2 months later showed no MRD. He maintained remission at one year post-diagnosis, on chemotherapy and imatinib. In addition, this study reports that expression of the ABL2-RCSD1 fusion protein in murine Ba/F3 cells promotes cytokine-independent proliferation and viable cells were reduced following exposure to dasatinib. 25207766 PubMed Roberts et al., 2014, N. Engl. J. Med. 3 accepted 7251 2571 101 Somatic 2020-05-01 22:12:54 UTC https://civicdb.org/links/evidence_items/7251 https://civicdb.org/links/variants/2571 https://civicdb.org/links/genes/101 false ABL1 25 FOXP1::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Young adult onset Oncogenic N/A C N/A In a 16-year old Caucasian female with pre B-cell ALL, the t(3;9)(p12;q34) was identified by FISH. 5'RACE PCR detected the in-frame FOXP1-ABL1 (exon 19 - exon 4) fusion was confirmed by RT-PCR (only detected in tumor cells; absent in normal control cells) and long PCR, cloning and Sanger sequencing. The patient was enrolled on the standard arm (based on positive MRD) for high-risk patients (on account of her age and white blood cell count) of the COALL-97 protocol. The patient was then consolidated with a haplo-identical transplant from her father and remained in complete remission. 21391972 PubMed Ernst et al., 2011, Br. J. Haematol. 2 accepted 7253 2682 4 The FOXP1-ABL1 fusion is composed of part of the FOXP1 (Forkhead box P1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 27 of FOXP1to exon 4 of ABL1 (FOXP1-ABL1). The fusion is the result of a reciprocal translocation t(3;9)(p12;q34) and has been identified by RT-PCR, Sanger sequencing, and NGS. FOXP1 is critical for the transcriptional regulatory network of B lymphopoiesis; it may also act as a tumor suppressor gene. Absence or deficiency of FOXP1 during early B-cell development may block pro-B cell to pre-B cell development. The FOXP1-ABL1 fusion protein leads to activated tyrosine kinase and may further alter the critical cellular function of these 2 genes. Clinical significance: The FOXP1-ABL1 fusion has been documented in 3 young adult patients (2 male, 1 female) with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. One patient had tyrosine kinase inhibitors (dasatinib) added to the chemotherapy regimens, who had bone marrow tested negative for MRD at end of consolidation. The clinical details of these cases may predict response to treatment with tyrosine kinase inhibitors. Functional studies are needed to substantiate the efficacy of TKI treatment of this particular ABL-class fusion. Somatic 2021-04-26 17:18:17 UTC https://civicdb.org/links/evidence_items/7253 https://civicdb.org/links/variants/2682 https://civicdb.org/links/genes/4 false ABL1 25 SNX2::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Young adult onset Imatinib Predictive Supports C Reduced Sensitivity In a 29-year-old man with pre B-cell ALL, the t(5;9)(q23;q34) [SNX2-ABL1] was identified. The SNX2-ABL1 fusion, which joins the N-terminal domain of SNX2 without the PX domain to ABL1 exon 4, was detected by RACE PCR and confirmed by RT-PCR and Sanger sequencing. The patient responded to initial chemotherapy, but relapsed early. He then demonstrated a response to hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-C-VAD), but relapsed again. The patient next received imatinib and supportive measures, including hydroxycarbamide, but unfortunately succumbed to his disease approximately one year after diagnosis. 21391972 PubMed Ernst et al., 2011, Br. J. Haematol. 1 accepted 7254 2678 4 5 122110691 122135550 ENST00000379516.2 9 133738150 133763062 ENST00000372348.2 75 GRCh37 The SNX2-ABL1 fusion is composed of part of the SNX2 (Sorting Nexin 2) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 3 of SNX2 to exon 4 of ABL1 (SNX2-ABL1 3-4). The fusion is the result of a reciprocal translocation t(5;9)(p23.2;q34.12) and has been identified by RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the sorting nexin, N-terminal domain of SNX2 and the SH2, tyrosine kinase, and F actin binding domains of ABL1, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The SNX2-ABL1 fusion has been documented in six young men between the ages of 7 and 29 years with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. Two patients had tyrosine kinase inhibitors (imatinib and dasatinib + imatinib) added to their chemotherapy regimens that, while producing initially encouraging results, ultimately did not prevent these individuals from succumbing to their disease. The clinical details of these cases may predict response to treatment with tyrosine kinase inhibitors and is the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-06-14 17:17:29 UTC https://civicdb.org/links/evidence_items/7254 https://civicdb.org/links/variants/2678 https://civicdb.org/links/genes/4 false JAK2 3717 SSBP2::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Ruxolitinib Predictive Supports C Sensitivity/Response The SSBP2-JAK2 fusion was identified in a 14 yo male with Ph-like B-ALL, a t(5;9)(q12;p1?3), and a WBC of 160,000. Following 4-drug induction therapy the patient had an MRD of 5.5%, indicating a poor response. After two additional weeks of induction, intermittent ruxolitinib was added to his regimen and a bone marrow performed 3 weeks after the addition of ruxolitinib showed 1% MRD. Following consolidation, the bone marrow showed 0.3% MRD. 25207766 PubMed Roberts et al., 2014, N. Engl. J. Med. 3 accepted 7257 2661 28 Somatic 2020-04-20 17:49:55 UTC https://civicdb.org/links/evidence_items/7257 https://civicdb.org/links/variants/2661 https://civicdb.org/links/genes/28 false BRAF 673 V600E Colorectal Cancer 9256 Encorafenib,Binimetinib,Cetuximab Combination Predictive Supports B Sensitivity/Response In a phase III trial, patients with BRAF V600E mutated metastatic colorectal cancer received triplet combination with encorafenib + binimetinib + cetuximab in a second or third-line setting. In the safety-lead in part of this trial, 30 patients were given triplet therapy, of which 29 with V600E mutation were included in the efficacy analysis. The objective response rate was 48% [95%CI: 29.4 - 67.5], median PFS was 8.0 mo [95%CI: 5.6 - 9.3], and median OS was 15.3 mo [95%CI: 9.6 - not reached]. The author concluded that triplet therapy was well tolerated and PFS and OS were substantially improved over historical standard of care. 168986 ASCO 688 Scott Kopetz, 2019, Gastrointestinal Cancers Symposium, Abstract 688 NCT02928224 3 accepted 7260 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2021-03-10 23:25:46 UTC https://civicdb.org/links/evidence_items/7260 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Biliary Tract Cancer 4607 Dabrafenib,Trametinib Combination Predictive Supports B Sensitivity/Response In a phase II trial, 33 patients with advanced or metastatic biliary tract cancer (BTC) received dabrafenib (D) and trametinib (T) in a second or higher line therapeutic context. Of the 33 patients, 30 had BRAF V600E mutated tumors, and 32 were evaluable. Objective response rate was 41% (13/32; 95% CI, 24 - 59%). Median PFS was 7.2 months (95% CI, 4.6 - 10.1 months), and median OS was 11.3 months (95% CI, 7.3 - 17.6 months). The author concluded that D+T therapy should be considered for patients with BRAF V600E mutated BTC. 169315 ASCO 187 Zev A. Wainberg, 2019, Gastrointestinal Cancers Symposium, Abstract 187 NCT02034110 3 accepted 7264 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2021-11-19 20:29:00 UTC https://civicdb.org/links/evidence_items/7264 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false MET 4233 EXON 14 SKIPPING MUTATION Lung Non-small Cell Carcinoma 3908 Tepotinib Predictive Supports B Sensitivity/Response In a interim analysis of Phase II trial for MET exon 14 skipping NSCLC, 34 patients received MEK selective inhibitor tepotinib. 9/15 (60.0%) evaluable patients had a confirmed PR and 3 (20.0%) had SD. 160289 ASCO 9016 Enriqueta Felip, 2018, ASCO Annual Meeting, Abstract 9016 NCT02864992 3 accepted 7272 324 52 7 116411903 116412043 ENST00000318493.6 75 GRCh37 Exon 14 mutations have been observed in ~3% of patients with NSCLC (28/933 reported by Awad et al J Clin Onc 2016), confirmed to cause exon skipping when available, and associated with concurrent MET amplification. Responses to the c-MET inhibitor crizotinib have been reported in preclinical models and in individual case reports as well as a small-scale clinical trial (17 patients treated, Drilon et al., 2016 (suppl; abstr 108; ASCO ID 167889-176)). Larger studies are needed but enrollment of patients with MET exon 14 skipping mutation in trials with MET inhibitors or off-label treatment is encouraged (Paik et al., 2015 (suppl; abstr 8021)). Somatic 2019-10-10 14:01:42 UTC https://civicdb.org/links/evidence_items/7272 https://civicdb.org/links/variants/324 https://civicdb.org/links/genes/52 false BRCA1 672 Mutation Ovarian Cancer 2394 Olaparib Predictive Supports A Sensitivity/Response In the phase 3 SOLO1 trial 390 patients with newly diagnosed advanced ovarian cancer with a mutation in BRCA1 or BRCA2 who had complete or partial response after platinum-based chemotherapy were randomized 2:1 to receive olaparib or placebo. The olaparib arm had 191 patients with BRCA1 mutation, 66 BRCA2, and 3 patients with both BRCA1 and BRCA2, while the placebo arm had 91 BRCA1 and 40 BRCA2 mutant patients. Analysis of PFS by blinded independent review found freedom from disease progression or death at 3 years was 69% in the olaparib arm compared with 35% in the placebo arm (hazard ratio for disease progression or death, 0.28; 95% CI, 0.20 to 0.39; P<0.001). 30345884 PubMed Moore et al., 2018, N. Engl. J. Med. NCT01844986 5 accepted 7274 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Rare Germline 2022-07-30 19:03:04 UTC https://civicdb.org/links/evidence_items/7274 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false BRCA1 672 Mutation Ovarian Cancer 2394 Olaparib Predictive Supports A Sensitivity/Response In the phase 3 SOLO1 trial 390 patients with newly diagnosed advanced ovarian cancer with a mutation in BRCA1 or BRCA2 who had complete or partial response after platinum-based chemotherapy were randomized 2:1 to receive olaparib or placebo. Two patients were found to have somatic BRCA1/2 mutations. Analysis of PFS by blinded independent review found freedom from disease progression or death at 3 years was 69% in the olaparib arm compared with 35% in the placebo arm (hazard ratio for disease progression or death, 0.28; 95% CI, 0.20 to 0.39; P<0.001). 30345884 PubMed Moore et al., 2018, N. Engl. J. Med. NCT01844986 1 accepted 7275 185 6 17 41197646 41277500 ENST00000471181.2 75 GRCh37 Somatic 2022-07-30 18:21:58 UTC https://civicdb.org/links/evidence_items/7275 https://civicdb.org/links/variants/185 https://civicdb.org/links/genes/6 false BRCA2 675 Mutation Ovarian Cancer 2394 Olaparib Predictive Supports A Sensitivity/Response In the phase 3 SOLO1 trial 390 patients with newly diagnosed advanced ovarian cancer with a mutation in BRCA1 or BRCA2 who had complete or partial response after platinum-based chemotherapy were randomized 2:1 to receive olaparib or placebo. The olaparib arm had 191 patients with BRCA1 mutation, 66 BRCA2, and 3 patients with both BRCA1 and BRCA2, while the placebo arm had 91 BRCA1 and 40 BRCA2 mutant patients. Analysis of PFS by blinded independent review found freedom from disease progression or death at 3 years was 69% in the olaparib arm compared with 35% in the placebo arm (hazard ratio for disease progression or death, 0.28; 95% CI, 0.20 to 0.39; P<0.001). 30345884 PubMed Moore et al., 2018, N. Engl. J. Med. NCT01844986 5 accepted 7276 186 7 13 32889611 32973347 ENST00000380152.3 75 GRCh37 Rare Germline 2022-07-30 18:50:17 UTC https://civicdb.org/links/evidence_items/7276 https://civicdb.org/links/variants/186 https://civicdb.org/links/genes/7 false IDH1 3417 Mutation Acute Myeloid Leukemia 9119 Ivosidenib Predictive Supports A Sensitivity/Response I phase 1 trial for patients with IDH1-mutated AML, patients who received ivosidenib (AG-120). The rate of complete remission was 21.6%, the over all response rate was 30.4%. 29860938 PubMed DiNardo et al., 2018, N. Engl. J. Med. NCT02074839 3 accepted 7278 645 26 2 209101803 209116275 ENST00000415913.1 75 GRCh37 Somatic 2019-12-20 09:45:01 UTC https://civicdb.org/links/evidence_items/7278 https://civicdb.org/links/variants/645 https://civicdb.org/links/genes/26 false ROS1 6098 Fusion Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports A Sensitivity/Response In the ongoing phase 1 study, patients with NSCLC with ROS1 rearrangement received crizotinib. ORR was 72%, median duration of response was 24.7 months, mPFS was 19.3 months and mOS was 51.4 months. 30980071 PubMed Shaw et al., 2019, Ann. Oncol. NCT00585195 5 accepted 7282 2693 4941 Somatic 2020-10-22 16:54:35 UTC https://civicdb.org/links/evidence_items/7282 https://civicdb.org/links/variants/2693 https://civicdb.org/links/genes/4941 false FLT3 2322 Mutation Acute Myeloid Leukemia 9119 Gilteritinib Predictive Supports B Sensitivity/Response In a phase 1/2 trial, patients with refractory or relapsed AML with FLT3 mutation (n=191; ITD n=162, D835 n=13, ITD-D835 n=16) received gilteritinib. 49% (93/191) of patients achieved an overall response, 9% (n=18) complete remission, 5% (n=10) complete remission with incomplete platelet recovery, 22% (n=42) complete remission with incomplete hematological recovery, and 12% (n=23) reached partial remission. The refractory or relapsed AML FLT wildtype group treated with gilteritinib(n=58) had lower overall response rate (12%), complete remission (2%), complete remission with incomplete platelet recovery (0%), complete remission with incomplete hematological recovery (7%), and fewer reached partiral remission (3%). Also, bone marrow myeloblast reduction was greater in FLT3 mutant patients compared to FLT3 wildtype. 28645776 PubMed Perl et al., 2017, Lancet Oncol. NCT02014558 4 accepted 7283 519 24 13 28577411 28674729 ENST00000241453.7 75 GRCh37 Somatic 2020-07-15 01:30:21 UTC https://civicdb.org/links/evidence_items/7283 https://civicdb.org/links/variants/519 https://civicdb.org/links/genes/24 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Alectinib Predictive Supports A Sensitivity/Response In a phase 3 trial, 303 patients with NSCLC with ALK fusion were randomly assigned to alectinib arm (N=152) or crizotinib arm (N=151). PFS was significantly longer with alectinib than with crizotinib (HR for disease progression or death 0.47, 95% CI: 0.34-0.65, p<0.001). Investigator-assessed RR was 82.9% in alectinib arm and 75.5% in crizotinib arm. CNS RR in patients with measurable CNS lesions was 81% and 50% for alectinib and crizotinib, respectively. Eight patients in the alectinib group, in comparison to one patient with crizotinib, had a complete CNS response. Despite longer treatment duration for alectinib, there were fewer grade 3-5 adverse events compared with crizotinib treatment. 28586279 PubMed Peters et al., 2017, N. Engl. J. Med. NCT02075840 5 accepted 7284 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2020-08-14 17:55:23 UTC https://civicdb.org/links/evidence_items/7284 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Ceritinib Predictive Supports A Sensitivity/Response In a phase 3 trial, patients with previously treatmented NSCLC with ALK fusion were randomly assigned to ceritinib or chemotherapy. Ceritinib showed a significant improvement in median PFS compared with chemotherapy (5·4 months [95% CI 4·1-6·9] for ceritinib vs 1·6 months [1·4-2·8] for chemotherapy; hazard ratio 0·49 [0·36-0·67]; p<0·0001). 28602779 PubMed Shaw et al., 2017, Lancet Oncol. NCT01828112 5 accepted 7285 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2020-08-13 17:27:55 UTC https://civicdb.org/links/evidence_items/7285 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Lorlatinib Predictive Supports B Sensitivity/Response In a phase 2 trial, patients with NSCLC with ALK fusion received lorlatinib. In treatment-naive patients, ORR was 90.0% In patients with at least one previous ALK tyrosine kinase inhibitor, ORR were achieved in 47.0%.In patients who had only received crizotinib ORR was achieved in 69.5%. 30413378 PubMed Solomon et al., 2018, Lancet Oncol. NCT01970865 4 accepted 7286 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2019-11-06 18:30:52 UTC https://civicdb.org/links/evidence_items/7286 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false BRAF 673 V600 Melanoma 1909 Binimetinib,Encorafenib Combination Predictive Supports A Sensitivity/Response In a phase 3 trial, patients with melanoma with BRAF V600E or V600K mutation were randomly assigned to encorafenib plus binimetinib or vemurafenib or encorafenib. mPFS was 14·9 months (95% CI 11·0-18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6-8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41-0·71; two-sided p<0·0001) 29573941 PubMed Dummer et al., 2018, Lancet Oncol. NCT01909453 5 accepted 7287 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2019-12-13 09:42:17 UTC https://civicdb.org/links/evidence_items/7287 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false KIT 3815 V555_V559DEL Gastrointestinal Stromal Tumor 9253 Sunitinib Predictive Supports C Resistance Patient 36 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) KIT V555_V559 deletion. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. The patient took 50 mg sunitinib per day on a treatment schedule of four weeks on/two weeks off. The patient experienced progressive disease. Time to progression and overall survival were 10 and 108 weeks. 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 2 accepted 7288 2695 29 Somatic 2019-05-03 23:45:39 UTC https://civicdb.org/links/evidence_items/7288 https://civicdb.org/links/variants/2695 https://civicdb.org/links/genes/29 false KIT 3815 K550_K559DEL Gastrointestinal Stromal Tumor 9253 Sunitinib Predictive Does Not Support C Resistance Patient 78 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) KIT K550_V559 deletion. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. The patient started on 50mg sunitinib on a schedule of two weeks on/one weeks off. This patient experienced partial response; time to progression and overall survival were censored at 54 weeks and 84 weeks (Table A1). 18955458 PubMed Heinrich et al., 2008, J. Clin. Oncol. 2 accepted 7289 2696 29 4 55593582 55593611 AAACCCATGTATGAAGTACAGTGGAAGGTT ENST00000288135.5 75 GRCh37 Somatic 2019-05-04 00:03:28 UTC https://civicdb.org/links/evidence_items/7289 https://civicdb.org/links/variants/2696 https://civicdb.org/links/genes/29 false ABL1 25 FOXP1::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Young adult onset Dasatinib Predictive Supports C Sensitivity/Response A 16-year-old Caucasian boy was diagnosed with B-ALL. Karyotype showed an abnormal clone characterized by the t(3;9)(p13;q34.1). This translocation results in an abnormal fusion between the FOXP1 gene in 3p13 and the ABL1 in 9q34.1. The FOXP1-ABL1 fusion is known to be associated with Ph-like B-ALL subtype of B-ALL. The patient was treated with Berlin-Frankfurt-Münster (BFM) high-risk 4-drug induction chemotherapy with prednisone, daunorubicin, vincristine, and pegasparaginase and had 0.013% MRD at the end of indusciton. Tyrosine kinase inhibitor dasatinib was added to the consolidationchemotherapy with cyclophosphamide, cytarabine, peg-asparaginase, mercaptopurine, and vincristine. End-of-consolidation bone marrow tested negative for MRD. The patient was continued on standard high-risk BFM therapy, plus dasatinib. 30938769 PubMed Yenamandra et al., 2019, Lab Med 1 accepted 7292 2682 4 The FOXP1-ABL1 fusion is composed of part of the FOXP1 (Forkhead box P1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 27 of FOXP1to exon 4 of ABL1 (FOXP1-ABL1). The fusion is the result of a reciprocal translocation t(3;9)(p12;q34) and has been identified by RT-PCR, Sanger sequencing, and NGS. FOXP1 is critical for the transcriptional regulatory network of B lymphopoiesis; it may also act as a tumor suppressor gene. Absence or deficiency of FOXP1 during early B-cell development may block pro-B cell to pre-B cell development. The FOXP1-ABL1 fusion protein leads to activated tyrosine kinase and may further alter the critical cellular function of these 2 genes. Clinical significance: The FOXP1-ABL1 fusion has been documented in 3 young adult patients (2 male, 1 female) with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. One patient had tyrosine kinase inhibitors (dasatinib) added to the chemotherapy regimens, who had bone marrow tested negative for MRD at end of consolidation. The clinical details of these cases may predict response to treatment with tyrosine kinase inhibitors. Functional studies are needed to substantiate the efficacy of TKI treatment of this particular ABL-class fusion. Somatic 2021-08-19 13:20:16 UTC https://civicdb.org/links/evidence_items/7292 https://civicdb.org/links/variants/2682 https://civicdb.org/links/genes/4 false CDKN2A 1029 Mutation Pancreatic Cancer 1793 Palbociclib Predictive Does Not Support B Sensitivity/Response In a phase 2 trial, patients with pancreatic cancer with CDKN2A loss or mutation were received palbociclib. Among 12 patients no overall response or stable disease at 16 weeks were observed. 158598 ASCO 2532 Tareq Al Baghdadi, 2018, ASCO Annual Meeting, Abstract 2532 NCT02693535 4 accepted 7299 2704 14 9 21968055 21974865 ENST00000498124.1 75 GRCh37 Somatic 2019-05-09 11:19:40 UTC https://civicdb.org/links/evidence_items/7299 https://civicdb.org/links/variants/2704 https://civicdb.org/links/genes/14 false CDKN2A 1029 Mutation Cholangiocarcinoma 4947 Palbociclib Predictive Does Not Support B Sensitivity/Response In a phase 2 trial, patients with gallbladder cancer or bile duct cancer with CDKN2A loss or mutation were received palbociclib. Among 10 patients, no overall response or stable disease at 16 weeks were observed. 158598 ASCO 2532 Tareq Al Baghdadi, 2018, ASCO Annual Meeting, Abstract 2532 NCT02693535 4 accepted 7300 2704 14 9 21968055 21974865 ENST00000498124.1 75 GRCh37 Somatic 2019-05-09 11:19:46 UTC https://civicdb.org/links/evidence_items/7300 https://civicdb.org/links/variants/2704 https://civicdb.org/links/genes/14 false ERBB2 2064 Amplification Colorectal Cancer 9256 Trastuzumab,Pertuzumab Combination Predictive Supports B Sensitivity/Response In an updated report of a part of the phase 2a MyPathway trial, 57 patients with treatment-refractory, metastatic colorectal cancer with HER2 amplification received pertuzumab and trastuzumab. Objective response rate was 32% (n=18/57). One patient had a complete response, and 17 experienced a partial response. Patients were determined to have HER2 amplification by NGS and/or FISH/CISH. In addition, the authors note that 27/35 patients had HER2 overexpression as determined by IHC, 3 of 47 tested had HER2 mutations, 8 had PIK3CA mutations, and 13 had mutated KRAS. Exploratory analysis found that KRAS wild-type patients had better ORR as compared to KRAS mutated patients (40% vs 8%). 30857956 PubMed Meric-Bernstam et al., 2019, Lancet Oncol. NCT02091141 3 accepted 7302 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2021-03-11 01:26:47 UTC https://civicdb.org/links/evidence_items/7302 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false BRAF 673 KIAA1549::BRAF Spindle Cell Sarcoma 4235 Bevacizumab,Temsirolimus,Sorafenib Combination Predictive Supports C Sensitivity/Response A patients with malignant spindle cell tumor treated as as soft tissue sarcoma harboring KIAA1549-BRAF fusion were treated with sorafenib in combination with bevacizumab and temsirolimus. Tumor of the chest wall showed good response. 26314551 PubMed Ross et al., 2016, Int. J. Cancer 2 accepted 7312 618 5 7 138545885 138666064 ENST00000440172.1 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2022-05-07 00:08:59 UTC https://civicdb.org/links/evidence_items/7312 https://civicdb.org/links/variants/618 https://civicdb.org/links/genes/5 false PIK3CA 5290 Mutation Breast Cancer 1612 Alpelisib,Fulvestrant Combination Predictive Supports A Sensitivity/Response In a phase 3 trial, patients with hormone receptor positive, HER2 receptor negative breast were allocated to alpelisib plus fulvestrant or placebo plus fulvestrant. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. In the cohort of patients with PIK3CA-mutated cancer (defined by the presence of any PIK3CA mutation in mutation hot spots in the C2, helical, and kinase domains of PI3K corresponding to exons 7, 9, and 20, respectively), PFS was 11 months in the alpelisib-fulvestrant group, as compared with 5.7 months in the placebo-fulvestrant group (HR 0.65, 95% CI, 0.50 to 0.85, p<0.001). In the cohort without PIK3CA-mutated cancer, the HR was 0.85 (95% CI, 0.58 to 1.25). Overall response rate was also greater in the PIK3CA-mutant group (26.6% vs. 12.8%). 31091374 PubMed André et al., 2019, N. Engl. J. Med. NCT02437318 5 accepted 7313 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2021-01-04 22:56:09 UTC https://civicdb.org/links/evidence_items/7313 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false EGFR 1956 EGFR::RAD51 Lung Adenocarcinoma 3910 Icotinib Predictive Supports C Sensitivity/Response A case of EGFR-RAD51 fusion in lung adenocarcinoma that showed a response to icotinib, . 31064887 PubMed Guan et al., 2019, Oncologist 2 accepted 7314 2203 19 Somatic 2020-08-12 15:43:10 UTC https://civicdb.org/links/evidence_items/7314 https://civicdb.org/links/variants/2203 https://civicdb.org/links/genes/19 false PIK3CA 5290 E542K Breast Cancer 1612 Fulvestrant,Alpelisib Combination Predictive Supports A Sensitivity/Response In a phase 3 trial, 572 patients with hormone receptor positive, HER2 receptor negative advanced breast cancer who previously received endocrine therapy were allocated to alpelisib plus fulvestrant or placebo plus fulvestrant. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status (N=341). PIK3CA mutation was determined according to the presence or absence of any hot spot mutation in the C2, helical, and kinase domains of PI3K (corresponding to exon 7, 9, and 20, respectively). In the cohort of patients with PIK3CA-mutated cancer, PFS was 11 months in the alpelisib-fulvestrant group, as compared with 5.7 months in the placebo-fulvestrant group (HR 0.65, p<0.001). In the cohort without PIK3CA-mutated cancer, the HR was 0.85. Analyses of PFS according to mutation types showed consistent benefit of treatment with alpelisib–fulvestrant across prespecified subgroups, including E542K (N=60, HR 0.60, 95% CI 0.29-1.23), E545X, and H1047X. 31091374 PubMed André et al., 2019, N. Engl. J. Med. NCT02437318 3 accepted 7315 103 37 3 178936082 178936082 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K variants are the second most recurrent PIK3CA mutations in breast cancer and are highly recurrent mutations in many other cancer types. Colorectal cancer patients with the PIK3CA E545K variant, and possibly other variants in the E545 region, may indicate poor prognosis relative to patients with other PIK3CA variants or wild-type PIK3CA. The literature also suggests that E545/E542 variants may confer resistance to EGFR inhibitors (e.g., cetuximab). An FDA approved treatment regimen including a targeted PIK3CA inhibitor is available for specific subtypes of breast cancer. While PIK3CA variants are highly prevalent in many other cancer types, targeted therapies for PIK3CA variants are still in early clinical trial phases in other cancer types. Somatic 2019-08-08 02:49:18 UTC https://civicdb.org/links/evidence_items/7315 https://civicdb.org/links/variants/103 https://civicdb.org/links/genes/37 false BRAF 673 KIAA1549::BRAF Pilocytic Astrocytoma 4851 Diagnostic Supports B Positive This study identified a novel rearrangement event between the uncharacterized gene KIAA-1549 and BRAF in 66% (29 of 44) of pilocytic astrocytoma but not in 244 higher-grade astrocytomas that were evaluated. An in vitro study further showed that this fusion gene lacks the N-terminal BRAF auto-regulatory domain, leading to constitutive activation of BRAF. 18974108 PubMed Jones et al., 2008, Cancer Res. 4 accepted 7319 618 5 7 138545885 138666064 ENST00000440172.1 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2019-12-12 22:59:53 UTC https://civicdb.org/links/evidence_items/7319 https://civicdb.org/links/variants/618 https://civicdb.org/links/genes/5 false FGFR2 2263 Fusion Intrahepatic Cholangiocarcinoma 4928 Cholangiocarcinoma Derazantinib Predictive Supports B Sensitivity/Response Actionable fibroblast growth factor receptor 2 (FGFR2) fusions have been identified in intrahepatic cholangiocarcinomas (iCCA). Derazantinib, a multi-kinase inhibitor with potent pan-FGFR activity showed anti-tumour activity and a manageable safety profile in patients with advanced, unresectable iCCA with FGFR2 fusion who progressed after chemotherapy. In twenty-nine patients, overall response rate was 20.7%, disease control rate was 82.8%, and median PFS was 5.7 months (95% CI: 4.0–9.2). Similar to other pan-FGFR inhibitors, common AEs included asthenia/fatigue, hyperphosphatemia, eye toxicity and increase in ALT/AST. 30420614 PubMed Mazzaferro et al., 2019, Br. J. Cancer NCT03230318 3 accepted 7329 2202 22 Somatic 2022-07-22 21:18:07 UTC https://civicdb.org/links/evidence_items/7329 https://civicdb.org/links/variants/2202 https://civicdb.org/links/genes/22 false BRAF 673 KIAA1549::BRAF Pilocytic Astrocytoma 4851 Oncogenic N/A D N/A This study identified a novel rearrangement event between the uncharacterized gene KIAA-1549 and BRAF in 66% (29 of 44) of pilocytic astrocytomas. The fusion gene was shown to delete the N-terminal BRAF auto-regulatory domain which in vitro assays indicated leads to constitutive activation of BRAF. Cos7 cells were transfected with two isoforms of KIAA1549-BRAF (both exon 16:exon 9), BRAF V600E, or wildtype BRAF and evaluated activity via BRAF kinase assay. Both fusion isoforms showed similar or higher kinase activity than V600E transfected cells. NIH3T3 cells transfected with V600E or the short fusion isoform also demonstrated anchorage-independent growth in soft agarose. 18974108 PubMed Jones et al., 2008, Cancer Res. 3 accepted 7337 618 5 7 138545885 138666064 ENST00000440172.1 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2021-08-26 19:29:07 UTC https://civicdb.org/links/evidence_items/7337 https://civicdb.org/links/variants/618 https://civicdb.org/links/genes/5 false BRAF 673 V600 Colorectal Cancer 9256 Cetuximab,Irinotecan,Vemurafenib Combination Predictive Supports B Sensitivity/Response A randomized clinical trial was done with metastatic colorectal cancer (mCRC) patients (50 in the control group, 49 in the experimental group) with BRAF V600 mutations and RAS wild type that were enrolled from December 2014 to April 2016. The patients were randomized into groups with irinotecan and cetuximab with vemurafenib (VIC group) or without (IC group). The VIC group showed an improvement of progression of free survival (HR 0.42, 95% CI: 0.26 to 0.66, p < 0.001) with a median value of 4.4 months compared to 2.0 months for the IC group. In addition, for the VIC group, there was a 16% drug response rate while the IC group had a 4% drug response rate (p-value = 0.08). Some grade 3/4 adverse events were higher in the experimental arm, and skin toxicity and fatigue showed no increase. 147167 ASCO 3505 Scott Kopetz, 2017, ASCO Annual Meeting, Abstract 3505 NCT02164916 3 accepted 7355 17 5 7 140453136 140453137 ENST00000288602.6 75 GRCh37 BRAF mutations of the valine 600 residue have been shown to be recurrent in many cancer types. Of the V600 mutations, V600E is the most widely researched. V600 mutations as a whole have been correlated to poorer prognosis in colorectal and papilarry thyroid cancers. V600 mutations have also been shown to confer sensitivity to the BRAF inhibitor dabrafenib. For a more detailed summary, click the individual mutations. Somatic 2019-06-04 21:03:35 UTC https://civicdb.org/links/evidence_items/7355 https://civicdb.org/links/variants/17 https://civicdb.org/links/genes/5 false EGFR 1956 Mutation Lung Non-small Cell Carcinoma 3908 Dacomitinib Predictive Supports B Sensitivity/Response In the ARCHER 1050 Phase 3 Trial (NCT01774721), 452 patients with newly diagnosed stage IIIB/IV or recurrent NSCLC exon 19 deletion or the Leu858Arg mutation, (with or without the T790M) were treated with second generation tyrosine kinase inhibitor (TKI) dacomitinib (227 patients) or first generation TKI gefitinib (225 patients). Primary endpoint was progression free survival (PFS), and median PFS according to masked independent review was 14.7 months (95% CI 11.1–16.6) with dacomitinib group 9.2 months (9.1–11.0) with gefitinib (HR 0·59, 95% CI 0·47–0·74; p<0·0001). Benefit of dacomitinib over gefitinib was lower in non-Asian patient subgroup (n=106) than in Asian group (n=346) although authors note smaller sample size may explain this. Authors state that PFS was significantly improved with first line dacomitinib treatment, and that dacomitinib should be considered for EGFR mutant NSCLC treatment. 28958502 PubMed Wu et al., 2017, Lancet Oncol. NCT01774721 4 accepted 7363 442 19 7 55086794 55279321 ENST00000275493.2 75 GRCh37 Somatic 2019-11-04 16:49:37 UTC https://civicdb.org/links/evidence_items/7363 https://civicdb.org/links/variants/442 https://civicdb.org/links/genes/19 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Ponatinib Predictive Supports D Sensitivity/Response In a preclinical trial, multiple experiments testing the effectiveness of ponatinib on the mutation FLT3-ITD in acute myeloid leukemia (AML) were conducted. Ponatinib was very effective in targeting the FLT3-ITD mutation in MV4-11 cell lines (growth inhibition: IC50=2 nmol/L) compared to native FLT3 in RS4;11 cell lines (IC50>100 nmol/L). Additionally, MV4-11 cell lines incubated for 1 hour were shown to have reduced phosphorylation of tyrosine kinases beginning at a ponatinib concentration of 0.3 nmol/L. Ponatinib was shown to induce apoptotic mechanisms measured by caspase-3/7 activity in MV4-cell lines. In mice with the MV4-11 xenograft, ponatinib was very effective in targeting the FLT3-ITD mutation, as dosages of 1-5 mg/kg led to tumor growth inhibition and regression, while dosages of 10 and 25 mg/kg led to complete tumor regression. In primary blast cells from AML patients, Ponatinib was selectively effective in growth inhibition of the FLT3-ITD patient cells (n=1, IC50=4nmol/L) when compared to the native FLT3 patient cells (n=3, IC50>100nmol/L). 21482694 PubMed Gozgit et al., 2011, Mol. Cancer Ther. 5 accepted 7369 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2019-06-21 20:48:08 UTC https://civicdb.org/links/evidence_items/7369 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false KIT 3815 N822K Acute Myeloid Leukemia 9119 Sunitinib,Sorafenib Substitutes Predictive Does Not Support D Sensitivity/Response In a preclinical trial, the AML cell line Kasumi-1 with the KIT mutation N822K was treated with the tyrosine kinase inhibitors (TKI) ponatinib, sorafenib, and sunitinib. Ponatinib was much more effective in the growth inhibition of cells harboring the KIT mutation (IC50=8 nmol/L) compared to sorafenib (IC50=59 nmol/L) and sunitinib (IC50=56 nmol/L). 21482694 PubMed Gozgit et al., 2011, Mol. Cancer Ther. 3 accepted 7370 1263 29 4 55599340 55599340 T A ENST00000288135.5 75 GRCh37 Somatic 2019-06-21 23:23:53 UTC https://civicdb.org/links/evidence_items/7370 https://civicdb.org/links/variants/1263 https://civicdb.org/links/genes/29 false FGFR1 2260 Fusion Acute Myeloid Leukemia 9119 Sorafenib,Sunitinib Substitutes Predictive Does Not Support D Sensitivity/Response In a preclinical trial, the AML cell line KG1 with the FGFR1OP2-FGFR1 fusion mutation was treated with the tyrosine kinase inhibitors (TKI) ponatinib, sorafenib, and sunitinib. Ponatinib was much more effective in the growth inhibition of cells harboring the fusion mutation (IC50=17 nmol/L) compared to sorafenib (IC50>100 nmol/L) and sunitinib (IC50>100 nmol/L). 21482694 PubMed Gozgit et al., 2011, Mol. Cancer Ther. 3 accepted 7375 569 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 Somatic 2019-06-21 23:22:04 UTC https://civicdb.org/links/evidence_items/7375 https://civicdb.org/links/variants/569 https://civicdb.org/links/genes/1885 false PDGFRA 5156 FIP1L1::PDGFRA Acute Myeloid Leukemia 9119 Sunitinib,Sorafenib Substitutes Predictive Supports D Sensitivity/Response In a preclinical trial, the AML cell line EOL1with the FIP1L1-PDGFRa fusion mutation was treated with the tyrosine kinase inhibitors (TKI) ponatinib, sorafenib, and sunitinib. Ponatinib was similarly effective in the growth inhibition of cells harboring the fusion mutation (IC50=0.5 nmol/L) compared to sorafenib (IC50=0.5 nmol/L) and sunitinib (IC50=3 nmol/L). 21482694 PubMed Gozgit et al., 2011, Mol. Cancer Ther. 3 accepted 7378 574 38 4 54243812 54294350 ENST00000337488.6 4 55141008 55164414 ENST00000257290.5 75 GRCh37 Prospective trials of patients with hypereosinophilic syndrome harboring the FIP1L1-PDGFRA fusion identified marked response to imatinib treatment (Gotlib and Cool, Leukemia 2008). Imatinib is FDA approved for the treatment of "adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase" (NDA021588). Somatic 2019-06-21 23:25:01 UTC https://civicdb.org/links/evidence_items/7378 https://civicdb.org/links/variants/574 https://civicdb.org/links/genes/38 false KIT 3815 N822K Acute Myeloid Leukemia 9119 Ponatinib Predictive Supports D Sensitivity/Response In this preclinial trial, the AML cell line Kasumi-1 with c-KIT N822K mutation was treated with Ponatinib. This drug effectively inhibits both KIT phosphorylation and viability for Kasumi-1 cells at IC50 values 20 nmol/L and 8 nmol/L respectively. 21482694 PubMed Gozgit et al., 2011, Mol. Cancer Ther. 2 accepted 7379 1263 29 4 55599340 55599340 T A ENST00000288135.5 75 GRCh37 Somatic 2019-06-21 22:48:26 UTC https://civicdb.org/links/evidence_items/7379 https://civicdb.org/links/variants/1263 https://civicdb.org/links/genes/29 false FGFR1 2260 FGFR1OP2::FGFR1 Acute Myeloid Leukemia 9119 Ponatinib Predictive Supports D Sensitivity/Response In this preclinial trial, the AML cell line KG1 with FGFR1OP2-FGFR1 mutation was treated with Ponatinib. This drug effectively inhibits both FGFR phosphorylation and viability for KG1 cells at IC50 values 3 nmol/L and 17 nmol/L respectively. 21482694 PubMed Gozgit et al., 2011, Mol. Cancer Ther. 2 accepted 7380 2743 1885 Somatic 2019-06-21 22:45:54 UTC https://civicdb.org/links/evidence_items/7380 https://civicdb.org/links/variants/2743 https://civicdb.org/links/genes/1885 false FLT3 2322 ITD Leukemia 1240 Sunitinib,Sorafenib Substitutes Predictive Supports D Sensitivity/Response In a preclinical trial, the leukemic cell line MV4-11 with the FLT3-ITD mutation and the leukemic cell line RS4;11 with the native FLT3 gene were treated with the tyrosine kinase inhibitors (TKI) ponatinib, sorafenib, and sunitinib. Ponatinib was similarly effective in the growth inhibition of cells harboring the FLT3-ITD mutation (IC50=2 nmol/L) compared to sorafenib (IC50=4 nmol/L) and sunitinib (IC50=12 nmol/L). Conversely, all three TKIs each were not effective in the growth inhibition of cells with native FLT3 (IC50>100 nmol/L). 21482694 PubMed Gozgit et al., 2011, Mol. Cancer Ther. 4 accepted 7382 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2019-06-21 23:13:32 UTC https://civicdb.org/links/evidence_items/7382 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false IKZF1 10320 IKZF1 deletion and mutation Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Prognostic Supports B Poor Outcome This study reports on two pediatric cohorts with B-ALL. In the first cohort of 221 high risk, BCR-ABL1-negative pediatric patients, 55.2% of IKZF1 positive patients had a hematologic relapse, 73.4% of IKZF1 positive patients had any relapse, and 74.6% of IKZF1 positive patients had an event (hematologic relapse, any relapse, a second malignant condition or death) as compared to 14%, 25.2%, and 27.1%, respectively, without an IKZF1 alteration. In a less selected cohort of 258 patients with both standard and high risk disease, with common aneuploidies including BCR-ABL1, 46.3% of IKZF1 positive patients had a hematologic relapse, 48.4% of IKZF1 positive patients had any relapse, and 60.5% of IKZF1 positive patients had an event as compared to 22.5%, 25.6%, and 27.6%, respectively, without an IKZF1 alteration. IKZF1 alteration is defined as a deletion or mutation in the gene. Gene expression profiles were found to be similar to BCR-ABL1 positive B-ALL, even when the BCR-ABL1 translocation was not present. The study concludes that IKZF1 alterations are associated with a very poor outcome in B-ALL. 19129520 PubMed Mullighan et al., 2009, N. Engl. J. Med. 4 accepted 7383 2744 73 Somatic 2020-10-08 19:59:46 UTC https://civicdb.org/links/evidence_items/7383 https://civicdb.org/links/variants/2744 https://civicdb.org/links/genes/73 false KIT 3815 A502_Y503insAY Gastrointestinal Stromal Tumor 9253 Sunitinib Predictive Supports D Sensitivity/Response In an in vitro study, an IL3 independant Ba/F3 cell line expressing KIT V560D primary activating mutation demonstrated sensitivity to sunitinib treatment (IC50: 5nmol/L). IC50 was determined by assessing cell viability. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 2 accepted 7392 1558 29 4 55592182 55592183 GCCTAT GRCh37 Somatic 2019-07-09 22:05:30 UTC https://civicdb.org/links/evidence_items/7392 https://civicdb.org/links/variants/1558 https://civicdb.org/links/genes/29 false KIT 3815 V560_L576DEL Gastrointestinal Stromal Tumor 9253 Ponatinib,Imatinib Substitutes Predictive Does Not Support D Sensitivity/Response In the patient-derived cell line GIST430 harboring KIT V560_L576del primary activating mutation implanted in mice, imatinib and ponatinib were shown to reduce KIT phosphorylation compared to the vehicle. In GIST430 cell lines, ponatinib and imatinib reduced phospho-AKT and phospho-ERK levels. A cell line derived from GIST430 patients expressing KIT V560_L576del primary mutation demonstrated sensitivity to imatinib (IC50: 61nmol/L) and ponatinib (IC50: 12nmol/L) treatments. In comparison, the insensitve KIT-independent GIST226 cell line showed IC50 >5000nmol/L and 2807nmol/L for these drugs respectively. IC50 was determined by assessing cell viability. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 4 accepted 7393 1550 29 4 55593612 55593662 GRCh37 Somatic 2019-07-09 22:36:55 UTC https://civicdb.org/links/evidence_items/7393 https://civicdb.org/links/variants/1550 https://civicdb.org/links/genes/29 false KIT 3815 V560G Gastrointestinal Stromal Tumor 9253 Regorafenib,Ponatinib,Imatinib Substitutes Predictive Supports D Sensitivity/Response In an in vitro kinase study, a KIT V560G primary activating mutant kinase demonstrated sensitivity to imatinib (IC50: 38nmol/L vs. 640nmol/L), regorafenib (IC50: 27nmol/L vs. 533nmol/L), and ponatinib (IC50: 0.3nmol/L vs. 6nmol/L) treatments compared to the wildtype KIT. IC50 was determined by assessing kinase activity. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 3 accepted 7395 972 29 4 55593613 55593613 T G ENST00000288135.5 75 GRCh37 Somatic 2019-07-09 23:18:43 UTC https://civicdb.org/links/evidence_items/7395 https://civicdb.org/links/variants/972 https://civicdb.org/links/genes/29 false KIT 3815 K642E Gastrointestinal Stromal Tumor 9253 Sunitinib,Ponatinib Substitutes Predictive Supports D Sensitivity/Response The GIST882 patient derived cell line expressing KIT K642E mutation demonstrated sensitivity to ponatinib (IC50: 31nmol/L) and sunitinib (IC50: 54nmol/L) treatments. In comparison, the insensitve KIT-independent GIST226 cell line showed IC50 >2807nmol/L and >5000nmol/L for these drugs respectively. IC50 was determined by assessing cell viability. The GIST882 cell line only showed reduced levels of phospho-KIT and phospho-ERK at high concentrations for ponatinib and sunitinib, while phospho-AKT levels were reduced at all concentrations for ponatinib and sunitinib. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 3 accepted 7397 978 29 4 55594221 55594221 A G ENST00000288135.5 75 GRCh37 Somatic 2019-07-09 23:29:48 UTC https://civicdb.org/links/evidence_items/7397 https://civicdb.org/links/variants/978 https://civicdb.org/links/genes/29 false KIT 3815 D816E Gastrointestinal Stromal Tumor 9253 Ponatinib Predictive Does Not Support D Resistance A preclinical study was done in order to test the effects of a tyrosine kinase inhibitor (TKI) on the ponatinib-sensitive KIT-mutant cell line GIST-T1 derived from Gastrointestinal Stromal Tumor (GIST) patients with primary mutation 560-578 deletion and additional secondary mutation D816E. The cells were tested for Ponatinib resistance. GIST-T1/816 cells containing del 560-578 and D816E mutations (IC50: 23 nM) did not show resistance towards Ponatinib compared to GIST-T1 cells with only del 560-578 mutation (IC50: 5 nM). Ponatinib reduced phosphorylation in KIT, AKT, and ERK at higher concentrations. According to the results, the authors suggest that Ponatinib remained highly active in GIST cell lines with secondary mutation D816E. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 4 accepted 7401 1559 29 4 55599322 55599322 C G ENST00000288135.5 75 GRCh37 Somatic 2019-07-19 22:43:39 UTC https://civicdb.org/links/evidence_items/7401 https://civicdb.org/links/variants/1559 https://civicdb.org/links/genes/29 false BRAF 673 KIAA1549::BRAF Childhood Pilocytic Astrocytoma 6812 Sorafenib,Vemurafenib Substitutes Predictive Supports D Resistance A pilocytic astrocytoma (PA) cell line named DKFZ-BT66 was generated from a 2-year old patient with the disease. Expression of KIAA1549-BRAF fusion in this cell line was identified. Treatment with sorafenib or vemurafenib resulted in paradoxical activation of MAPK/ERK as seen by increased pERK in western blots. Authors note that their observation aligns with results from a phase II clinical trial wherein PA patients experienced tumor growth under sorafenib treatment induced by paradoxical MAPK activation. 28002790 PubMed Selt et al., 2017, Oncotarget 2 accepted 7402 618 5 7 138545885 138666064 ENST00000440172.1 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2020-11-30 21:55:53 UTC https://civicdb.org/links/evidence_items/7402 https://civicdb.org/links/variants/618 https://civicdb.org/links/genes/5 false KIT 3815 A829P Gastrointestinal Stromal Tumor 9253 Ponatinib Predictive Does Not Support D Resistance Ponatinib possesses potent activity against A829P KIT mutant cells in preclinical experiments. A preclinical study tested the effect of a tyrosine kinase inhibitor (TKI) on Ba/F3 cell lines with representative primary ponatinib-sensitizing mutation del 557-558, which induced IL-3 independent growth, and secondary mutation A829P. The cells were tested for Ponatinib resistance. Ba/F3 cells with del 557-558 and A829P mutations (IC50 for growth inhibition: 2 nM) did not show resistance towards Ponatinib compared to Ba/F3 cells with the del 557-558 mutation alone (IC50: 3 nM). Ponatinib was shown to inhibit KIT phosphorylation in moderate concentrations. Similarly, GIST-T1/829 cells with 560-578 deletion/A829P mutations (IC50 = 16 nM) were not resistant to Ponatinib compared to GIST T1 cells with 560-578 deletion alone (IC50 = 5 nM). Ponatinib inhibited phosphorylation in KIT, ERK, and AKT at moderate to high concentrations in GIST-T1/829 cells. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 4 accepted 7413 990 29 4 55602664 55602664 G C GRCh37 Somatic 2019-07-22 21:00:45 UTC https://civicdb.org/links/evidence_items/7413 https://civicdb.org/links/variants/990 https://civicdb.org/links/genes/29 false KIT 3815 N822K Gastrointestinal Stromal Tumor 9253 Imatinib,Sunitinib Substitutes Predictive Supports D Resistance Several preclinical studies tested the effects of various tyrosine kinase inhibitors (TKIs) on Ba/F3 cell lines with primary TKI-sensitizing del 557-558 mutation, which induced IL-3 independent growth, and secondary mutation N822K. The cells were tested for Sunitinib and Imatinib resistances. Ba/F3 cells with del 557-558 and N822K mutations (Sunitinib IC50 for growth inhibition: 225 +- 19 nM, Imatinib IC50: 483 +- 24 nM) did show resistance towards Sunitinib and Imatinib compared to Ba/F3 cells with the del 557-558 alone (Sunitinib IC50: 7 +- 2 nM, Imatinib IC50: 27 +- 8 nM). Sunitinib and Imatinib did not completely inhibit KIT phosphorylation at 1000 nM, which was the highest concentration tested. Additionally, Ba/F3 cells were mutagenized with N-ethyl-N-nitrosourea and incubated with varying concentrations of Sunitinib and Imatinib separately. From these results, N822K mutations were the most frequent KIT mutation observed in resistant Ba/F3 cell populations incubated in Sunitinib. In Imatinib incubated cells, N822K mutations were seen in approximately 10% of resistant Ba/F3 cell clones. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 4 accepted 7414 1263 29 4 55599340 55599340 T A ENST00000288135.5 75 GRCh37 Somatic 2019-07-19 22:12:43 UTC https://civicdb.org/links/evidence_items/7414 https://civicdb.org/links/variants/1263 https://civicdb.org/links/genes/29 false KIT 3815 A829P Gastrointestinal Stromal Tumor 9253 Imatinib,Sunitinib Substitutes Predictive Supports D Resistance Several preclinical studies tested the effects of various tyrosine kinase inhibitors (TKIs) on Ba/F3 cell lines with representative primary sunitinib and imatinib sensitizing mutation del 557-558, which induced IL-3 independent growth, and secondary mutation A829P. The cells were tested for Sunitinib and Imatinib resistances. Ba/F3 cells with del 557-558 and A829P mutations did show resistance towards Sunitinib and Imatinib (Sunitinib IC50 for growth inhibition: 319 +- 88 nM and Imatinib IC50: 179 +- 27 nM) compared to Ba/F3 cells with the del 557-558 mutation (Sunitinib IC50: 7 +- 2 nM and Imatinib IC50: 27 +- 8 nM). Imatinib and Sunitinib were shown to not reduce p-KIT at all in Ba/F3 cells with del 557-558/ A829P mutations. Patient-derived GIST-T1/829 cells with 560-578 deletion/A829P mutations (Sunitinib IC50: 1168 nM and Imatinib IC50:1201 nM) did show resistance towards Sunitinib and Imatinib compared to GIST-T1 cells with 560-578 deletion alone (Sunitinib IC50: 15 nM and Imatinib IC50: 30 nM). Sunitinib and Imatinib did not inhibit p-KIT, p-ERK, and p-AKT in GIST-T1/829 cells. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 4 accepted 7415 990 29 4 55602664 55602664 G C GRCh37 Somatic 2019-07-22 22:04:42 UTC https://civicdb.org/links/evidence_items/7415 https://civicdb.org/links/variants/990 https://civicdb.org/links/genes/29 false KIT 3815 T670I Gastrointestinal Stromal Tumor 9253 Imatinib Predictive Supports D Resistance A preclinical study tested the effects of a tyrosine kinase inhibitor (TKI) on Ba/F3 cell lines with representative primary imatinib-sensitizing mutation del 557-558, which induced IL-3 independent growth, and secondary mutation T670I. The cells were tested for Imatinib resistance. Ba/F3 cells with del 557-558/T670I mutations (IC50 = >10000 nM) showed resistance towards Imatinib compared to Ba/F3 cells with del 557-558 alone (IC50 = 27 +- 8 nM). Similarly, patient-derived GIST-T1/670 cells with 560-578 deletion/T670I mutations (IC50 > 5000 nM) did show resistance towards Imatinib compared to GIST-T1 cells with 560-578 deletion (IC50 = 30 nM). Del 557-558/T670I cells were implanted into mice and treated with Imatinib. Imatinib was not effective in treating the del 557-558/T670I cells in mice as tumor volume progressively increased. In addition, Ba/F3 cells were mutagenized with N-ethyl-N-nitrosourea and incubated with varying concentrations of Imatinib. In Imatinib incubated cells, T670I mutations were seen in approximately 80% of the resistant cell populations. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 5 accepted 7416 1267 29 4 55595519 55595519 C T ENST00000288135.5 75 GRCh37 Somatic 2019-07-22 23:00:43 UTC https://civicdb.org/links/evidence_items/7416 https://civicdb.org/links/variants/1267 https://civicdb.org/links/genes/29 false KIT 3815 T670I Gastrointestinal Stromal Tumor 9253 Ponatinib,Sunitinib Substitutes Predictive Does Not Support D Resistance Several preclinical studies tested the effects of various tyrosine kinase inhibitors (TKIs) on Ba/F3 cell lines with representative primary ponatinib and sunitinib sensitizing mutation del 557-558, which induced IL-3 independent growth, and secondary mutation T670I. The cells were tested for Ponatinib and Sunitinib resistances. Ba/F3 cells with del 557-558/T670I mutations (Ponatinib IC50 = 15 +/- 1 nM, Sunitinib IC50 = 12 +/- 2 nM) did not show resistance towards Ponatinib and Sunitinib compared to Ba/F3 cells with del 557-558 alone (Ponatinib IC50 = 3 +/- 0, Sunitinib IC50 = 7 +/- 2 nM). Similarly, patient-derived GIST-T1/670 cells with 560-578 deletion/T670I mutations (Ponatinib IC50 = 8 nM, Sunitinib IC50 = 15 nM) showed no resistance towards Ponatinib and Sunitinib compared to GIST-T1 cells with 560-578 deletion (Ponatinib IC50 = 5 nM, Sunitinib IC50 = 48 nM). Additionally, del 557-558/T670I cells was implanted into mice and treated with Ponatinib or Sunitinib. Ponatinib or Sunitinib were shown to be effective in treating the Ba/F3 mutant cells as tumor volume progressively decreased to zero at around 14 days. 25239608 PubMed Garner et al., 2014, Clin. Cancer Res. 5 accepted 7417 1267 29 4 55595519 55595519 C T ENST00000288135.5 75 GRCh37 Somatic 2019-07-22 23:19:14 UTC https://civicdb.org/links/evidence_items/7417 https://civicdb.org/links/variants/1267 https://civicdb.org/links/genes/29 false NTRK3 4916 ETV6::NTRK3 Congenital Fibrosarcoma 8418 Larotrectinib Predictive Supports C Sensitivity/Response In a pediatric phase 1 trial (NCT02637687) after initial chemotherapy failure, two ETV6-NTRK3 positive children (2 year old and 5 month old) were treated with Larotrectinib, resulting in reduced tumor burden (4 cycles showed ~50% reduction). Treatment was followed up by surgical resection resulting in a disease-free status at the time of last follow-up (>1 year). 30204247 PubMed DuBois et al., 2018, Cancer NCT02637687 3 accepted 7418 801 3985 12 11802788 12022903 ENST00000396373.4 15 88483984 88418230 ENST00000394480.2 75 GRCh37 Somatic 2020-09-11 21:00:26 UTC https://civicdb.org/links/evidence_items/7418 https://civicdb.org/links/variants/801 https://civicdb.org/links/genes/3985 false NTRK1 4914 TPM3::NTRK1 Spindle Cell Sarcoma 4235 Juvenile onset Larotrectinib Predictive Supports C Sensitivity/Response In a pediatric phase 1 trial (NCT02637687), a 12-year-old boy with TPM3-NTRK1 fusion was treated with Larotrectinib as first line treatment as no standard treatment options were available. Following a significant tumor burden reduction of 31%, he underwent surgical resection, with R0 resection and no evidence for tumor recurrence at the time of last follow-up (>7 months). 30204247 PubMed DuBois et al., 2018, Cancer NCT02637687 3 accepted 7419 2992 3983 Somatic 2020-09-15 17:13:41 UTC https://civicdb.org/links/evidence_items/7419 https://civicdb.org/links/variants/2992 https://civicdb.org/links/genes/3983 false NTRK1 4914 PDE4DIP::NTRK1 Sarcoma 1115 Larotrectinib Predictive Supports C Sensitivity/Response In a pediatric phase 1 trial (NCT02637687), a boy aged 15 months with soft tissue sarcoma of the right upper thigh harbored the PDE4DIP-NTRK1 fusion. After resection and the failure of initial chemotherapy, Larotrectinib reduced tumor size by 37% after 2 cycles and 64% after 6 cycles. An R2 resection was performed and Larotrectinib again reduced tumor progression. A second R2 resection was followed by adjuvant radiotherapy and Larotrectinib cycles and the patient remained in complete response at the time of the last follow-up. 30204247 PubMed DuBois et al., 2018, Cancer NCT02637687 2 accepted 7420 2289 3983 Somatic 2020-09-15 18:01:45 UTC https://civicdb.org/links/evidence_items/7420 https://civicdb.org/links/variants/2289 https://civicdb.org/links/genes/3983 false ALK 238 Alternative Transcript (ATI) Mucosal Melanoma 0050929 Entrectinib Predictive Does Not Support C Sensitivity/Response ALK expression was analyzed in 45 melanoma patient-derived xenografts (PDXs), with 11/45 showing ALK expression. Four PDX tumours had only wild-type ALK expression, four had only ALK alternative transcript (ATI) expression, two had wild-type and ATI expression, and one had ALK ATI and multiple EML4-ALK fusion variants. In vitro and in vivo experiments showed that an EML4-ALK fusion expressing sample responded to ALK inhibitors while wild-type ALK and ALK ATI expressing samples did not. Decreased activity in downstream signaling targets with ALK inhibitor treatment was noted for samples expressing fusion ALK but not those expressing only ALK ATI. Further, a patient with metastatic mucosal melanoma expressing ALK ATI was treated with the ALK/ROS1/TRK inhibitor entrectinib but experienced rapid clinical and radiologic progression resulting in treatment discontinuation after two weeks. 29054983 PubMed Couts et al., 2018, Mol. Cancer Ther. 4 accepted 7421 839 1 This novel ALK transcript (alternative isoform) initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19. N/A 2020-05-13 18:05:53 UTC https://civicdb.org/links/evidence_items/7421 https://civicdb.org/links/variants/839 https://civicdb.org/links/genes/1 false FGFR3 2261 Mutation Transitional Cell Carcinoma 2671 Erdafitinib Predictive Supports A Sensitivity/Response In a phase 2 trial, patients with locally advanced and unresectable or metastatic urothelial carcinoma harboring FGFR3 mutation or FGFR2/3 fusion were treated with Erdafitinib. All the patients had a history of disease progression during or after at least one course of chemotherapy. The response rate in patients receiving continuous daily 8 or 9mg Erdafitinib treatment was 40% (40/99). Within this treatment group, the response rate of patients with FGFR3 mutation was 49% (36/74). FGFR3 mutations included G370C, R248C, S249C, and Y373C. 31340094 PubMed Loriot et al., 2019, N. Engl. J. Med. NCT02365597 4 accepted 7422 827 23 4 1795039 1810599 ENST00000340107.4 75 GRCh37 Somatic 2021-04-26 18:33:48 UTC https://civicdb.org/links/evidence_items/7422 https://civicdb.org/links/variants/827 https://civicdb.org/links/genes/23 false TP53 7157 R273H Osteosarcoma 3347 Doxorubicin,Methotrexate Substitutes Predictive Supports D Resistance Several preclinical studies were testing drug resistance mechanisms of TP53-R273H variant. Saos-2 cells were transfected with TP53-R273H mutation and these cells were used in the study. Using a western blot, Saos-2/TP53-R273H cells were shown to have a 0.6-fold down-regulation (compared to the Control) for Procaspase-3 protein expression. In addition, Saos-2/TP53-R273H cells were shown to be more resistant to methotrexate and doxorubicin. Reduced levels of drug-induced apoptosis were seen in Saos-2/TP53-R273H cells treated with doxorubicin (0.05 uM and 0.10 uM) and methotrexate (25 nM and 50 nM) in DNA fragmentation assays. According to the results, TP53-R273H induces drug resistance when procaspase-3 is down-regulated. 17363498 PubMed Wong et al., 2007, Mol. Cancer Ther. 3 accepted 7430 122 45 17 7577120 7577120 C T ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R273 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been suggested that the R273 mutants have been correlated with worse overall survival in breast cancer patients when compared to wild-type. Somatic 2020-03-23 20:04:55 UTC https://civicdb.org/links/evidence_items/7430 https://civicdb.org/links/variants/122 https://civicdb.org/links/genes/45 false CDKN2A 1029 Loss Lung Non-small Cell Carcinoma 3908 Palbociclib Predictive Does Not Support B Resistance TAPUR, a phase II basket trial, included a cohort of patients with advanced non-small lung cell carcinoma (NSCLC) harboring with CDKN2A loss or mutation and no RB mutations. Twenty-nine patients were treated with CDK4/6 inhibitor palbociclib; one experienced a partial response and 6 experienced stable disease lasting longer than 16 weeks (disease control rate: 29%). Median PFS was 7.9 weeks and median OS was 20.6 weeks. Authors concluded that palbociclib is worthy of further study in advanced NSCLC when standard treatment options aren't available. 174591 ASCO 9041 Eugene R Ahn, 2019, ASCO Annual Meeting, Abstract 9041 NCT02693535 2 accepted 7444 554 14 9 21967752 21994623 ENST00000579755.1 75 GRCh37 Somatic 2021-08-19 13:35:36 UTC https://civicdb.org/links/evidence_items/7444 https://civicdb.org/links/variants/554 https://civicdb.org/links/genes/14 false NFE2L2 4780 Mutation Lung Squamous Cell Carcinoma 3907 Sapanisertib Predictive Supports B Sensitivity/Response In an NCI-CTEP phase 2 trial, patients with squamous cell lung carcinoma with NFE2L2 mutations were treated with TORC1/2 inhibitor TAK-228. The response rate was 29% (2/7）and disease control rate was 100%. NFE2L2 mutations included Exon 2 deletion, F37V, D29H, W24C, E79K, G31R, R34G, R34Q, W24R, D77H, and T80R. 174406 ASCO 9085 Paul K. Paik, 2019, ASCO Annual Meeting, Abstract 9085 NCT02417701 3 accepted 7446 2749 3878 Somatic 2019-11-04 16:35:18 UTC https://civicdb.org/links/evidence_items/7446 https://civicdb.org/links/variants/2749 https://civicdb.org/links/genes/3878 false IDH1 3417 Mutation Cholangiocarcinoma 4947 Ivosidenib Predictive Supports B Sensitivity/Response In a phase1 trial, 73 patients with cholangiocarcinoma harboring IDH1 mutations were treated with mutant IDH1 inhibitor ivosidenib. The response rate was 5%, median progression free survival was 3.8 months, and median overall survival was 13.8 months. 31300360 PubMed Lowery et al., 2019, Lancet Gastroenterol Hepatol NCT02073994 3 accepted 7447 645 26 2 209101803 209116275 ENST00000415913.1 75 GRCh37 Somatic 2019-12-20 09:43:47 UTC https://civicdb.org/links/evidence_items/7447 https://civicdb.org/links/variants/645 https://civicdb.org/links/genes/26 false RICTOR 253260 Amplification Lung Small Cell Carcinoma 5409 Vistusertib Predictive Does Not Support C Sensitivity/Response In a phase 2 basket trial, patients with small-cell lung carcinoma (SLC) who failed platinum-based chemotherapy and harbored RICTOR amplification were treated with mTOR 1/2 inhibitor vistusertib (AZD2014). Among 4 patients enrolled in this study, no patients showed tumor response or disease control. Progression free survival was 1.25 months, and three patients experienced adverse effects grade 3 or greater. Authors conclude that further development of the tested AZD2014 regimen is not warranted. 173496 ASCO 8514 Sehhoon Park, 2019, ASCO Annual Meeting, Abstract 8514 NCT02593019, NCT03106155, NCT03366675 3 accepted 7449 573 20480 5 38938021 39074510 ENST00000357387.3 75 GRCh37 Somatic 2021-01-27 01:40:41 UTC https://civicdb.org/links/evidence_items/7449 https://civicdb.org/links/variants/573 https://civicdb.org/links/genes/20480 false STAG2 10735 MUTATION Acute Myeloid Leukemia 9119 Prognostic Does Not Support B Poor Outcome In a retrospective cohort study of 389 uniformly treated acute myeloid leukemia (AML) patients, 23 patients harbored mutations in genes of the cohesin complex including 5 who harbored mutations in STAG2. Mutation in the cohesin complex was not associated with worse overall survival (OS) or relapse free survival (RFS) compared to wildtype patients. The presence of STAG2 mutations had no influence on OS or RFS compared to wildtype (OS HR: 1.53, p = 0.4; RFS HR: 1.26, P = 0.7), though the authors note that the analysis was limited by the small number of patients. Authors speculate that co-occurring mutations in NPM1 may mask prognostic effects of STAG2 mutations. 24335498 PubMed Thol et al., 2014, Blood NCT00209833 2 accepted 7451 669 8553 X 123176418 123217308 ENST00000218089.9 75 GRCh37 Somatic 2020-07-27 01:30:35 UTC https://civicdb.org/links/evidence_items/7451 https://civicdb.org/links/variants/669 https://civicdb.org/links/genes/8553 false KIT 3815 S628N Melanoma 1909 Imatinib Predictive Does Not Support C Sensitivity/Response A melanoma patient harboring the KIT S628N activating mutation underwent second-line imatinib therapy following lung metastatic progression that appeared after an eighth cycle of chemotherapy. The S628N mutation was not present in the blood, which confirmed that it was a somatic mutation. After 3 months of imatinib treatment (300 mg/d for first three weeks, then 400 mg/d), the patient exhibited disease progression and increased tumor size, and after an additional three months of imatinib treatment (400 mg/d), the patient developed multiple supratentorial brain metastases in addition to increased lung metastases and died 5 days later. The authors reported preclinical data which indicated variant sensitivity to imatinib. although this outcome did not coroberate the preclinical result, the authors still concluded the variant may be sensitive. 25317746 PubMed Vita et al., 2014, JAMA Dermatol 3 accepted 7463 1659 29 4 55594180 55594180 G A GRCh37 Somatic 2019-08-05 23:10:55 UTC https://civicdb.org/links/evidence_items/7463 https://civicdb.org/links/variants/1659 https://civicdb.org/links/genes/29 false KIT 3815 D816V Cancer 162 Imatinib,Dasatinib Substitutes Predictive Supports C Resistance In an in vitro study, COS-7 cells expressing KIT D816V activating mutation demonstrated resistance to 1uM dasatinib treatment. In a separate in vitro study, TF-1 cells expressing KIT D816V activating mutation demonstrated resistance to 1 and 10 uM imatinib treatment. Sensitivity was determined by assessing reduced mutant KIT auto-phosphorylation with addition of inhibitors. No reduction in D816V autophosphorylation was observed with inhibitor treatment. 25317746 PubMed Vita et al., 2014, JAMA Dermatol 2 accepted 7465 65 29 4 55599321 55599321 A T ENST00000288135.5 75 GRCh37 KIT D816V is a mutation observed in acute myeloid leukemia (AML). This variant has been linked to poorer prognosis and worse outcome in AML patients. Somatic 2019-08-05 23:11:19 UTC https://civicdb.org/links/evidence_items/7465 https://civicdb.org/links/variants/65 https://civicdb.org/links/genes/29 false RET 5979 CCDC6::RET Colorectal Cancer 9256 Agerafenib Predictive Supports C Sensitivity/Response A patient with right-sided, MSI-High and CCDC6-RET positive metastatic colorectal cancer showed complete response to the selective RET inhibitor RXDX-105. The patient remained progression-free after 19 months on treatment. 29538669 PubMed Pietrantonio et al., 2018, Ann. Oncol. NCT01877811 3 accepted 7480 626 42 Somatic 2020-06-23 04:47:17 UTC https://civicdb.org/links/evidence_items/7480 https://civicdb.org/links/variants/626 https://civicdb.org/links/genes/42 false ALK 238 CAD::ALK Colorectal Cancer 9256 Entrectinib Predictive Supports C Sensitivity/Response A patient with colorectal cancer harboring a CAD-ALK fusion gene was treated with the ALK inhibitor entrectinib, resulting in durable objective tumor response. A CT scan four weeks after treatment initiation showed a 38% reduction in target lesions, and response was ongoing after 4 months. 26633560 PubMed Amatu et al., 2015, Br. J. Cancer 3 accepted 7481 2769 1 Somatic 2022-02-17 21:13:54 UTC https://civicdb.org/links/evidence_items/7481 https://civicdb.org/links/variants/2769 https://civicdb.org/links/genes/1 false ROS1 6098 GOPC::ROS1 Glioblastoma 3068 Lorlatinib Predictive Supports D Sensitivity/Response Ectopic expression of GOPC–ROS1 in Ba/F3 cells induced cytokine-independent growth whereas overexpression of ROS1 alone did not. Using a series of tyrosine kinase inhibitors, lorlatinib was the most effective inhibitor of cytokine-independent growth. The glioblastoma cell line U118MG was shown to have the GOPC–ROS1 fusion. Lorlatinib and other TKIs were unable to inhibit growth of U118MG in standard growth assays (2D). However, lorlatinib did induce cell death in both ultra-low attachment dishes and spheroid assays, and significantly increased overall survival in an orthotopic intracranial xenograft model using this cell line (N=4) compared to mice on vehicle alone (N=4, p<0.001, ANOVA). Authors postulated that cell adhesion permitted sufficient to bypass survival signaling. 30171048 PubMed Davare et al., 2018, Clin. Cancer Res. 3 accepted 7483 2770 4941 Somatic 2020-05-13 22:03:29 UTC https://civicdb.org/links/evidence_items/7483 https://civicdb.org/links/variants/2770 https://civicdb.org/links/genes/4941 false NF1 4763 Mutation Childhood Low-grade Glioma 0080830 Selumetinib Predictive Supports B Sensitivity/Response In a phase 2 trial, patients with pediatric low-grade glioma after at least one standard therapy were treated with MEK1/2 inhibitor selumetinib. In stratum 1, nine patients with WHO grade I pilocytic astrocytoma harboring KIAA1549-BRAF fusion or BRAF V600E mutation showed tumor response. The response rate was 36% (9/25). In stratum 3, ten patients with neurofibromatosis type 1 associated pediatric low-grade glioma showed tumor response. The response rate was 40% (10/25). 31151904 PubMed Fangusaro et al., 2019, Lancet Oncol. NCT01089101 3 accepted 7487 587 3867 17 29421945 29704695 ENST00000358273.4 75 GRCh37 Rare Germline 2021-02-10 17:48:41 UTC https://civicdb.org/links/evidence_items/7487 https://civicdb.org/links/variants/587 https://civicdb.org/links/genes/3867 false FGFR1 2260 Amplification Breast Cancer 1612 Lucitanib Predictive Supports B Sensitivity/Response In a phase 1 trial, patients with advanced solid tumors were treated with FGFR1/2, VEGFR1/2/3, and PDGFR inhibitor lucitanib. Among 12 patients with breast cancer harboring FGFR alterations (8 FGFR1 amplification, 4 11q amplification), 6 patients showed tumor response. The response rate was 50% and the duration of response was 48.7 weeks. Among the 8 patients with FGFR1 amplification, 4 showed a partial response and 4 achieved stable disease. 25193991 PubMed Soria et al., 2014, Ann. Oncol. 3 accepted 7488 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). Somatic 2022-01-14 04:28:20 UTC https://civicdb.org/links/evidence_items/7488 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false NRG1 3084 ATP1B1::NRG1 Pancreatic Ductal Adenocarcinoma 3498 Afatinib Predictive Supports C Sensitivity/Response Whole genome sequencing and transcriptomic analysis were performed on 47 advanced PDAC patients. 3/47 patients were KRAS wildtype and all three of these cases harbored a NRG1 fusion. A 59-year-old metastatic PDAC patient harbored an in-frame fusion of exon 3 of ATP1B1 with exon 2 of NRG1 and no other observed clinically relevant small mutations. Compared to this PDAC cohort, significant overexpression of NRG1 (exons 2-7) was observed in the tumor. Of note, the EGF-like domain of NRG1 (exons 6 & 7), which is required for HER-family kinase activation, is preserved in the fusion. Treatment with afatinib resulted in significant clinical response as measured by imaging, as well as a drastic reduction in CA19-9 levels. Disease progression was noted 5.5 months after treatment initiation. 31068372 PubMed Jones et al., 2019, Clin. Cancer Res. 3 accepted 7492 2178 2593 Somatic 2020-04-14 16:46:31 UTC https://civicdb.org/links/evidence_items/7492 https://civicdb.org/links/variants/2178 https://civicdb.org/links/genes/2593 false NRG1 3084 APP::NRG1 Pancreatic Ductal Adenocarcinoma 3498 Afatinib Predictive Supports C Sensitivity/Response Whole genome sequencing and transcriptomic analysis were performed on 47 advanced PDAC patients. 3/47 patients were KRAS wildtype and all three of these cases harbored a NRG1 fusion. In a 54-year-old with metastatic PDAC, a complex rearrangement involving the insertion of exons 6 and 7 of NRG1 between exons 15 and 16 of APP was found. This in-frame fusion resulted in the preservation and increased expression of the EGF-like domain of NRG1, which is required for HER-family kinase activation. Treatment with afatinib resulted in the resolution of multiple metastases and imaging showed ongoing response 5 months after treatment initiation. 31068372 PubMed Jones et al., 2019, Clin. Cancer Res. 3 accepted 7493 2772 2593 Somatic 2020-04-14 16:59:45 UTC https://civicdb.org/links/evidence_items/7493 https://civicdb.org/links/variants/2772 https://civicdb.org/links/genes/2593 false NTRK3 4916 ETV6::NTRK3 Solid Tumor Larotrectinib Predictive Supports A Sensitivity/Response In this phase 1 dose-escalation study seventy patients with metastatic solid tumours were enrolled. Eight patient tumours were found to harbour NTRK gene fusions, six of which were ETV6-NTRK3. Treatment with larotrectinib resulted in reduced tumour burden for all patients with NTRK fusions. The average time on treatment was 28.4 months for patients with NTRK fusion cancer, compared to 1.8 months for those without an NTRK fusion. 30624546 PubMed Hong et al., 2019, Ann. Oncol. NCT02122913 3 accepted 7496 801 3985 12 11802788 12022903 ENST00000396373.4 15 88483984 88418230 ENST00000394480.2 75 GRCh37 Somatic 2021-07-25 04:36:05 UTC https://civicdb.org/links/evidence_items/7496 https://civicdb.org/links/variants/801 https://civicdb.org/links/genes/3985 false MET 4233 R1004G Head And Neck Cancer 11934 Crizotinib Predictive Supports C Sensitivity/Response A patient with platinum-refractory oral cavity head and neck squamous carcinoma underwent comprehensive genomic profiling that identified an activating MET R1004G mutation. The patient showed a rapid response to the treatment of crizotinib. 31391294 PubMed Chu et al., 2019, Oncologist 3 accepted 7498 2774 52 Somatic 2019-10-10 14:07:08 UTC https://civicdb.org/links/evidence_items/7498 https://civicdb.org/links/variants/2774 https://civicdb.org/links/genes/52 false TP53 7157 R248Q Functional Supports D Dominant Negative CRISPR-Cas9 editing was used to create five isogenic MOLM13-TP53 AML cell lines with combinations of wild-type, mutant, and null TP53 alleles at the endogenous locus: p53+/+, p53+/-, p53-/-, R248Q/+, and R248Q/-. Cells were treated with and without DNA damaging agent and p53 inducing agent Daunorubicin and western blot used to assess p21 induction. p21 was induced in +/+ and +/-, but not -/-, R248Q/+, and R248Q/- cells. Daunorubicin treatment caused less cell death in +/- than in +/+ cells, but induced significantly less death in -/-, R248Q/+, and R248Q/-, where these three conditions were not statistically different. A similar result was seen with p53 activating agent Nutlin-3a, where p53-/-, R248Q/+, and R248Q/- cells grouped together with equivalent resistance to the agent in comparison to +/+ and +/- cells. The grouping in results of -/-, R248Q/+, and R248Q/- suggest that R248Q inactivates the wt p53 copy, which does not occur in the +/- condition. 31395785 PubMed Boettcher et al., 2019, Science 4 accepted 7525 117 45 17 7577538 7577538 C T ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R248 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, R248 mutations have been shown to confer worse overall survival. The R248Q mutation has also shown an increased invasive behavior in cell lines. This is specific to the 248Q variant. Unknown 2022-08-22 17:59:48 UTC https://civicdb.org/links/evidence_items/7525 https://civicdb.org/links/variants/117 https://civicdb.org/links/genes/45 false TP53 7157 Y220C Functional Does Not Support D Neomorphic The Y220C mutation was used to create isogenic AML cell lines using MOLM13 and K526 lines. Y220C/- cells showed resistance to chemotherapeutic agents and failure to induce p21, indicating disruption of p53 function. ChIP assays demonstrated reduced p53 occupation across the genome for most p53 variants tested, including Y220C. RNAseq studies determined that a novel gene expression program was not induced in Y220C cells at baseline or with DNA damage induced p53 signal activation, and that the signature of gene expression was most similar to that of p53 loss, indicating that Y220C mutation does not induce a neomophic p53 function. 31395785 PubMed Boettcher et al., 2019, Science 4 accepted 7527 922 45 17 7578190 7578190 T C ENST00000269305.4 75 GRCh37 Unknown 2022-08-22 17:58:55 UTC https://civicdb.org/links/evidence_items/7527 https://civicdb.org/links/variants/922 https://civicdb.org/links/genes/45 false TP53 7157 M237I Functional Does Not Support D Neomorphic The M237I mutation was used to create isogenic AML cell lines using MOLM13 and K526 lines. M237I/- cells showed resistance to chemotherapeutic agents and failure to induce p21, indicating disruption of p53 function. ChIP assays demonstrated reduced p53 occupation across the genome for most p53 variants tested, including M237I. RNAseq studies determined that a novel gene expression program was not induced in M237I cells at baseline or with DNA damage induced p53 signal activation, and that the signature of gene expression was most similar to that of p53 loss, indicating that M237I mutation does not induce a neomophic p53 function. 31395785 PubMed Boettcher et al., 2019, Science 4 accepted 7528 1066 45 17 7577570 7577570 C A ENST00000269305.4 75 GRCh37 Unknown 2022-08-22 17:58:44 UTC https://civicdb.org/links/evidence_items/7528 https://civicdb.org/links/variants/1066 https://civicdb.org/links/genes/45 false TP53 7157 R248Q Functional Does Not Support D Neomorphic The R248Q mutation was used to create isogenic AML cell lines using MOLM13 and K526 lines. R248Q/- cells showed resistance to chemotherapeutic agents and failure to induce p21, indicating disruption of p53 function. ChIP assays demonstrated reduced p53 occupation across the genome for most p53 variants tested, including R248Q. RNAseq studies determined that a novel gene expression program was not induced in R248Q cells at baseline or with DNA damage induced p53 signal activation, and that the signature of gene expression was most similar to that of p53 loss, indicating that R248Q mutation does not induce a neomophic p53 function. 31395785 PubMed Boettcher et al., 2019, Science 4 accepted 7529 117 45 17 7577538 7577538 C T ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R248 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, R248 mutations have been shown to confer worse overall survival. The R248Q mutation has also shown an increased invasive behavior in cell lines. This is specific to the 248Q variant. Unknown 2022-08-22 17:58:31 UTC https://civicdb.org/links/evidence_items/7529 https://civicdb.org/links/variants/117 https://civicdb.org/links/genes/45 false TP53 7157 R273H Functional Does Not Support D Neomorphic The R273H mutation was used to create isogenic AML cell lines using MOLM13 and K526 lines. R273H/- cells showed resistance to chemotherapeutic agents and failure to induce p21, indicating disruption of p53 function. ChIP assays demonstrated reduced p53 occupation across the genome for most p53 variants tested, including R273H. RNAseq studies determined that a novel gene expression program was not induced in R273H cells at baseline or with DNA damage induced p53 signal activation, and that the signature of gene expression was most similar to that of p53 loss, indicating that R273H mutation does not induce a neomophic p53 function. 31395785 PubMed Boettcher et al., 2019, Science 4 accepted 7530 122 45 17 7577120 7577120 C T ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R273 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been suggested that the R273 mutants have been correlated with worse overall survival in breast cancer patients when compared to wild-type. Unknown 2022-08-22 17:57:56 UTC https://civicdb.org/links/evidence_items/7530 https://civicdb.org/links/variants/122 https://civicdb.org/links/genes/45 false TP53 7157 R282W Functional Does Not Support D Neomorphic The R282W mutation was used to create isogenic AML cell lines using MOLM13 and K526 lines. R282W/- cells showed resistance to chemotherapeutic agents and failure to induce p21, indicating disruption of p53 function. ChIP assays demonstrated reduced p53 occupation across the genome for most p53 variants tested, while R282W cells indicated mutant p53 neomorphic binding at sites not occupied by wt. RNAseq studies determined that a novel gene expression program was not induced in R282W cells at baseline or with DNA damage induced p53 signal activation, and that the signature of gene expression was most similar to that of p53 loss, indicating that R282W mutation does not induce a neomophic p53 function. 31395785 PubMed Boettcher et al., 2019, Science 3 accepted 7531 916 45 GRCh37 Unknown 2022-08-22 17:59:09 UTC https://civicdb.org/links/evidence_items/7531 https://civicdb.org/links/variants/916 https://civicdb.org/links/genes/45 false IKZF1 10320 Deletion Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Prognostic Supports B Poor Outcome A meta-analysis of 8 published studies including 1008 adult patients (all patients were >14 years old) with B-ALL showed that IKZF 1 deletion had a negative impact on overall survival (HR=1.4, 95% CI 1.13–1.73) and event-free survival (EFS) (HR=1.67, 95% CI 1.28–2.17). In addition, IKZF1 deletion could independently predict unfavorable OS (HR=1.6) and EFS (HR= 1.67) in BCR-ABL1-negative but not BCR-ABL1 positive patients. 27815723 PubMed Zhang et al., 2017, Ann. Hematol. 4 accepted 7532 200 73 7 50344378 50472799 ENST00000331340.3 75 GRCh37 IKZF1 deletions have been reported in a variety of cancer types including pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL), Chronic Myeloid Leukemia, diffuse large B-cell lymphoma, myelodysplastic syndrome, T-cell ALL as well as solid tumors of the large intestine, lung, and liver. The clinical impact of these deletions is unknown for many cancer types however a poor outcome has been observed in leukemia based disease. This gene has been strongly implicated as a regulator for "normal hematopoiesis". In regards to BCP ALL, mouse models have shown that mutations in IKZF1 are not sufficient in and of themselves to cause disease. Haploinsuffeciency in combination with BCR-ABL1 however, will accelerate leukemiagenesis possibly indicating that at least in regards to BCP ALL these are secondary events that may be necessary for the development of leukaemic clones. Somatic 2020-10-08 19:59:46 UTC https://civicdb.org/links/evidence_items/7532 https://civicdb.org/links/variants/200 https://civicdb.org/links/genes/73 false IKZF1 10320 Deletion Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Prognostic Supports B Poor Outcome This study reports on a cohort of NCI high-risk, Ph-negative pediatric patients with B-ALL. Twenty eight out of 94 patients (~30%) were found to harbor IKZF1 deletions, which were associated with male sex (P=0.45), Hispanic ethnicity (P=0.011) and an inferior outcome. IKZF1 deletion was associated with inferior event-free survival (EFS) in univariate (HR: 3.21, P=0.002) and multivariate analysis (HR: 2.64, P=0.016). IKZF1 deletion was associated with inferior disease-free survival (DFS) in univariate analysis (HR: 3.27, P=0.008) and showed a trend toward inferior DFS in multivariate analysis (HR: 2.7, P=0.087). The IKZF1 deletion was an independent predictor of adverse outcome, irrespective of the presence of a kinase-activating fusion. 29507076 PubMed Tran et al., 2018, Blood Adv 3 accepted 7541 200 73 7 50344378 50472799 ENST00000331340.3 75 GRCh37 IKZF1 deletions have been reported in a variety of cancer types including pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL), Chronic Myeloid Leukemia, diffuse large B-cell lymphoma, myelodysplastic syndrome, T-cell ALL as well as solid tumors of the large intestine, lung, and liver. The clinical impact of these deletions is unknown for many cancer types however a poor outcome has been observed in leukemia based disease. This gene has been strongly implicated as a regulator for "normal hematopoiesis". In regards to BCP ALL, mouse models have shown that mutations in IKZF1 are not sufficient in and of themselves to cause disease. Haploinsuffeciency in combination with BCR-ABL1 however, will accelerate leukemiagenesis possibly indicating that at least in regards to BCP ALL these are secondary events that may be necessary for the development of leukaemic clones. Somatic 2020-10-08 19:59:46 UTC https://civicdb.org/links/evidence_items/7541 https://civicdb.org/links/variants/200 https://civicdb.org/links/genes/73 false BRAF 673 G466V Colorectal Cancer 9256 Irinotecan,Panitumumab Combination Predictive Supports D Sensitivity/Response In the study with a tumor from a patient with metastatic colorectal cancer BRAF (G466V) and wild-type RAS and NF1. Treament with Panitumumab and irinotecan cause tumor regression. And in tumor cells of patient-derived xenograft generated from this patient, ERK signaling was sensitive to cetuximab and resistant to vemurafenib. 28783719 PubMed Yao et al., 2017, Nature 3 accepted 7552 2222 5 7 140481411 140481411 C A ENST00000288602.6 75 GRCh37 Somatic 2019-11-22 16:19:52 UTC https://civicdb.org/links/evidence_items/7552 https://civicdb.org/links/variants/2222 https://civicdb.org/links/genes/5 false BRAF 673 G466V Colorectal Cancer 9256 Vemurafenib Predictive Does Not Support D Sensitivity/Response In the study with a tumor from a patient with metastatic colorectal cancer BRAF (G466V) and wild-type RAS and NF1. Treatment with Panitumumab and irinotecan cause tumor regression. And in tumor cells of patient-derived xenograft generated from this patient, ERK signaling was sensitive to cetuximab and resistant to vemurafenib. 28783719 PubMed Yao et al., 2017, Nature 3 accepted 7553 2222 5 7 140481411 140481411 C A ENST00000288602.6 75 GRCh37 Somatic 2019-11-22 16:19:49 UTC https://civicdb.org/links/evidence_items/7553 https://civicdb.org/links/variants/2222 https://civicdb.org/links/genes/5 false BRAF 673 G466V Solid Tumor Vemurafenib Predictive Does Not Support D Sensitivity/Response RAF inhibitor vemurafenib failed to inhibit ERK signaling in tumor cells and NIH3T3 that express class 3 BRAF mutations (G466V, G466E, D594G, D594N, and G596R). 28783719 PubMed Yao et al., 2017, Nature 3 accepted 7554 2222 5 7 140481411 140481411 C A ENST00000288602.6 75 GRCh37 Somatic 2021-09-09 17:56:40 UTC https://civicdb.org/links/evidence_items/7554 https://civicdb.org/links/variants/2222 https://civicdb.org/links/genes/5 false BRAF 673 D594G Cancer 162 Vemurafenib Predictive Does Not Support D Sensitivity/Response RAF inhibitor vemurafenib failed to inhibit ERK signaling in tumor cells and NIH3T3 that express class 3 BRAF mutations (G466V, G466E, D594G, D594N, and G596R). 28783719 PubMed Yao et al., 2017, Nature 3 accepted 7556 611 5 7 140453154 140453154 T C ENST00000288602.6 75 GRCh37 This BRAF mutation has a markedly reduced kinase activity and leads to paradoxical MEK-pathway activation via CRAF binding. Somatic 2021-04-09 20:07:42 UTC https://civicdb.org/links/evidence_items/7556 https://civicdb.org/links/variants/611 https://civicdb.org/links/genes/5 false FGFR3 2261 Mutation Urinary Bladder Cancer 11054 Gemcitabine,Cisplatin Combination Predictive Supports B Sensitivity/Response In this study, 52 patients with Muscle Invasive Bladder Cancer (MIBC) were randomly selected and administered neoadjuvant cisplatin and gemcitabine chemotherapy. 39 out of 52 patients showed pathological response (partial & complete) and 13 patients were resistant to neoadjuvant chemotherapy.35.9% (14/39) patients that responded to neoadjuvant chemotherapy had the following FGFR3 somatic mutations - p.S249C,p.V372C, p.G299S, p.V411M. FGFR3 somatic mutations exclusively occurred in the responder group.The somatic FGFR3 mutation frequency in the responder group was also compared with three unselected bladder cancer populations from TCGA, Kim et al.study and Guo et al. studies.This analysis revealed that FGFR3 somatic mutations were significantly enriched in the responder cohort compared with the unselected bladder cancer cohorts. 29941343 PubMed Yang et al., 2018, EBioMedicine 3 accepted 7566 827 23 4 1795039 1810599 ENST00000340107.4 75 GRCh37 Somatic 2020-08-24 23:33:42 UTC https://civicdb.org/links/evidence_items/7566 https://civicdb.org/links/variants/827 https://civicdb.org/links/genes/23 false BRAF 673 V600E Langerhans Cell Sarcoma 7146 Vemurafenib Predictive Supports B Sensitivity/Response Off-label use of vemurafenib to treat BRAF V600E mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. Fifty-four patients from 12 countries were treated with vemurafenib 20 mg/kg/day. Because LCH is a heterogeneous systemic disease, the quantitative Disease Activity Score (DAS), which reflects overall LCH extension, was used as an evaluation criterion. At 8 weeks, 38 patients had CRs (non-active disease) and 16 PRs (active disease better). 31513482 PubMed Donadieu et al., 2019, J. Clin. Oncol. 4 accepted 7583 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2021-11-19 20:15:14 UTC https://civicdb.org/links/evidence_items/7583 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false H3-3A 3020 K28M Glioma Akt/ERK Inhibitor ONC201 Predictive Supports B Sensitivity/Response In a phase 2 trial, patients with H3 K27M mutant glioma have been treated with DRD2 antagonist ONC201. Among 29 patients, 1 patient experienced complete clinical regression lasting >14 months, and 3 patients experienced durable partial response by RANO. 10 patients had a best response of stable disease by RANO, with a few of these patients showing substantial tumor regression in some lesions. Author concluded that ONC201 is well tolerated and has clinical activity against K27M-mutated glioma. 172409 ASCO 3005 Isabel Arrillaga, 2019, ASCO Annual Meeting, Abstract 3005 NCT03295396; NCT02525692 4 accepted 7601 2416 2537 1 226064434 226064434 A T ENST00000366813.1 105 GRCh38 K28M is a highly recurrent mutation in this gene in multiple cancer types but particularly well known in brain cancers. In amino acid position 27 of H3F3A there is an arginine (R). The medically relevant Lysine (K) is in position 28. Also UNIPROT records the lysine in position 28. However, K27M is common in the literature so is included as a synonym. Somatic 2021-09-09 17:56:39 UTC https://civicdb.org/links/evidence_items/7601 https://civicdb.org/links/variants/2416 https://civicdb.org/links/genes/2537 false BRAF 673 V600E Colorectal Cancer 9256 Binimetinib,Cetuximab,Encorafenib Combination Predictive Supports B Sensitivity/Response 665 patients with BRAF V600E-mutated metastatic CRC were enrolled In this open-label, phase 3 trial. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI. The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (triplet group vs. control P<0.001). The median progression-free survival in the triplet-therapy group was 4.3 months (95% CI, 4.1 to 5.2) and 1.5 months (95% CI, 1.5 to 1.7) in the control group (hazard ratio for disease progression or death, 0.38; 95% CI, 0.29 to 0.49; P<0.001). 31566309 PubMed Kopetz et al., 2019, N. Engl. J. Med. NCT02928224 5 accepted 7612 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2022-02-11 23:46:25 UTC https://civicdb.org/links/evidence_items/7612 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 A728V Functional Supports D Gain of Function The BRAF mutation A728V (also known as A727V) resulted in elevated kinase activity relative to wild-type BRAF in vitro, as well as increased phosphorylation of ERK1/2 in COS cells. B-RAF activity was determined using kinase dead MEK as a substrate. A727V activity was 14 times higher than basal WT BRAF. The authors classified A727V activity as intermediate, since its kinase activity was between basal WT BRAF and G12V RAS-activated WT B-RAF cells. In comparison, some BRAF variants displayed high kinase activity above the G12V RAS-activated WT BRAF cells. 15035987 PubMed Wan et al., 2004, Cell 2 accepted 7614 1198 5 7 140434515 140434515 G A GRCh37 Unknown 2022-08-22 17:16:15 UTC https://civicdb.org/links/evidence_items/7614 https://civicdb.org/links/variants/1198 https://civicdb.org/links/genes/5 false BRAF 673 V600D Melanoma 1909 BRAF Inhibitor Predictive Supports C Sensitivity/Response In a retrospective study from 20 institutes in 4 countries, the efficacy of BRAF inhibitor and/or MEK inhibitor in patients with melanoma harboring BRAF nonV600E/K mutations were evaluated. Treated with BRAF inhibitor monotherapy, response rate were 27%(4/15) for V600R, 100%(2/2) for V600D, 0% (0/2) for V600_K601>E, 0% (0/1) for V600G, 0% (0/1) for V600L, 0% (0/9) for V600_S602>DT, 0% (0/5) for L597, 0% (0/6) for K601E, 0% (0/2) for G469, 0% (0/1) for G593D,and 0% (0/1) for T599_V600insT Treated with MEK inhibitor monotherapy, response rate were 100% (1/1) for L597, and 0% (0/1) for K601E. Treated with BRAF inhibitor and MEK inhibitor combination thearpy, response rate were 55% (16/29) for V600R, 67% (2/3) for V600D, 50% (1/2) for V600_K601>E, 50% (1/2) for V600M, 22% (2/9) for L597,25% (1/4) for K601E, 67% (2/3) for G469, and 0% (0/1) for A598V. 31580757 PubMed Menzer et al., 2019, J. Clin. Oncol. 3 accepted 7616 11 5 7 140453135 140453136 CA AT ENST00000288602.6 75 GRCh37 Patients harboring mutations in valine 600 residue of BRAF have been shown to be sensitive to dabrafenib. For more information on the V600 locus, see the V600E entry. Somatic 2020-07-09 05:31:36 UTC https://civicdb.org/links/evidence_items/7616 https://civicdb.org/links/variants/11 https://civicdb.org/links/genes/5 false BRAF 673 V600D Melanoma 1909 BRAF Inhibitor,Mitogen-Activated Protein Kinase Kinase Inhibitor Combination Predictive Supports C Sensitivity/Response In a retrospective study from 20 institutes in 4 countries, the efficacy of BRAF inhibitor and/or MEK inhibitor in patients with melanoma harboring BRAF nonV600E/K mutations were evaluated. Treated with BRAF inhibitor monotherapy, response rate were 27%(4/15) for V600R, 100%(2/2) for V600D, 0% (0/2) for V600_K601>E, 0% (0/1) for V600G, 0% (0/1) for V600L, 0% (0/1) for V600_S602>DT, 0% (0/5) for L597, 0% (0/6) for K601E, 0% (0/2) for G469, 0% (0/1) for G593D,and 0% (0/1) for T599_V600insT Treated with MEK inhibitor monotherapy, response rate were 100% (1/1) for L597, and 0% (0/1) for K601E. Treated with BRAF inhibitor and MEK inhibitor combination thearpy, response rate were 55% (16/29) for V600R, 67% (2/3) for V600D, 50% (1/2) for V600_K601>E, 50% (1/2) for V600M, 22% (2/9) for L597,25% (1/4) for K601E, 67% (2/3) for G469, and 0% (0/1) for A598V. 31580757 PubMed Menzer et al., 2019, J. Clin. Oncol. 3 accepted 7629 11 5 7 140453135 140453136 CA AT ENST00000288602.6 75 GRCh37 Patients harboring mutations in valine 600 residue of BRAF have been shown to be sensitive to dabrafenib. For more information on the V600 locus, see the V600E entry. Somatic 2020-07-09 05:33:00 UTC https://civicdb.org/links/evidence_items/7629 https://civicdb.org/links/variants/11 https://civicdb.org/links/genes/5 false BRAF 673 V600_K601>E Melanoma 1909 Mitogen-Activated Protein Kinase Kinase Inhibitor,BRAF Inhibitor Combination Predictive Supports C Sensitivity/Response In a retrospective study from 20 institutes in 4 countries, the efficacy of BRAF inhibitor and/or MEK inhibitor in patients with melanoma harboring BRAF nonV600E/K mutations were evaluated. Treated with BRAF inhibitor monotherapy, response rate were 27%(4/15) for V600R, 100%(2/2) for V600D, 0% (0/2) for V600_K601>E, 0% (0/1) for V600G, 0% (0/1) for V600L, 0% (0/1) for V600_S602>DT, 0% (0/5) for L597, 0% (0/6) for K601E, 0% (0/2) for G469, 0% (0/1) for G593D,and 0% (0/1) for T599_V600insT Treated with MEK inhibitor monotherapy, response rate were 100% (1/1) for L597, and 0% (0/1) for K601E. Treated with BRAF inhibitor and MEK inhibitor combination thearpy, response rate were 55% (16/29) for V600R, 67% (2/3) for V600D, 50% (1/2) for V600_K601>E, 50% (1/2) for V600M, 22% (2/9) for L597,25% (1/4) for K601E, 67% (2/3) for G469, and 0% (0/1) for A598V. 31580757 PubMed Menzer et al., 2019, J. Clin. Oncol. 3 accepted 7630 2820 5 Somatic 2020-07-10 19:32:56 UTC https://civicdb.org/links/evidence_items/7630 https://civicdb.org/links/variants/2820 https://civicdb.org/links/genes/5 false BRAF 673 G469 Melanoma 1909 BRAF Inhibitor,Mitogen-Activated Protein Kinase Kinase Inhibitor Combination Predictive Supports B Sensitivity/Response In a retrospective study from 20 institutes in 4 countries, the efficacy of BRAF inhibitor and/or MEK inhibitor in patients with melanoma harboring BRAF nonV600E/K mutations were evaluated. Treated with BRAF inhibitor monotherapy, response rate were 27%(4/15) for V600R, 100%(2/2) for V600D, 0% (0/2) for V600_K601>E, 0% (0/1) for V600G, 0% (0/1) for V600L, 0% (0/1) for V600_S602>DT, 0% (0/5) for L597, 0% (0/6) for K601E, 0% (0/2) for G469, 0% (0/1) for G593D,and 0% (0/1) for T599_V600insT Treated with MEK inhibitor monotherapy, response rate were 100% (1/1) for L597, and 0% (0/1) for K601E. Treated with BRAF inhibitor and MEK inhibitor combination thearpy, response rate were 55% (16/29) for V600R, 67% (2/3) for V600D, 50% (1/2) for V600_K601>E, 50% (1/2) for V600M, 22% (2/9) for L597,25% (1/4) for K601E, 67% (2/3) for G469, and 0% (0/1) for A598V. 31580757 PubMed Menzer et al., 2019, J. Clin. Oncol. 3 accepted 7634 2822 5 Somatic 2020-03-04 07:02:14 UTC https://civicdb.org/links/evidence_items/7634 https://civicdb.org/links/variants/2822 https://civicdb.org/links/genes/5 false BRAF 673 A598V Melanoma 1909 Mitogen-Activated Protein Kinase Kinase Inhibitor,BRAF Inhibitor Combination Predictive Does Not Support C Sensitivity/Response In a retrospective study from 20 institutes in 4 countries, the efficacy of BRAF inhibitor and/or MEK inhibitor in patients with melanoma harboring BRAF nonV600E/K mutations were evaluated. Treated with BRAF inhibitor monotherapy, response rate were 27%(4/15) for V600R, 100%(2/2) for V600D, 0% (0/2) for V600_K601>E, 0% (0/1) for V600G, 0% (0/1) for V600L, 0% (0/1) for V600_S602>DT, 0% (0/5) for L597, 0% (0/6) for K601E, 0% (0/2) for G469, 0% (0/1) for G593D,and 0% (0/1) for T599_V600insT Treated with MEK inhibitor monotherapy, response rate were 100% (1/1) for L597, and 0% (0/1) for K601E. Treated with BRAF inhibitor and MEK inhibitor combination thearpy, response rate were 55% (16/29) for V600R, 67% (2/3) for V600D, 50% (1/2) for V600_K601>E, 50% (1/2) for V600M, 22% (2/9) for L597,25% (1/4) for K601E, 67% (2/3) for G469, and 0% (0/1) for A598V. 31580757 PubMed Menzer et al., 2019, J. Clin. Oncol. 3 accepted 7635 2826 5 7 140453142 140453142 G A ENST00000288602.6 75 GRCh37 Somatic 2019-11-22 11:44:09 UTC https://civicdb.org/links/evidence_items/7635 https://civicdb.org/links/variants/2826 https://civicdb.org/links/genes/5 false FGF19 9965 Overexpression Hepatocellular Carcinoma 684 Fisogatinib Predictive Supports B Sensitivity/Response In a phase 1 trial, patients with hepatocellular carcinoma were treated with selective FGFR4 inhibitor, fisogatinib (BLU-554). For dose escalation, 25 patients received 140 to 900 mg fisogatinib once daily. FGF19 expression was evaluated by immunohistochemistry. Across doses, the overall response rate was 17% (11/66) in FGF19 positive patients and 0% (0/32) in FGF19 negative patients. 31575541 PubMed Kim et al., 2019, Cancer Discov 4 accepted 7636 2784 7909 N/A 2021-04-12 19:58:57 UTC https://civicdb.org/links/evidence_items/7636 https://civicdb.org/links/variants/2784 https://civicdb.org/links/genes/7909 false ERBB2 2064 Amplification Cholangiocarcinoma 4947 Trastuzumab,Pertuzumab Combination Predictive Supports C Sensitivity/Response A patient with cholangiocarcinoma harboring with ERBB2 amplification (3+) detected by circulating tumor DNA testing and confirmed by tissue-based testing was treated with trastuzumab and pertuzumab. This treatment showed a tumor response and continued over 12 months. 31453370 PubMed Yarlagadda et al., 2019, NPJ Precis Oncol 3 accepted 7638 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2021-05-25 22:41:58 UTC https://civicdb.org/links/evidence_items/7638 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false MET 4233 EXON 14 SKIPPING MUTATION Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports B Sensitivity/Response Pts with MET exon 14-altered NSCLC were enrolled into an expansion cohort of the phase I PROFILE 1001 study (NCT00585195) and received crizotinib. Responses were assessed. By data-cut off 18 pts with MET exon 14-altered NSCLC had enrolled and 17 received treatment (15 response-evaluable). Antitumor activity per RECIST was documented in 10/15 pts: 5 with confirmed PRs and 5 with unconfirmed PRs. Median PFS could not be calculated, with no deaths or PD by the data cut-off. Treatment-related AEs were generally tolerable, and were most commonly edema, nausea, vision disorder, bradycardia, and vomiting. AEs were mostly grade 1 or 2, with one grade 3 edema, and no grade 4/5 AEs. 123413 ASCO 108 Alexander E. Drilon, 2016, ASCO Annual Meeting, Abstract 108 NCT00585195 1 accepted 7642 324 52 7 116411903 116412043 ENST00000318493.6 75 GRCh37 Exon 14 mutations have been observed in ~3% of patients with NSCLC (28/933 reported by Awad et al J Clin Onc 2016), confirmed to cause exon skipping when available, and associated with concurrent MET amplification. Responses to the c-MET inhibitor crizotinib have been reported in preclinical models and in individual case reports as well as a small-scale clinical trial (17 patients treated, Drilon et al., 2016 (suppl; abstr 108; ASCO ID 167889-176)). Larger studies are needed but enrollment of patients with MET exon 14 skipping mutation in trials with MET inhibitors or off-label treatment is encouraged (Paik et al., 2015 (suppl; abstr 8021)). Somatic 2020-01-21 10:55:36 UTC https://civicdb.org/links/evidence_items/7642 https://civicdb.org/links/variants/324 https://civicdb.org/links/genes/52 false MET 4233 EXON 14 SKIPPING MUTATION Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Sensitivity/Response In this case Report, a 67-year old female patient with a lung adenocarcinoma displaying a MET exon 14 donor splice site mutation (D1028N) detected using next generation sequencing. Within 5 weeks of crizotinib therapy, a partial response was observed. 26892698 PubMed Mahjoubi et al., 2016, Invest New Drugs 2 accepted 7643 324 52 7 116411903 116412043 ENST00000318493.6 75 GRCh37 Exon 14 mutations have been observed in ~3% of patients with NSCLC (28/933 reported by Awad et al J Clin Onc 2016), confirmed to cause exon skipping when available, and associated with concurrent MET amplification. Responses to the c-MET inhibitor crizotinib have been reported in preclinical models and in individual case reports as well as a small-scale clinical trial (17 patients treated, Drilon et al., 2016 (suppl; abstr 108; ASCO ID 167889-176)). Larger studies are needed but enrollment of patients with MET exon 14 skipping mutation in trials with MET inhibitors or off-label treatment is encouraged (Paik et al., 2015 (suppl; abstr 8021)). Somatic 2020-01-09 00:56:01 UTC https://civicdb.org/links/evidence_items/7643 https://civicdb.org/links/variants/324 https://civicdb.org/links/genes/52 false VHL 7428 Y98H (c.292T>C) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Cerebellar hemangioblastoma,Pheochromocytoma Predisposing N/A B N/A Peripheral blood from 116 VHL-affected patients in an interrelated group of 14 German and 2 American families with common ancestry was tested for mutations of the VHL gene, revealing a c.292T>C mutation leading to a p.Tyr89His missense protein change. Among these 116 affected patients, 116 retinal angiomas, 17 CNS hemangioblastomas, 73 pheochromocytomas, and 4 renal cell carcinomas were noted. ACMG evidence codes: 'PP1', with the allele significant cosegregation with the disease in family members for a gene known to cause the described syndrome, and 'PP4' because the patients' phenotypes or family histories are highly specific for a disease with a single genetic etiology. 7759077 PubMed Brauch et al., 1995, Hum. Genet. 4 accepted 7645 1741 58 3 10183823 10183823 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/7645 https://civicdb.org/links/variants/1741 https://civicdb.org/links/genes/58 false ERBB2 2064 Amplification Stomach Cancer 10534 Trastuzumab Deruxtecan Predictive Supports B Sensitivity/Response In a phase 1 trial, 44 patients with HER2-positive gastric or gastroesophageal junction cancer previously treated with trastuzumab were treated with Trastuzumab Deruxtecan (DS-8201a). The response rate was 43.2% (19/44). All patients had at least one treatment-emergent adverse event (AE). A serious AE was recorded in 11 patients but without a drug-related death. 31047804 PubMed Shitara et al., 2019, Lancet Oncol. NCT02564900 3 accepted 7647 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2021-01-13 01:14:37 UTC https://civicdb.org/links/evidence_items/7647 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false ABL1 25 FOXP1::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Prognostic Supports C Poor Outcome The FOXP1-ABL1 fusion was identified in a male patient in a Dutch/German cohort of 77 BCR-ABL1-like cases. The FOXP1-ABL1 fusion was confirmed by PCR and targeted ligation amplification, and was found to fuse exon 27 of FOXP1 to exon 4 of ABL1. The case was shown previously to have BCR-ABL1-like signature by hierarchical clustering of gene expression data (PMID: 23974192). The patient was treated with the ALL9-high risk protocol, did not respond to therapy, and passed away. 27894077 PubMed Boer et al., 2017, Oncotarget 1 accepted 7651 2682 4 The FOXP1-ABL1 fusion is composed of part of the FOXP1 (Forkhead box P1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 27 of FOXP1to exon 4 of ABL1 (FOXP1-ABL1). The fusion is the result of a reciprocal translocation t(3;9)(p12;q34) and has been identified by RT-PCR, Sanger sequencing, and NGS. FOXP1 is critical for the transcriptional regulatory network of B lymphopoiesis; it may also act as a tumor suppressor gene. Absence or deficiency of FOXP1 during early B-cell development may block pro-B cell to pre-B cell development. The FOXP1-ABL1 fusion protein leads to activated tyrosine kinase and may further alter the critical cellular function of these 2 genes. Clinical significance: The FOXP1-ABL1 fusion has been documented in 3 young adult patients (2 male, 1 female) with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. One patient had tyrosine kinase inhibitors (dasatinib) added to the chemotherapy regimens, who had bone marrow tested negative for MRD at end of consolidation. The clinical details of these cases may predict response to treatment with tyrosine kinase inhibitors. Functional studies are needed to substantiate the efficacy of TKI treatment of this particular ABL-class fusion. Somatic 2021-05-17 17:55:40 UTC https://civicdb.org/links/evidence_items/7651 https://civicdb.org/links/variants/2682 https://civicdb.org/links/genes/4 false ABL1 25 SNX2::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Imatinib,Dasatinib Substitutes Predictive Supports D Resistance SNX2-ABL1 protein (SNX2 exon 3 to ABL1 exon 4) was transfected in murine Ba/F3 cells and proliferation rates in the presence of IL-3, and tyrosine kinase inhibitors, imatinib and dasatinib was compared to BCR-ABL1 p190 and p210 transfected Ba/F3 cells. Cell proliferation assays showed that SNX2-ABL1 transfected cells had over 20% and 50% of cell survival after 24-hr incubation with imatinib (2µM) and dasatinib (10nM). SNX2-ABL1 transfected cells continued to proliferate again 48 hr after treatment with dasatinib (10nM). This data was further supported by apoptosis (annexin V-propidium iodide) studies. In addition, newer tyrosine kinase inhibitors including nilotinib (500nM), bafetinib (500nM), rebastinib (500nM), and ponatinib (100nM), were examined and SNX2-ABL1 cells showed a better response, but still some resistance to these compounds. Further examination of downstream phosphorylation of SNX2-ABL1 cells showed only partial inhibition with imatinib and dasatinib. 24367893 PubMed Tomita et al., 2014, Leuk. Res. 3 accepted 7655 2678 4 5 122110691 122135550 ENST00000379516.2 9 133738150 133763062 ENST00000372348.2 75 GRCh37 The SNX2-ABL1 fusion is composed of part of the SNX2 (Sorting Nexin 2) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 3 of SNX2 to exon 4 of ABL1 (SNX2-ABL1 3-4). The fusion is the result of a reciprocal translocation t(5;9)(p23.2;q34.12) and has been identified by RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the sorting nexin, N-terminal domain of SNX2 and the SH2, tyrosine kinase, and F actin binding domains of ABL1, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The SNX2-ABL1 fusion has been documented in six young men between the ages of 7 and 29 years with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. Two patients had tyrosine kinase inhibitors (imatinib and dasatinib + imatinib) added to their chemotherapy regimens that, while producing initially encouraging results, ultimately did not prevent these individuals from succumbing to their disease. The clinical details of these cases may predict response to treatment with tyrosine kinase inhibitors and is the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-06-14 17:17:50 UTC https://civicdb.org/links/evidence_items/7655 https://civicdb.org/links/variants/2678 https://civicdb.org/links/genes/4 false JAK2 3717 ATF7IP::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In one male patient, an in-frame ATF7IP-JAK2 fusion (exon 13 and exon 17) with the tyrosine kinase domain intact was identified and confirmed by RT-PCR, Sanger and FISH. This patient also harbored an IKZF1 deletion, was designated NCI high risk and Ph-like non-CRLF2. 25207766 PubMed Roberts et al., 2014, N. Engl. J. Med. 3 accepted 7671 2846 28 The ATF7IP-JAK2 fusion is composed of part of the ATF7IP (Activating Transcription Factor 7 Interacting Protein) gene at the 5’ end (N-terminus of the fusion protein), and a part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion. Known breakpoint/splice variants join exon 10 of ATF7IP to exon 8 of JAK2 (ATF7IP-JAK2 10-8), exon 13 of ATF7IP to exon 16 of JAK2 (ATF7IP-JAK2 13-16), or exon 13 of ATF7IP to exon 17 of JAK2 (ATF7IP-JAK2 13-17). The fusion is predicted to result from a reciprocal translocation t(9;12) (p24;p13.1), and has been identified by RNA sequencing and Sanger sequencing in three adult patients with BCR-ABL1-like B-lymphoblastic leukemia. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the coiled coil and MDN1 domains from ATF7IP and the JH2 pseudokinase and JH1 kinase domains from JAK2. The coiled coil domain is hypothesized to constitutively activate the JAK2 kinase domain, thereby upregulating the pathway shared with signal transducers and activators of transcription (STATs). Clinical significance: The novel ATF7IP-JAK2 fusion has been documented in three cases for which specific clinical information is unavailable. A pre-clinical xenograft model containing the fusion was sensitive to exposure to the JAK2 inhibitor, ruxolitinib. Therefore, the presence of the JAK2 JH1 kinase domain in the fusion protein may offer a target for therapeutic inhibition. Prospective clinical trials are ongoing to evaluate the efficacy of adding JAK2 inhibitors to the treatment of B-lymphoblastic leukemia patients with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2020-09-25 22:38:39 UTC https://civicdb.org/links/evidence_items/7671 https://civicdb.org/links/variants/2846 https://civicdb.org/links/genes/28 false JAK2 3717 EBF1::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In one adolescent female, an in-frame EBF1-JAK2 fusion (exon 14 and exon 17) with the tyrosine kinase domain intact was identified and confirmed by RT-PCR and Sanger. This patient also harbored an IKZF1 deletion and was designated Ph-like non CRLF2. 25207766 PubMed Roberts et al., 2014, N. Engl. J. Med. 3 accepted 7672 2847 28 The EBF1-JAK2 fusion is composed of part of the EBF1 (Early B-Cell Factor Transcription Factor 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 14 of EBF1 to exon 17 of JAK2 (EBF1-JAK2 14-17). The fusion is predicted to result from a reciprocal translocation t(5;9) (q33.3;p24), and has been identified by RNA sequencing in one adolescent patient with BCR-ABL1-like B-lymphoblastic leukemia. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the DNA binding, immunoglobulin-life fold, and helix-loop-helix domains from EBF1 and an intact JH1 kinase domain from JAK2, as confirmed by RT-PCR and Sanger sequencing. The inclusion of the JH1 kinase domain is hypothesized to upregulate the pathway shared with signal transducers and activators of transcription (STATs). Functional analysis of the EBF1-JAK2 fusion protein has not been performed. Clinical significance: The novel EBF1-JAK2 fusion has been documented in one case for which specific clinical information is unavailable. However, the presence of the JAK2 JH1 kinase domain in the fusion protein may offer a target for therapeutic inhibition. Prospective clinical trials are ongoing to evaluate the efficacy of adding JAK2 inhibitors to the treatment of B-lymphoblastic leukemia patients with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2020-10-17 23:57:33 UTC https://civicdb.org/links/evidence_items/7672 https://civicdb.org/links/variants/2847 https://civicdb.org/links/genes/28 false JAK2 3717 PPFIBP1::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In one young adult male patient, an in-frame PPFIBP1-JAK2 fusion (exon 12 and exon 19) with the tyrosine kinase domain intact was identified and confirmed by RT-PCR, Sanger, and FISH. This patient also harbored an IKZF1 deletion and was designated Ph-like non-CRLF2. 25207766 PubMed Roberts et al., 2014, N. Engl. J. Med. 3 accepted 7673 2848 28 Somatic 2020-10-20 15:12:21 UTC https://civicdb.org/links/evidence_items/7673 https://civicdb.org/links/variants/2848 https://civicdb.org/links/genes/28 false JAK2 3717 STRN3::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In one childhood NCI high risk female, an in-frame STRN3-JAK2 fusion (exon 9 and exon 17) with the tyrosine kinase domain intact was identified and confirmed by RT-PCR and Sanger. This patient also harbored an IKZF1 frameshift and deletion and was designated Ph-like non CRLF2. 25207766 PubMed Roberts et al., 2014, N. Engl. J. Med. 3 accepted 7674 2849 28 The STRN3-JAK2 fusion is composed of part of the STRN3 (Striatin 3) gene at the 5’ end (N-terminus of the fusion protein), and a part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion. The published breakpoint joins exon 9 of STRN3 to exon 17 of JAK2 (STRN3 -JAK2 9-17). The fusion is predicted to result from a reciprocal translocation t(9;14) (p24;q12), and has been identified by RNA sequencing in one pediatric patient with BCR-ABL1-like B-lymphoblastic leukemia. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the Striatin domain from STRN3 and the JH2 pseudokinase domain and intact JH1 kinase domain from JAK2, as confirmed by RT-PCR and Sanger sequencing. The inclusion of the JH1 kinase domain is hypothesized to upregulate the pathway shared with signal transducers and activators of transcription (STATs). Functional analysis of the STRN3-JAK2 fusion protein has not been performed. Clinical significance: The novel STRN3-JAK2 fusion has been documented in a single case for which specific clinical information is unavailable. However, the presence of the JAK2 JH1 kinase domain in the fusion protein may offer a target for therapeutic inhibition. Prospective clinical trials are ongoing to evaluate the efficacy of adding JAK2 inhibitors to the treatment of B-lymphoblastic leukemia patients with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2020-10-20 15:13:59 UTC https://civicdb.org/links/evidence_items/7674 https://civicdb.org/links/variants/2849 https://civicdb.org/links/genes/28 false JAK2 3717 TPR::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In one young adult male, an in-frame TPR-JAK2 fusion (exon 39 and exon 17) with the tyrosine kinase domain intact was identified and confirmed by RT-PCR, Sanger and FISH. This patient also harbored an IKZF1 deletion and was designated Ph-like non CRLF2. 25207766 PubMed Roberts et al., 2014, N. Engl. J. Med. 3 accepted 7675 2850 28 The TPR-JAK2 fusion is composed of part of the TPR (Translocated Promoter Region, Nuclear Basket Protein) gene at the 5’ end (N-terminus of the fusion protein), and a part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion. The published breakpoint joins exon 39 of TPR to exon 17 of JAK2 (TPR -JAK2 39-17). The fusion stems from a reciprocal translocation t(1;9) (q31.1;p24), and has been identified by FISH and RNA sequencing in one young adult patient with BCR-ABL1-like B-lymphoblastic leukemia. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the TPR/MLP1/MLP2-like protein domain from TERF2 and the JH2 pseudokinase domain and intact JH1 kinase domain from JAK2, as confirmed by RT-PCR and Sanger sequencing. The inclusion of the JH1 kinase domain is hypothesized to upregulate the pathway shared with signal transducers and activators of transcription (STATs). Functional analysis of the TPR-JAK2 fusion protein has not been performed. Clinical significance: The novel TPR-JAK2 fusion has been documented in one case for which specific clinical information is unavailable. However, the presence of the JAK2 JH1 kinase domain in the fusion protein may offer a target for therapeutic inhibition. Prospective clinical trials are ongoing to evaluate the efficacy of adding JAK2 inhibitors to the treatment of B-lymphoblastic leukemia patients with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2020-10-20 15:16:39 UTC https://civicdb.org/links/evidence_items/7675 https://civicdb.org/links/variants/2850 https://civicdb.org/links/genes/28 false BRAF 673 Amplification Melanoma 1909 Trametinib,Dabrafenib Combination Predictive Supports C Resistance In a retrospective study, authors analyzed BRAF V600 mutated melanoma metastases derived from 10 patients treated with the combination of dabrafenib and trametinib for resistance mechanisms and genetic correlates of response. An acquired resistance mechanism activating the MAPK pathway was identified in 9 tumors; BRAF amplification (n=4), MEK1/2 mutation (n=3), NRAS mutations (n=3). Among them, mutual exclusive alterations were BRAF amplification (n=4), MEK2 C125S (n=1), and NRAS Q61K (n=2). 25452114 PubMed Long et al., 2014, Nat Commun 4 accepted 7677 1269 5 7 140434279 140624564 ENST00000288602.6 75 GRCh37 Somatic 2021-04-14 22:36:56 UTC https://civicdb.org/links/evidence_items/7677 https://civicdb.org/links/variants/1269 https://civicdb.org/links/genes/5 false ABL1 25 SNX2::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Young adult onset Prognostic Supports C Poor Outcome A 16 yr-old male with precursor B-ALL was found to have the t(5;9)(q23;q34) in his peripheral blasts. Fluorescence in situ hybridization (FISH), RT-PCR, and sequencing of the product confirmed a SNX2-ABL1 fusion gene (SNX2 exon 3 fused in frame to ABL1 exon 4) was present. The patient also was found to carry an IKZF1 deletion (exons 2-8) and amplification of PAX5. The patient was treated with vindesine, idarubicin, and dexamethasone (VDP) and VDCP (plus cyclophosphamide) regimens. He received two bone marrow transplants, but eventually died of disease. The patient did not receive tyrosine-kinase inhibitors. 28278724 PubMed Mu et al., 2017, Leuk. Lymphoma 1 accepted 7694 2678 4 5 122110691 122135550 ENST00000379516.2 9 133738150 133763062 ENST00000372348.2 75 GRCh37 The SNX2-ABL1 fusion is composed of part of the SNX2 (Sorting Nexin 2) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 3 of SNX2 to exon 4 of ABL1 (SNX2-ABL1 3-4). The fusion is the result of a reciprocal translocation t(5;9)(p23.2;q34.12) and has been identified by RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the sorting nexin, N-terminal domain of SNX2 and the SH2, tyrosine kinase, and F actin binding domains of ABL1, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The SNX2-ABL1 fusion has been documented in six young men between the ages of 7 and 29 years with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. Two patients had tyrosine kinase inhibitors (imatinib and dasatinib + imatinib) added to their chemotherapy regimens that, while producing initially encouraging results, ultimately did not prevent these individuals from succumbing to their disease. The clinical details of these cases may predict response to treatment with tyrosine kinase inhibitors and is the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-06-14 17:17:38 UTC https://civicdb.org/links/evidence_items/7694 https://civicdb.org/links/variants/2678 https://civicdb.org/links/genes/4 false JAK2 3717 ETV6::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In two patients, an in-frame ETV6-JAK2 fusion (exon 4 and exon 17; exon 5 and exon 17) with the tyrosine kinase domain intact was identified and confirmed by RT-PCR, FISH, and/or Sanger. One patients was shown to also harbored an IKZF1 deletion and was designated Ph-like non CRLF2. This information was not provided for the second fusion patient. 25207766 PubMed Roberts et al., 2014, N. Engl. J. Med. 3 accepted 7696 2859 28 The ETV6-JAK2 fusion is composed of part of the ETV6 (ETS Variant Transcription Factor 6) gene at the 5’ end (N-terminus of the fusion protein), and part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion. Known breakpoint/splice variants join exon 4 of ETV6 to exon 17 of JAK2 (ETV6-JAK2 4-17), exon 5 of ETV6 to exon 12 of JAK2 (ETV6-JAK2 5-12), or exon 5 of ETV6 to exon 19 of JAK2 (ETV6-JAK2 5-19). The fusion results from the reciprocal translocation t(9;12)(p24;p13), cytogenetically cryptic, and has been identified by FISH and RNA sequencing. The fusion gene is expressed from the der(9) chromosome. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the PNT domain from ETV6 and JH1 kinase domain from JAK2. The ETV6 PNT domain is hypothesized to result in dimerization, which leads to aberrant JAK2 kinase domain activation. Depending on the breakpoint variant, the fusion protein may also contain the JAK2 JH2 pseudokinase domain. The inclusion of the JH1 domain may affect functional effects and disease specificity of the abnormal fusion. Functionally, the fusion results in aberrant activation of JAK2 kinase, leading to activation of downstream signaling through the signal transducers and activators of transcription (STATs). The ETV6-JAK2 fusion is associated with hematologic malignancies and has been observed in B-lymphoblastic leukemia (~10%), T-lymphoblastic leukemia (isolated cases), and myeloid/lymphoid neoplasms with eosinophilia and gene rearrangements (rare cases). Clinical significance: As a diagnostic biomarker, the ETV6-JAK2 fusion in B-lymphoblastic leukemia is associated with the BCR-ABL1-like subtype. As a prognostic marker, the ETV6-JAK2 fusion has been associated with high-risk disease. As a predictive marker, the ETV6-JAK2 fusion has been shown by limited pre-clinical data and case reports to predict response to treatment with JAK2 inhibitors. Prospective clinical trials are ongoing to evaluate the efficacy of adding JAK2 inhibitors to treatment of pediatric B-lymphoblastic leukemia patients with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2020-10-06 06:24:34 UTC https://civicdb.org/links/evidence_items/7696 https://civicdb.org/links/variants/2859 https://civicdb.org/links/genes/28 false JAK2 3717 BCR::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In two male patients, in-frame BCR-JAK2 fusions (exon 1 and exon 19 (FISH validated); exon 1 and exons 15&17) with the tyrosine kinase domain intact were identified and confirmed by RT-PCR, Sanger. Both patients harbored an IKZF1 deletion and were designated Ph-like non-CRLF2. One patient was NCI childhood high risk while the other was young adult. 25207766 PubMed Roberts et al., 2014, N. Engl. J. Med. 3 accepted 7697 2860 28 The BCR-JAK2 fusion is composed of part of the BCR (Breakpoint Cluster Region) gene at the 5’ end (N-terminus of the fusion protein), and part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion. Known breakpoint/splice variants join exon 14 of BCR to exon 17 of JAK2 (BCR-JAK2 4-17) and exon 1 of BCR to exons 15 (BCR-JAK2 1-15), 17 (BCR-JAK2 1-17), or 19 (BCR-JAK2 1-19). The fusion results from the reciprocal translocation t(9;22)(p24;p11.2), and has been identified by karyotype analysis, FISH, RT-PCR, targeted ligation amplification (TLA), and RNA sequencing. The fusion gene is expressed from the der(9) chromosome. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the coiled coil domain from BCR and the JH1 kinase domain from JAK2. Depending on the breakpoint variant, the fusion protein may also contain the JAK2 JH2 pseudokinase domain. In pre-clinical studies, the coiled coil domain of BCR has been shown to mediate oligomeric activation of the JAK2 kinase domain, thereby promoting downstream signaling by signal transducers and activators of transcription (STATs). The BCR-JAK2 fusion is associated with hematologic malignancies and has been observed in myeloproliferative neoplasms with eosinophilia (multiple cases), B-lymphoblastic leukemia (multiple cases), acute myeloid leukemia (a rare case), and B-cell lymphoma (rare case of Burkitt lymphoma). Clinical significance: As a diagnostic biomarker in B-lymphoblastic leukemia, the BCR-JAK2 fusion is frequently observed in the BCR-ABL1-like subtype. As a prognostic marker, the fusion appears to be associated with high-risk disease in pediatric and adult populations. As a predictive marker, patients whose diseases exhibit the BCR-JAK2 fusion have experienced partial responses or even complete remission with hydroxyurea and/or interferon alfa. Case reports have demonstrated the limited utility of tyrosine kinase inhibitors. One patient diagnosed with a myeloid neoplasm initially responded to the JAK2 inhibitor ruxolitinib, but relapsed after 18 months. Current research has suggested a survival advantage following allogeneic or autologous stem cell transplantation. Somatic 2020-10-06 00:26:03 UTC https://civicdb.org/links/evidence_items/7697 https://civicdb.org/links/variants/2860 https://civicdb.org/links/genes/28 false JAK2 3717 BCR::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In this study which included 1389 cases of high-risk pediatric B-ALL, 284 were identified by TaqMan Low Density Array to have a Ph-like gene expression signature. RT-PCR or RNAseq performed on the 129 CRLF2 negative patients revealed that 4.9% of them had JAK2 rearrangements including two patients with a BCR-JAK2 fusion. These fusions were confirmed by Sanger sequencing and identified alternate breakpoint in BCR. All fusion-positive patient cases in this study were confirmed to have in-frame fusion of the 5′ partner to the 3′ kinase gene and retention of the tyrosine kinase domain of the 3′ fusion partner. 28408464 PubMed Reshmi et al., 2017, Blood 4 accepted 7698 2860 28 The BCR-JAK2 fusion is composed of part of the BCR (Breakpoint Cluster Region) gene at the 5’ end (N-terminus of the fusion protein), and part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion. Known breakpoint/splice variants join exon 14 of BCR to exon 17 of JAK2 (BCR-JAK2 4-17) and exon 1 of BCR to exons 15 (BCR-JAK2 1-15), 17 (BCR-JAK2 1-17), or 19 (BCR-JAK2 1-19). The fusion results from the reciprocal translocation t(9;22)(p24;p11.2), and has been identified by karyotype analysis, FISH, RT-PCR, targeted ligation amplification (TLA), and RNA sequencing. The fusion gene is expressed from the der(9) chromosome. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the coiled coil domain from BCR and the JH1 kinase domain from JAK2. Depending on the breakpoint variant, the fusion protein may also contain the JAK2 JH2 pseudokinase domain. In pre-clinical studies, the coiled coil domain of BCR has been shown to mediate oligomeric activation of the JAK2 kinase domain, thereby promoting downstream signaling by signal transducers and activators of transcription (STATs). The BCR-JAK2 fusion is associated with hematologic malignancies and has been observed in myeloproliferative neoplasms with eosinophilia (multiple cases), B-lymphoblastic leukemia (multiple cases), acute myeloid leukemia (a rare case), and B-cell lymphoma (rare case of Burkitt lymphoma). Clinical significance: As a diagnostic biomarker in B-lymphoblastic leukemia, the BCR-JAK2 fusion is frequently observed in the BCR-ABL1-like subtype. As a prognostic marker, the fusion appears to be associated with high-risk disease in pediatric and adult populations. As a predictive marker, patients whose diseases exhibit the BCR-JAK2 fusion have experienced partial responses or even complete remission with hydroxyurea and/or interferon alfa. Case reports have demonstrated the limited utility of tyrosine kinase inhibitors. One patient diagnosed with a myeloid neoplasm initially responded to the JAK2 inhibitor ruxolitinib, but relapsed after 18 months. Current research has suggested a survival advantage following allogeneic or autologous stem cell transplantation. Somatic 2020-10-20 18:19:13 UTC https://civicdb.org/links/evidence_items/7698 https://civicdb.org/links/variants/2860 https://civicdb.org/links/genes/28 false JAK2 3717 PAX5::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports B Positive In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In seven patients, an in-frame PAX5-JAK2 fusion (exon 5 and exon 19) with the tyrosine kinase domain intact was identified and confirmed by RT-PCR and Sanger. FISH validated the presence of the fusion in 2 patients. All patients were designated Ph-like non-CRLF2 and 5/7 had IKZF1 deletion. 25207766 PubMed Roberts et al., 2014, N. Engl. J. Med. 3 accepted 7699 2861 28 The PAX5-JAK2 fusion is composed of part of the PAX5 (Paired Box 5) gene at the 5’ end (N-terminus of the fusion protein), and part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 5 of PAX5 to exon 19 of JAK2 (PAX5-JAK2 5-19). The fusion is hypothesized to result from an intrachromosomal translocation, inversion, or deletion of chromosome 9 (involving loci p13 and p24), and has been identified by RNA sequencing, RT-PCR, Sanger sequencing, and FISH in patients B-lymphoblastic leukemia. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the DNA-binding paired domain from PAX5 and the JH1 kinase domain from JAK2. A pre-clinical study has revealed that this fusion protein deregulates the PAX5 transcriptional pathway while also autophosphorylating the JAK2 kinase domain, thereby promoting downstream signaling by signal transducers and activators of transcription (STATs). Clinical significance: As a diagnostic biomarker, the PAX5-JAK2 fusion in B-lymphoblastic leukemia is frequently associated with the BCR-ABL1-like subtype. As a prognostic marker, the fusion has been associated with intermediate to high-risk disease. As a predictive marker, the PAX5-JAK2 fusion has been shown in pre-clinical data to predict response to treatment with JAK2 inhibitors. Prospective clinical trials are ongoing to evaluate the efficacy of adding JAK2 inhibitors to treatment of B-lymphoblastic leukemia patients with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2020-10-20 15:07:48 UTC https://civicdb.org/links/evidence_items/7699 https://civicdb.org/links/variants/2861 https://civicdb.org/links/genes/28 false JAK2 3717 PAX5::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In this study which included 1389 cases of high-risk pediatric B-ALL, 284 were identified by TaqMan Low Density Array to have a Ph-like gene expression signature. RT-PCR or RNAseq performed on CRLF2 negative patients revealed 4.9% had JAK2 rearrangements. Four individuals had a PAX5-JAK2 fusion that was identified and confirmed by Sanger sequencing. These patients were designated Ph-like non CRLF2. All fusion-positive patient cases in this study were confirmed to have in-frame fusion of the 5′ partner to the 3′ kinase gene and retention of the tyrosine kinase domain of the 3′ fusion partner. 28408464 PubMed Reshmi et al., 2017, Blood 3 accepted 7700 2861 28 The PAX5-JAK2 fusion is composed of part of the PAX5 (Paired Box 5) gene at the 5’ end (N-terminus of the fusion protein), and part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 5 of PAX5 to exon 19 of JAK2 (PAX5-JAK2 5-19). The fusion is hypothesized to result from an intrachromosomal translocation, inversion, or deletion of chromosome 9 (involving loci p13 and p24), and has been identified by RNA sequencing, RT-PCR, Sanger sequencing, and FISH in patients B-lymphoblastic leukemia. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the DNA-binding paired domain from PAX5 and the JH1 kinase domain from JAK2. A pre-clinical study has revealed that this fusion protein deregulates the PAX5 transcriptional pathway while also autophosphorylating the JAK2 kinase domain, thereby promoting downstream signaling by signal transducers and activators of transcription (STATs). Clinical significance: As a diagnostic biomarker, the PAX5-JAK2 fusion in B-lymphoblastic leukemia is frequently associated with the BCR-ABL1-like subtype. As a prognostic marker, the fusion has been associated with intermediate to high-risk disease. As a predictive marker, the PAX5-JAK2 fusion has been shown in pre-clinical data to predict response to treatment with JAK2 inhibitors. Prospective clinical trials are ongoing to evaluate the efficacy of adding JAK2 inhibitors to treatment of B-lymphoblastic leukemia patients with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2020-10-20 18:15:58 UTC https://civicdb.org/links/evidence_items/7700 https://civicdb.org/links/variants/2861 https://civicdb.org/links/genes/28 false JAK2 3717 TERF2::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In one adolescent female, an in-frame TERF2-JAK2 fusion (exon 8 and exon 19) with the tyrosine kinase domain intact was identified and confirmed by RT-PCR and Sanger. This patient also harbored an IKZF1 deletion and was designated Ph-like non CRLF2. 25207766 PubMed Roberts et al., 2014, N. Engl. J. Med. 3 accepted 7702 2862 28 Somatic 2020-10-20 15:15:22 UTC https://civicdb.org/links/evidence_items/7702 https://civicdb.org/links/variants/2862 https://civicdb.org/links/genes/28 false JAK2 3717 PCM1::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive The PCM1-JAK2 fusion is typically associated with 'myeloid/lymphoid neoplasms with eosinophilia and gene rearrangements', which is a specific disease entity according to WHO classification. However, in this study, which investigated 1389 high-risk pediatric B-ALL cases, 284 of whom had a Ph-like gene signature (identified by TaqMan Low Density Array) the PCM1-JAK2 fusion was detected in association with Ph-like B-ALL in one individual. This fusion was detected by RT-PCR and was confirmed by Sanger sequencing. This patient was designated PH-like non CRLF2. All fusion-positive patient cases in this study were confirmed to have in-frame fusion of the 5′ partner to the 3′ kinase gene and retention of the tyrosine kinase domain of the 3′ fusion partner. 28408464 PubMed Reshmi et al., 2017, Blood 3 accepted 7704 571 28 GRCh37 Somatic 2020-10-20 18:15:20 UTC https://civicdb.org/links/evidence_items/7704 https://civicdb.org/links/variants/571 https://civicdb.org/links/genes/28 false JAK2 3717 USP25::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. The USP25-JAK2 fusion is rare; this study involved 1389 cases of high risk pediatric B-ALL. Of those, 284 had Ph-like expression signature, and only one of those cases had the USP25-JAK2 fusion. USP25 was detected as a novel JAK2 partner in Ph-like B-ALL. 28408464 PubMed Reshmi et al., 2017, Blood 3 accepted 7705 2863 28 Somatic 2021-04-23 17:21:12 UTC https://civicdb.org/links/evidence_items/7705 https://civicdb.org/links/variants/2863 https://civicdb.org/links/genes/28 false JAK2 3717 ZNF274::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive This study included 1389 cases of high-risk pediatric B-ALL, out of which 284 were identified by TaqMan Low Density Array to have a Ph-like gene expression signature. RT-PCR or RNAseq performed on the 129 CRLF2 negative patients revealed that 4.9% of them had JAK2 rearrangements including one patient with a rare and novel ZNF274-JAK2 fusion. All fusion-positive patient cases in this study were confirmed to have in-frame fusion of the 5′ partner to the 3′ kinase gene and retention of the tyrosine kinase domain of the 3′ fusion partner. In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. 28408464 PubMed Reshmi et al., 2017, Blood 3 accepted 7706 2864 28 Somatic 2020-10-20 18:17:56 UTC https://civicdb.org/links/evidence_items/7706 https://civicdb.org/links/variants/2864 https://civicdb.org/links/genes/28 false JAK2 3717 RFX3::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive This study included 1389 cases of high-risk pediatric B-ALL, out of which 284 were identified by TaqMan Low Density Array to have a Ph-like gene expression signature. RT-PCR or RNAseq performed on the 129 CRLF2 negative patients revealed that 4.9% of them had JAK2 rearrangements including one patient with a rare and novel RFX3-JAK2 fusion. All fusion-positive patient cases in this study were confirmed to have in-frame fusion of the 5′ partner to the 3′ kinase gene and retention of the tyrosine kinase domain of the 3′ fusion partner. In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. 28408464 PubMed Reshmi et al., 2017, Blood 3 accepted 7707 2865 28 Somatic 2020-10-20 18:17:04 UTC https://civicdb.org/links/evidence_items/7707 https://civicdb.org/links/variants/2865 https://civicdb.org/links/genes/28 false RET 5979 M918T Thyroid Gland Medullary Carcinoma 3973 Cabozantinib Predictive Supports B Sensitivity/Response In this retrospective analysis of a phase 3 trial of cabozantinib or placebo in 330 patients. Among those, 51.2% were RET mutation-positive (38.2% with RET M918T), 34.8% were RET mutation-unknown, and 13.9% were RET mutation-negative. Sixteen patients were RAS mutation-positive. Cabozantinib appeared to prolong PFS versus the placebo in the RET mutation-positive subgroup (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.14-0.38; P < .0001). Patients in a RET mutation-negative population showed relatively smaller benefits from cabozantinib (HR 0.53). The RET M918T subgroup achieved the greatest observed PFS benefit from cabozantinib versus the placebo (HR 0.15). 27525386 PubMed Sherman et al., 2016, Cancer 4 accepted 7710 113 42 10 43617416 43617416 T C ENST00000355710.3 75 GRCh37 RET M819T is the most common somatically acquired mutation in medullary thyroid cancer (MTC). While there currently are no RET-specific inhibiting agents, promiscuous kinase inhibitors have seen some success in treating RET overactivity. Data suggests however, that the M918T mutation may lead to drug resistance, especially against the VEGFR-inhibitor motesanib. It has also been suggested that RET M819T leads to more aggressive MTC with a poorer prognosis. Somatic 2021-01-13 01:28:57 UTC https://civicdb.org/links/evidence_items/7710 https://civicdb.org/links/variants/113 https://civicdb.org/links/genes/42 false BRCA2 675 K3326* Glioblastoma 3068 Childhood onset Temozolomide,Olaparib Combination Predictive Supports C Sensitivity/Response In a case report, a 3‐year‐old girl with glioblastoma harboring a probable germline heterozygous BRCA2 Lys3326Ter (K3326*) nonsense variant. After debulking surgery, the patient received standard‐of‐care treatment with radiation and temozolomide. Nine months later the PARP inhibitor olaparib was administered in combination with temozolomide for 16 cycles. This regimen was well tolerated by the patient and serial imaging showed a reduction in tumor size. 32043779 PubMed Valiakhmetova et al., 2019, Oncologist 3 accepted 7724 2871 7 Unknown 2022-01-12 00:45:26 UTC https://civicdb.org/links/evidence_items/7724 https://civicdb.org/links/variants/2871 https://civicdb.org/links/genes/7 false IDH1 3417 Mutation Chondrosarcoma 3371 Prognostic Supports B Better Outcome In a retrospective study, the authors evaluated the association between IDH1/IDH2 mutation and prognosis in patients with high-grade central chondrosarcoma. Although no association was discovered between IDH mutation status and the patient's overall survival, IDH1/IDH2 mutation was found to be associated with longer relapse free and metastasis free survival in high-grade chondrosarcomas. 31615936 PubMed Zhu et al., 2020, Clin. Cancer Res. 4 accepted 7725 645 26 2 209101803 209116275 ENST00000415913.1 75 GRCh37 Somatic 2019-11-27 00:40:09 UTC https://civicdb.org/links/evidence_items/7725 https://civicdb.org/links/variants/645 https://civicdb.org/links/genes/26 false IDH2 3418 Mutation Chondrosarcoma 3371 Prognostic Supports B Better Outcome In a retrospective study, the authors evaluated the association between IDH1/IDH2 mutation and prognosis in patients with high-grade central chondrosarcoma. Although no association was discovered between IDH mutation status and the patient's overall survival, IDH1/IDH2 mutation was found to be associated with longer relapse free and metastasis free survival in high-grade chondrosarcomas. 31615936 PubMed Zhu et al., 2020, Clin. Cancer Res. 4 accepted 7726 570 27 15 90626277 90645736 ENST00000330062.3 75 GRCh37 Somatic 2019-11-27 01:11:13 UTC https://civicdb.org/links/evidence_items/7726 https://civicdb.org/links/variants/570 https://civicdb.org/links/genes/27 false FLT3 2322 Mutation Acute Myeloid Leukemia 9119 Gilteritinib Predictive Supports B Sensitivity/Response In this phase 3 trial (ADMIRAL), 371 patients with relapsed or refractory FLT3-mutated AML (required to have FLT3 ITD or TKD D835 or I836 mutations) were randomly assigned in a 2:1 ratio to receive either gilteritinib (n=247, at a dose of 120 mg per day) or salvage chemotherapy (n=124). Median overall survival in the gilteritinib group was significantly longer than in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). Median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The complete remission rate with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). Notably, gilteritinib treatment resulted in similar median overall survival (9.3 months vs. 8.0 months) and percentage of complete remission (20.5% vs. 19.0%) in patients with ITD mutations and patients with TKD mutations. The authors concluded gilteritinib therapy in relapsed or refractory FLT3-mutated AML patients resulted longer survival and improved response versus salvage chemotherapy. 31665578 PubMed Perl et al., 2019, N. Engl. J. Med. NCT02421939 5 accepted 7728 519 24 13 28577411 28674729 ENST00000241453.7 75 GRCh37 Somatic 2020-07-14 01:21:25 UTC https://civicdb.org/links/evidence_items/7728 https://civicdb.org/links/variants/519 https://civicdb.org/links/genes/24 false BRAF 673 N486_P490del Pancreatic Cancer 1793 Trametinib Predictive Supports C Sensitivity/Response In a case report, a patient with pancreatic cancer harboring BRAF N486-P490del was treated with trametinib. Within 4 weeks of initiating therapy, her serum CA19-9 had fallen from 36,000 to 8,100 U/mL, and the radiographic partial response was revealed by CT at 8 weeks after initiation of trametinib. cfDNA measurements for BRAF and TP53 alleles revealed a dramatic decline in response to trametinib. After 6 months of therapy, radiographic progression was identified. 29903880 PubMed Aguirre et al., 2018, Cancer Discov 3 accepted 7730 2794 5 Somatic 2019-11-14 10:41:26 UTC https://civicdb.org/links/evidence_items/7730 https://civicdb.org/links/variants/2794 https://civicdb.org/links/genes/5 false ABL1 25 SNX2::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Juvenile onset Prognostic Supports C Poor Outcome This case report describes a 7-year old boy with B-ALL who presented with high white blood count (115.4x109 /L). Karyotype analysis showed a t(5;9)(q22;q34), resulting in a SNX2-ABL1 fusion. The patient was treated based on the ALL-BFM95 regimen; although he received remission, he relapsed during maintenance, 15 months after the initial diagnosis. He could not achieve the second remission using chemotherapy, but was treated at this time with imatinib (dose of 240 mg/m2 /d once daily); this allowed to achieve disease control and proceed with an umbilical cord blood transplant. However, at 6 months from transplantation, the patient developed bone marrow relapse again. He never achieved a remission after the second relapse (despite salvage chemotherapies and therapy with both imatinib and dasatinib). The patient died of progressive disease. 24215620 PubMed Masuzawa et al., 2014, Eur. J. Haematol. 1 accepted 7744 2678 4 5 122110691 122135550 ENST00000379516.2 9 133738150 133763062 ENST00000372348.2 75 GRCh37 The SNX2-ABL1 fusion is composed of part of the SNX2 (Sorting Nexin 2) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 3 of SNX2 to exon 4 of ABL1 (SNX2-ABL1 3-4). The fusion is the result of a reciprocal translocation t(5;9)(p23.2;q34.12) and has been identified by RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the sorting nexin, N-terminal domain of SNX2 and the SH2, tyrosine kinase, and F actin binding domains of ABL1, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The SNX2-ABL1 fusion has been documented in six young men between the ages of 7 and 29 years with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. Two patients had tyrosine kinase inhibitors (imatinib and dasatinib + imatinib) added to their chemotherapy regimens that, while producing initially encouraging results, ultimately did not prevent these individuals from succumbing to their disease. The clinical details of these cases may predict response to treatment with tyrosine kinase inhibitors and is the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-06-14 17:17:09 UTC https://civicdb.org/links/evidence_items/7744 https://civicdb.org/links/variants/2678 https://civicdb.org/links/genes/4 false BRAF 673 D594G Cancer 162 Trametinib Predictive Supports D Sensitivity/Response In a BRAF-mutation inducible model in the NIH3T3 cell line, class 3 BRAF mutations (G466V, G466E, D594G, D594N, and G596R) were resistant to vemurafenib but sensitive to MEK-inhibitor trametinib. 28783719 PubMed Yao et al., 2017, Nature 2 accepted 7760 611 5 7 140453154 140453154 T C ENST00000288602.6 75 GRCh37 This BRAF mutation has a markedly reduced kinase activity and leads to paradoxical MEK-pathway activation via CRAF binding. Somatic 2019-11-26 21:52:44 UTC https://civicdb.org/links/evidence_items/7760 https://civicdb.org/links/variants/611 https://civicdb.org/links/genes/5 false BRAF 673 NRF1::BRAF Transitional Cell Carcinoma 2671 Trametinib Predictive Supports C Sensitivity/Response In a case report, a patient with urothelial carcinoma harboring with NRF1-BRAF fusion was treated with trametinib. After two and a half months of treatment, MRI revealed 48.4% decrease in size of liver metastasis. 31010895 PubMed Isaacson et al., 2019, Cold Spring Harb Mol Case Stud 3 accepted 7763 2883 5 Somatic 2020-11-20 15:48:06 UTC https://civicdb.org/links/evidence_items/7763 https://civicdb.org/links/variants/2883 https://civicdb.org/links/genes/5 false ABL1 25 BCR::ABL T315V Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Sensitivity/Response In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed reduced incorporation when treated with axitinib in fusions with the T315V variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 45nM vs. 823 nM), indicating the T315V variant induces sensitivity compared to BCR-ABL1 without secondary variants. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 7766 2885 4 Somatic 2019-12-30 03:30:10 UTC https://civicdb.org/links/evidence_items/7766 https://civicdb.org/links/variants/2885 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL V299L Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Sensitivity/Response In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed decreased incorporation when harboring fusions with the V299L variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 188nM vs. 823 nM), indicating V299L induces sensitivity compared to BCR-ABL1 without secondary variants. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 7767 1231 4 9 133747588 133747588 G C ENST00000318560.5 75 GRCh37 Somatic 2019-12-30 03:31:28 UTC https://civicdb.org/links/evidence_items/7767 https://civicdb.org/links/variants/1231 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315A Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Sensitivity/Response In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed decreased incorporation when harboring fusions with the T315A variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 389nM vs. 823 nM), indicating T315A induces sensitivity compared to BCR-ABL1 without secondary variants. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 7768 2335 4 9 133748282 133748282 A G ENST00000318560.5 75 GRCh37 Somatic 2019-12-30 03:32:55 UTC https://civicdb.org/links/evidence_items/7768 https://civicdb.org/links/variants/2335 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M351T Chronic Myeloid Leukemia 8552 Axitinib Predictive Does Not Support D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed decreased incorporation when harboring fusions with the M351T variant of ABL1 compared to those with wildtype ABL1 (IC50 of 553nM vs. 823 nM), indicating the M351T variant induces sensitivity compared to BCR-ABL1 without secondary variants. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 7769 1029 4 9 133748391 133748391 T C ENST00000318560.5 75 GRCh37 Somatic 2019-12-30 04:36:13 UTC https://civicdb.org/links/evidence_items/7769 https://civicdb.org/links/variants/1029 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL H396P Chronic Myeloid Leukemia 8552 Axitinib Predictive Does Not Support D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed lower incorporation when harboring fusions with the H396P variant of ABL1 compared to those with wildtype ABL1 (IC50 of 683nM vs. 823 nM), indicating the H396P variant induces sensitivity compared to BCR-ABL1 without secondary variants. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 7770 1531 4 9 133750356 133750356 A C ENST00000318560.5 75 GRCh37 Somatic 2019-12-30 04:37:35 UTC https://civicdb.org/links/evidence_items/7770 https://civicdb.org/links/variants/1531 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M244V Chronic Myeloid Leukemia 8552 Axitinib Predictive Does Not Support D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the M244V variant of ABL1 compared to those with wildtype ABL1 (IC50 of 690nM vs. 823 nM), indicating that the M244V variant does not induce resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 7771 1021 4 9 133738330 133738330 A G ENST00000318560.5 75 GRCh37 Somatic 2019-12-30 04:38:24 UTC https://civicdb.org/links/evidence_items/7771 https://civicdb.org/links/variants/1021 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E279K Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Sensitivity/Response In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the E279K variant of ABL1 compared to those with wildtype ABL1 (IC50 of 778nM vs. 823 nM), indicating that the E279K variant does not induce resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 7772 2886 4 Somatic 2019-12-30 03:51:28 UTC https://civicdb.org/links/evidence_items/7772 https://civicdb.org/links/variants/2886 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E292L Chronic Myeloid Leukemia 8552 Axitinib Predictive Does Not Support D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the E292L variant of ABL1 compared to those with wildtype ABL1 (IC50 of 863nM vs. 823 nM), indicating that the E292L variant does not induce resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 7773 2887 4 Somatic 2019-12-30 03:52:34 UTC https://civicdb.org/links/evidence_items/7773 https://civicdb.org/links/variants/2887 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317R Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed higher incorporation when harboring fusions with the F317R variant of ABL1 compared to those with wildtype ABL1 (IC50 of 1286nM vs. 823 nM), indicating resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 7774 2888 4 Somatic 2019-12-30 03:53:45 UTC https://civicdb.org/links/evidence_items/7774 https://civicdb.org/links/variants/2888 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L248R and F359I Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar sensitivity to axitinib in fusions with the L248R and F359I variants of ABL1 compared to those with wildtype ABL1 (IC50 of 1385nM vs. 823 nM), indicating resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 7775 2889 4 Somatic 2019-12-30 03:57:13 UTC https://civicdb.org/links/evidence_items/7775 https://civicdb.org/links/variants/2889 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L248R Chronic Myeloid Leukemia 8552 Axitinib Predictive Supports D Resistance In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the L248R variant of ABL1 compared to those with wildtype ABL1 (IC50 of 1399nM vs. 823 nM), indicating resistance. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 7776 2340 4 9 133738343 133738343 T G ENST00000318560.5 75 GRCh37 Somatic 2019-12-30 03:58:28 UTC https://civicdb.org/links/evidence_items/7776 https://civicdb.org/links/variants/2340 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Acute Lymphoblastic Leukemia 9952 Ponatinib,Axitinib Substitutes Predictive Does Not Support D Resistance Bone marrow mononuclear cells (BM MNCs) were isolated from three acute lymphoblastic leukemia patients with the BCR-ABL1 T315I variant who were pretreated with various chemotherapeutics and dasatinib. 2/3 patient's BM MNCs were considered sensitive to ponatinib and axitinib using drug sensitivity scoring of proliferation assays. Additionally, BCR-ABL T315I showed sensitivity to ponitinib and axitinib in Ba/F3 cells. 25686603 PubMed Pemovska et al., 2015, Nature 3 accepted 7777 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2019-12-30 04:09:08 UTC https://civicdb.org/links/evidence_items/7777 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Acute Lymphoblastic Leukemia 9952 Imatinib,Nilotinib,Dasatinib Substitutes Predictive Supports D Resistance Bone marrow mononuclear cells (BM MNCs) isolated from three acute lymphoblastic leukemia patients with the BCR-ABL1 T315I variant. Patients were pretreated with various chemotherapeutics and dasatinib. The patients' cells were sensitive to Ponatinib and Axitinib and insensitive to Nilotinib, Imatinib, and Dasatinib using drug sensitivity scoring detailed in a referenced paper. Additionally, in a proliferation assay, T315I variants were resistant to imatinib. 25686603 PubMed Pemovska et al., 2015, Nature 3 accepted 7778 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2019-12-30 04:22:02 UTC https://civicdb.org/links/evidence_items/7778 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Ponatinib Predictive Does Not Support D Resistance Bone marrow mononuclear cells (BM MNCs) were isolated from a chronic myeloid leukemia patient with the BCR-ABL1 T315I variant. The patient was pretreated with imatinib, dasatinib, and chemotherapy. The patients' cells were sensitive to Ponatinib and Axitinib and insensitive to Nilotinib, Imatinib, and Dasatinib compared to BM MNCs from healthy controls using drug sensitivity scoring of proliferation assays. In a rezasurin proliferation assay, Ba/F3 cells carrying the T315I variant in the ABL1 portion of the BCR-ABL fusion showed high sensitivity to ponatinib (IC50 of 11 nM vs. 3.1 nM in wildtype fusions). 25686603 PubMed Pemovska et al., 2015, Nature 3 accepted 7779 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2019-12-30 04:59:14 UTC https://civicdb.org/links/evidence_items/7779 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315I Chronic Myeloid Leukemia 8552 Dasatinib,Imatinib,Nilotinib Substitutes Predictive Supports D Resistance Bone marrow mononuclear cells (BM MNCs) were isolated from a chronic myeloid leukemia patients with the BCR-ABL1 T315I variant who was pretreated with imatinib, dasatinib, and chemotherapy. The patient's cells were sensitive to Ponatinib and Axitinib and insensitive to Nilotinib, Imatinib, and Dasatinib compared to BM MNCs from healthy controls using drug sensitivity scoring of proliferation assays. Additionally, in a rezasurin proliferation assay, Ba/F3 cells carrying the BCR-ABL1 variant were resistant to imatinib in fusions with the T315I variant of ABL1 compared to wildtype ABL1 (IC50 of >4,000 nM vs. 257 nM). 25686603 PubMed Pemovska et al., 2015, Nature 3 accepted 7780 2 4 9 133748283 133748283 C T ENST00000318560.5 75 GRCh37 While the efficacy of imatinib has revolutionized chronic myelogenous leukemia (CML) treatment, it is still not a cure-all. Both initial resistance and acquired resistance as a result of selection have been seen in a small subset of CML patients. The ABL kinase domain mutation T315I (aka T334I) has been shown to be one such mutation that confers resistance to imatinib. Second generation TKI's (dasatinib and ponatinib) specific to BCR-ABL have shown efficacy in treating resistant cases. Somatic 2019-12-30 04:27:55 UTC https://civicdb.org/links/evidence_items/7780 https://civicdb.org/links/variants/2 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E255K V299L Chronic Myeloid Leukemia 8552 Ponatinib,Dasatinib Substitutes Predictive Supports D Sensitivity/Response Bone marrow mononuclear cells isolated from a chronic myeloid leukemia patient with the BCR-ABL1 fusion and E255K and V299L secondary variants in ABL1 showed a high drug sensitivity score to ponatinib and dasatinib. 25686603 PubMed Pemovska et al., 2015, Nature 2 accepted 7781 2890 4 Somatic 2019-12-30 04:29:16 UTC https://civicdb.org/links/evidence_items/7781 https://civicdb.org/links/variants/2890 https://civicdb.org/links/genes/4 false ABL1 25 RCSD1::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Juvenile onset Imatinib Predictive Supports C Sensitivity/Response This case report describes a 15 year old patient with relapsed B-ALL positive for the RCSD1-ABL1 fusion, who was successfully treated with chemotherapy with addition of imatinib; the patient remained disease free for 36 months. This case supports sensitivity of B-ALL with RCSD1-ABL1 fusions to ABL-type tyrosine kinase inhibitors. 27125982 PubMed Perwein et al., 2016, Haematologica 3 accepted 7783 2681 4 The RCSD1-ABL1 fusion is composed of part of the RCSD1 (RCS Domain Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 2 or, more frequently, exon 3 of RCSD1 to exon 4 of ABL1 (RCSD1-ABL1 3-4). The fusion is the result of a reciprocal translocation t(1;9)(q24.2;q34.12) and has been identified by FISH/karyotype, RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the ABL1 SH2, actin binding domain, and tyrosine kinase domain, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The RCSD1-ABL1 fusion has been documented in greater than fifteen pediatric and adult patients with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. The majority that that were exposed to tyrosine kinase inhibitors (TKIs: imatinib, dasatinib, or ponatinib) experienced durable remissions until the TKIs were discontinued. The clinical details of these cases may predict response to treatment with TKIs and are the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-08-19 13:03:40 UTC https://civicdb.org/links/evidence_items/7783 https://civicdb.org/links/variants/2681 https://civicdb.org/links/genes/4 false CTNNB1 1499 Exon 3 Mutation Desmoid Tumor 0080366 Prognostic Does Not Support B N/A This study illustrates the prevalence of CTNNB1 mutations in sporadic desmoid tumors, and examines whether the presence of CTNNB1 mutations correlates with the disease outcome. CTNNB1 mutations (including specific exon 3 mutations T41A, S45F, S45P, and S45C) were found in 106 out of 145 desmoid tumor specimens, and in 86 out of 115 specimens from patients who had undergone complete surgical resection. At a median follow-up of 31 months, the 5-year recurrence free survival rate of patients with the beta-catenin mutated tumors was worse than that of the patients with wild-type tumors (58% vs 74%), however, the difference was not statistically significant (p = 0.285). Thus, the study shows that there is no statistically significant correlation between the CTNNB1 mutation and the recurrence risk of sporadic desmoid tumors, even though specific exon 3 CTNNB1 mutations are commonly identified in these tumors. 23960186 PubMed Mullen et al., 2013, Oncologist 4 accepted 7784 2892 1290 3 41266017 41266244 ENST00000349496.5 75 GRCh37 Somatic 2020-11-25 00:14:18 UTC https://civicdb.org/links/evidence_items/7784 https://civicdb.org/links/variants/2892 https://civicdb.org/links/genes/1290 false DPYD 1806 EXON 11-19 DELETION Head And Neck Squamous Cell Carcinoma 5520 Leucovorin,Fluorouracil Combination Predictive Supports C Sensitivity/Response A 69 year old patient diagnosed with HNSCC presented with an unresectable neck mass three months after surgery and adjuvant radiation therapy. A biopsy was taken for whole genome and transcriptome analysis and the patient was started on systemic therapy. After showing resistance to the systemic therapy treatment with 5-FU and leucovorin was initiated based on the discovery of a somatic exon 11-19 in frame deletion in DPYD, which was hypothesized to increase sensitivity to 5-FU in the tumour. A dramatic clinical and radiographic response was sustained for 17 weeks, but following a 3 week treatment break a new nodule appeared. This recurrence showed resistance to re-initiation of treatment with capecitabine (oral 5-FU), and analysis of an additional biopsy provided no evidence as to the mechanism of resistance. 31871216 PubMed Majounie et al., 2019, Cold Spring Harb Mol Case Stud 4 accepted 7787 2893 1526 1 97700408 98039526 ENST00000370192.3 75 GRCh37 Somatic 2020-01-03 17:30:23 UTC https://civicdb.org/links/evidence_items/7787 https://civicdb.org/links/variants/2893 https://civicdb.org/links/genes/1526 false MET 4233 MET::ATXN7L1 Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports C Sensitivity/Response Case Report of a a 56-year-old female (never-smoker) patient with stage IV NSCLC. NGS revealed a MET–ATXN7L1 fusion. No additional known driver gene alterations were identified. Following progression after three months of chemotherapy [paclitaxel (135 mg/m2 days 1 and 8; carboplatin AUC = 5 day 1)], the patient received crizotinib treatment (250 mg/b.i.d. orally) and exhibited a partial response that lasted for 4 months. 30339198 PubMed Zhu et al., 2018, Ann. Oncol. 3 accepted 7793 2894 52 N/A 2020-09-19 00:14:17 UTC https://civicdb.org/links/evidence_items/7793 https://civicdb.org/links/variants/2894 https://civicdb.org/links/genes/52 false MET 4233 EXON 14 SKIPPING MUTATION Histiocytic And Dendritic Cell Cancer 5621 Crizotinib Predictive Supports C Sensitivity/Response An 84 year old never-smoker with an upper chest mass was found to have stage 3 histiocytic sarcoma. Genomic profiling discovered a MET exon 14 variant c.2888-5_2944del62, as well as TP53 p.R175H and ZMYM3 c.3008-1G>A. After four months of crizotinib treatment tumour volume had decreased by >60%, however the patient showed progression at 11 months. 25971938 PubMed Frampton et al., 2015, Cancer Discov 3 accepted 7796 324 52 7 116411903 116412043 ENST00000318493.6 75 GRCh37 Exon 14 mutations have been observed in ~3% of patients with NSCLC (28/933 reported by Awad et al J Clin Onc 2016), confirmed to cause exon skipping when available, and associated with concurrent MET amplification. Responses to the c-MET inhibitor crizotinib have been reported in preclinical models and in individual case reports as well as a small-scale clinical trial (17 patients treated, Drilon et al., 2016 (suppl; abstr 108; ASCO ID 167889-176)). Larger studies are needed but enrollment of patients with MET exon 14 skipping mutation in trials with MET inhibitors or off-label treatment is encouraged (Paik et al., 2015 (suppl; abstr 8021)). Somatic 2020-01-21 11:01:03 UTC https://civicdb.org/links/evidence_items/7796 https://civicdb.org/links/variants/324 https://civicdb.org/links/genes/52 false MET 4233 EXON 14 SKIPPING MUTATION Cancer 162 Capmatinib Predictive Supports D Sensitivity/Response MET exon 14 skipping was modelled in vitro by expressing human MET cDNA with exon 14 deletion in HEK293 cells and mouse MET with homologous exon 15 deletion in NIH3T3 cells. NIH3T3 cells expressing MET with exon 15 deletion showed dose dependent inhibition of cell proliferation upon treatment with capmatinib, with significantly lower cell survival compared to control cells. In addition, HEK293 cells expressing MET with exon 14 deletion had increased ERK phosphorylation, while NIH3T3 cells expressing mouse MET with exon 15 deletion had increased MET phosphorylation and increased anchorage-independent colony formation compared to wt MET. 25971938 PubMed Frampton et al., 2015, Cancer Discov 3 accepted 7797 324 52 7 116411903 116412043 ENST00000318493.6 75 GRCh37 Exon 14 mutations have been observed in ~3% of patients with NSCLC (28/933 reported by Awad et al J Clin Onc 2016), confirmed to cause exon skipping when available, and associated with concurrent MET amplification. Responses to the c-MET inhibitor crizotinib have been reported in preclinical models and in individual case reports as well as a small-scale clinical trial (17 patients treated, Drilon et al., 2016 (suppl; abstr 108; ASCO ID 167889-176)). Larger studies are needed but enrollment of patients with MET exon 14 skipping mutation in trials with MET inhibitors or off-label treatment is encouraged (Paik et al., 2015 (suppl; abstr 8021)). Somatic 2020-01-21 11:01:57 UTC https://civicdb.org/links/evidence_items/7797 https://civicdb.org/links/variants/324 https://civicdb.org/links/genes/52 false CDK4 1019 EXPRESSION Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Ribociclib,Dexamethasone Combination Predictive Supports D Sensitivity/Response CDK4 was found to be significantly overexpressed in the bone marrow of MLL-rearranged B-ALL patients (n=70) compared to normal bone marrow (n=74, p<.001). Combination treatment with dexamethasone (glucocorticoid) and Ribociclib (a highly selective CDK4 / CDK6 inhibitor) of both glucocorticoid sensitive (Rs4;11 & NALM6) and glucocorticoid resistant (RCH-ACV & SEM) B-ALL cell lines synergistically reduced cell viability of all four lines greater than individual drug exposures. Combination therapy also synergistically reduced the cell viability of 5 primary B-ALL lines derived from diagnosis bone marrow compared to individual treatment. (Note: Expression of CDK4 was not quantitatively measured in the derived and primary B-ALL lines used). Further investigation in RCH-ACV and SEM lines revealed dexamethasone and Ribociclib combined increased apoptosis (annexin-V) and increased G1 arrest along with increased p16 (a CDK4 & CDK6 inhibitor) and decreased phosphorylation of downstream G1 to S cell cycle progression markers compared to single treatments. Combination treatment also led to the increase of NR3C1 expression. Knockdown of CDK4 and CDK6 by siRNAs in RCH-ACV sensitized these cells to dexamethasone treatment and increased NR3C1 expression. 29408328 PubMed Bortolozzi et al., 2018, Biochem. Pharmacol. 2 accepted 7798 25 13 12 58141510 58146304 ENST00000257904.6 75 GRCh37 CDK4, along with its partner CDK6, are key players in cell cycle progression. The complex has been implicated in a number of cancer types, and is the focus of therapeutic research and development. One targeted therapy for CDK inhibition is palbociclib, which may slow the growth of advanced stage breast cancers. It has also been shown, in mouse, that CDK inhibition may sensitize mutant PIK3CA tumors to PI3K inhibitors. N/A 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7798 https://civicdb.org/links/variants/25 https://civicdb.org/links/genes/13 false CDK6 1021 Overexpression Glioblastoma Proneural Subtype 0050804 Palbociclib Predictive Supports D Sensitivity/Response Study of vehicle versus oral palbociclib (150 mg/kg/day) in mice with intracranial implantation of proneural GBM stem cell-like G448 cells, which are shown to have higher than normal expression of CDK6. Mice receiving palbociclib had significantly longer survival time (p=0.038). 28903422 PubMed Li et al., 2017, Oncotarget 2 accepted 7800 602 12 7 92234235 92463231 ENST00000265734.4 75 GRCh37 N/A 2020-05-07 22:46:19 UTC https://civicdb.org/links/evidence_items/7800 https://civicdb.org/links/variants/602 https://civicdb.org/links/genes/12 false CDK6 1021 EXPRESSION Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Dexamethasone,Ribociclib Combination Predictive Supports D Sensitivity/Response CDK6 was found to be significantly overexpressed in the bone marrow of B-ALL patients (n=299) compared to normal bone marrow (n=74, p<.001). Combination treatment with dexamethasone (glucocorticoid) and Ribociclib (a highly selective CDK4 / CDK6 inhibitor) of both glucocorticoid sensitive (Rs4;11 & NALM6) and glucocorticoid resistant (RCH-ACV & SEM) B-ALL cell lines synergistically reduced cell viability of all four lines greater than individual drug exposures. Combination therapy synergistically reduced the cell viability of 5 primary B-ALL lines derived from diagnosis bone marrow compared to individual treatment. (Note: Expression of CDK6 was not quantitatively measured in the derived and primary B-ALL lines used). Further investigation in RCH-ACV and SEM revealed dexamethasone and Ribociclib combined increased apoptosis (annexin-V) and increased G1 arrest along with increased p16 (a CDK4 & CDK6 inhibitor) expression and decreased phosphorylation of downstream G1 to S cell cycle progression markers compared to single treatments. Combination treatment also led to the increase of NR3C1 expression. Knockdown of CDK4 and CDK6 by siRNAs in RCH-ACV sensitized these cells to dexamethasone treatment and increased NR3C1 expression. 29408328 PubMed Bortolozzi et al., 2018, Biochem. Pharmacol. 2 accepted 7801 3042 12 N/A 2020-12-10 20:17:06 UTC https://civicdb.org/links/evidence_items/7801 https://civicdb.org/links/variants/3042 https://civicdb.org/links/genes/12 false ERBB2 2064 Amplification Colorectal Cancer 9256 Afatinib Predictive Supports D Sensitivity/Response Afatinib monotherapy was tested in patient-derived colorectal cancer (M051) mouse xenografts and gastric cancer cell-line (NCI-N87) mouse xenografts. Tumor shrinkage was observed and tumor volume was significantly decreased compared to treatment with vehicle or lapatinib monotherapy (p<0.0001 (M051 Afatinib vs. Lapatinib) and p=0.0003 (NCI-N87 Afatinib vs. Lapatinib). 26296355 PubMed Leto et al., 2015, Clin. Cancer Res. 3 accepted 7807 306 20 17 37856333 37884915 ENST00000269571.5 75 GRCh37 Her2 (ERBB2) amplifications are seen in up to 20% of breast cancers and were associated with aggressive disease and poor prognosis when discovered. Trastuzumab first found considerable success, and was approved for treatment, in HER2 positive metastatic breast cancer (MBC) which had progressed under chemotherapy. These metastatic cancers nonetheless progressed under trastuzumab, and other forms of therapy were studied for next line treatments, including tyrosine kinase inhibitors. Lapatinib, a reversible inhibitor of tyrosine kinase activity in ErbB1 and ErbB2, and afatinib, an irreversible inhibitor of all 4 ErbB forms were shown to have activity in trastuzumab-progressed HER2 MBC. Interestingly trastuzumab itself also turned out to remain effective in treatment of trastuzumab-progressed HER2 MBC. The LUX-Breast 1 trial compared a TKI-based treatment (afatinib) to a trastuzumab-based treatment of trastuzumab-progressed HER2 MBC, and the LUX-Breast 3 trial addressed TKI application in the context of HER2 MBC with difficult to treat brain metastases. In neither of these cases was the TKI more effective, making successful future replacement of trastuzumab-based therapy with a TKI in trastuzumab-progressed HER2 MBC seem unlikely. Instead, a potential role for TKIs in this disease context is revealed in preclinical work suggesting synergism between TKI and trastuzumab action, and clinical trials with lapatinib or afatinib combined with trastuzumab indicate that dual HER2 blockade may be an effective therapy. Dual antibody HER2 blockade with pertuzumab instead of TKI in HER2 MBC has also recently shown strong results in the CLEOPATRA trial. HER2 overexpression is targeted in neoadjuvant breast cancer treatment, and has also been successfully targeted in gastric cancer. Somatic 2022-05-12 21:34:43 UTC https://civicdb.org/links/evidence_items/7807 https://civicdb.org/links/variants/306 https://civicdb.org/links/genes/20 false FGFR1 2260 Amplification Adenosquamous Lung Carcinoma 4829 Pazopanib Predictive Supports C Sensitivity/Response Patient diagnosed with metastatic squamous cell lung cancer had high-level amplification of FGFR1 and high expression of MYC. Patient was treated with 400 mg pazopanib twice a day. CT taken four and eight weeks after start of pazopanib showed tumor regression and cavitation. Due to side effects, patient stopped taking pazopanib after 6 months. No clinical or radiologic signs of tumor progression were present at that time. 24302556 PubMed Malchers et al., 2014, Cancer Discov 3 accepted 7811 267 1885 8 38268656 38325363 ENST00000425967.3 75 GRCh37 FGFR1 amplifications are the most common aberrations of the FGFR family in cancer. One study reports FGFR1 aberrations in 3.5% of 4,853 patients of which most are FGFR1 amplifications (Helsten et. al., 2016). Preclinically, FGFR1 amplifications have also been shown to confer sensitivity to FGFR1 inhibitors (Weiss et. al., 2010). Clinical studies are currently ongoing (e.g. NCT01004224). Somatic 2020-01-10 15:55:12 UTC https://civicdb.org/links/evidence_items/7811 https://civicdb.org/links/variants/267 https://civicdb.org/links/genes/1885 false NT5C2 22978 R367Q Childhood Acute Lymphocytic Leukemia 0080144 Thioguanine,Mercaptopurine Substitutes Predictive Supports C Resistance 71 Childhood B-cell acute lymphocytic leukemia relapse patients had their diagnosis and relapse samples sequenced for NT5C2 mutations. Sequencing revealed an early relapse case with NT5C2 R367Q enriched to a variant allele frequency (VAF) of 25% at relapse and only a VAF of .02% at diagnosis. R367Q could drive clonal outgrowth through the promotion of drug resistance, specifically to thiopurines, which are a staple of ALL maintenance therapy that are administered daily. 23377183 PubMed Meyer et al., 2013, Nat. Genet. 2 accepted 7812 238 9189 10 104852955 104852955 C T ENST00000343289.5 75 GRCh37 Somatic 2020-01-23 23:39:55 UTC https://civicdb.org/links/evidence_items/7812 https://civicdb.org/links/variants/238 https://civicdb.org/links/genes/9189 false NT5C2 22978 R238W Childhood Acute Lymphocytic Leukemia 0080144 Mercaptopurine,Thioguanine Substitutes Predictive Supports D Resistance Lentiviral-mediated overexpression of NT5C2 R238W in Reh cells resulted in significant resistance against thiopurines (mercaptopurine and thioguanine) versus wildtype and GFP controls, as indicated by reduced apoptosis. Compared to controls, overexpression cells also displayed reduced intercellular thioguanoside nucleotides after 24 hours of drug exposure, as measured by HPLC. Additionally, recombinant protein expression of R238W led to increased 5’ nucleotidase activity. 23377183 PubMed Meyer et al., 2013, Nat. Genet. 4 accepted 7813 2896 9189 10 104857107 104857107 G A ENST00000343289.5 75 GRCh37 Somatic 2020-03-27 08:54:22 UTC https://civicdb.org/links/evidence_items/7813 https://civicdb.org/links/variants/2896 https://civicdb.org/links/genes/9189 false NT5C2 22978 S445F Childhood Acute Lymphocytic Leukemia 0080144 Thioguanine,Mercaptopurine Substitutes Predictive Supports D Resistance Lentiviral-mediated overexpression of NT5C2 S445F in Reh cells resulted in significant resistance against thiopurines (mercaptopurine and thioguanine) versus wildtype and GFP controls, as indicated by reduced apoptosis. Compared to controls, overexpression cells also displayed reduced intercellular thioguanoside nucleotides after 24 hours of drug exposure, as measured by HPLC. Additionally, recombinant protein expression of S445F led to increased 5’ nucleotidase activity. 23377183 PubMed Meyer et al., 2013, Nat. Genet. 4 accepted 7814 2897 9189 10 104850483 104850483 G A ENST00000343289.5 75 GRCh37 Somatic 2020-03-27 08:56:33 UTC https://civicdb.org/links/evidence_items/7814 https://civicdb.org/links/variants/2897 https://civicdb.org/links/genes/9189 false NT5C2 22978 R367Q Childhood Acute Lymphocytic Leukemia 0080144 Cytarabine,Gemcitabine,Prednisolone,Doxorubicin Substitutes Predictive Does Not Support D Resistance Lentiviral mediated overexpression of NT5C2 R367Q in Reh cells resulted in no change in apoptosis after exposure to cytarabine, gemcitabine, doxorubicin, or prednisolone compared to wildtype NT5C2 overexpression and GFP control lines. 23377183 PubMed Meyer et al., 2013, Nat. Genet. 4 accepted 7815 238 9189 10 104852955 104852955 C T ENST00000343289.5 75 GRCh37 Somatic 2020-02-14 16:20:22 UTC https://civicdb.org/links/evidence_items/7815 https://civicdb.org/links/variants/238 https://civicdb.org/links/genes/9189 false NT5C2 22978 R238W Childhood Acute Lymphocytic Leukemia 0080144 Cytarabine,Gemcitabine,Doxorubicin,Prednisolone Substitutes Predictive Does Not Support D Resistance Overexpression of NT5C2 R238W in Reh cells resulted in no change in response to cytarabine, gemcitabine, doxorubicin or prednisolone versus wildtype or GFP controls as indicated by similar apoptosis. 23377183 PubMed Meyer et al., 2013, Nat. Genet. 4 accepted 7816 2896 9189 10 104857107 104857107 G A ENST00000343289.5 75 GRCh37 Somatic 2020-03-27 08:57:54 UTC https://civicdb.org/links/evidence_items/7816 https://civicdb.org/links/variants/2896 https://civicdb.org/links/genes/9189 false NT5C2 22978 S445F Childhood Acute Lymphocytic Leukemia 0080144 Prednisolone,Cytarabine,Gemcitabine,Doxorubicin Substitutes Predictive Does Not Support D Resistance Overexpression of NT5C2 S445F in Reh cells resulted in no change in response to cytarabine, gemcitabine, doxorubicin or prednisolone versus wildtype or GFP controls as indicated by similar apoptosis. 23377183 PubMed Meyer et al., 2013, Nat. Genet. 4 accepted 7817 2897 9189 10 104850483 104850483 G A ENST00000343289.5 75 GRCh37 Somatic 2020-03-27 08:58:14 UTC https://civicdb.org/links/evidence_items/7817 https://civicdb.org/links/variants/2897 https://civicdb.org/links/genes/9189 false NT5C2 22978 Mutation Childhood Acute Lymphocytic Leukemia 0080144 Prognostic Supports B Poor Outcome Within a cohort of 71 pediatric B-ALL relapse cases, all 7 patients with NT5C2 mutations detected at relapse demonstrated early relapse (<36 months from initial diagnosis) with a median time to relapse of 516 days versus a 930-day median time to relapse for the 64 patients wild type for NT5C2 (p=.03). Patients were derived from the Children's Oncology Group (COG), but Individual patient treatment regimens were not given. 23377183 PubMed Meyer et al., 2013, Nat. Genet. 4 accepted 7818 2898 9189 Somatic 2020-01-23 22:41:01 UTC https://civicdb.org/links/evidence_items/7818 https://civicdb.org/links/variants/2898 https://civicdb.org/links/genes/9189 false ABL1 25 BCR::ABL D363G Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance One chronic myeloid leukemia patient in chronic phase had a partial best cytogenetic response to imatinib but became resistant. Bacterial clones generated using peripheral blood RNA revealed the BCR-ABL1 fusion with the D363G secondary variant in 2/10 clones. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 1 accepted 7820 2900 4 Somatic 2020-02-18 04:27:53 UTC https://civicdb.org/links/evidence_items/7820 https://civicdb.org/links/variants/2900 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E98G Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance One chronic myeloid leukemia patient in chronic phase had a complete best cytogenetic response to imatinib but became resistant. Bacterial clones generated using peripheral blood RNA later revealed the BCR-ABL1 fusion with the E98G secondary variant in 11/11 clones. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 1 accepted 7822 2901 4 Somatic 2020-02-18 05:53:51 UTC https://civicdb.org/links/evidence_items/7822 https://civicdb.org/links/variants/2901 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL H396R Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with H396R and E355G variants in 9/11 and 1/11 clones, respectively. Clones were generated using peripheral blood RNA. The patient had no best cytogenetic and complete best hematologic responses to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 7823 1030 4 9 133750356 133750356 A G ENST00000318560.5 75 GRCh37 Somatic 2020-03-11 20:50:04 UTC https://civicdb.org/links/evidence_items/7823 https://civicdb.org/links/variants/1030 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M244V Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance One chronic myeloid leukemia patient in chronic phase had no response to imatinib. Bacterial clones generated using peripheral blood RNA later revealed the BCR-ABL1 fusion with the M244V secondary variant in 12/12 clones. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 1 accepted 7825 1021 4 9 133738330 133738330 A G ENST00000318560.5 75 GRCh37 Somatic 2020-02-18 22:02:24 UTC https://civicdb.org/links/evidence_items/7825 https://civicdb.org/links/variants/1021 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL L364I Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance One chronic myeloid leukemia patient in chronic phase had no response to imatinib. Bacterial clones generated using peripheral blood RNA later showed the BCR-ABL1 fusion with the L364I secondary variant in 9/12 clones. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 1 accepted 7826 2902 4 Somatic 2020-07-31 22:07:40 UTC https://civicdb.org/links/evidence_items/7826 https://civicdb.org/links/variants/2902 https://civicdb.org/links/genes/4 false FGFR2 2263 P253R Head And Neck Squamous Cell Carcinoma 5520 Pazopanib Predictive Supports C Sensitivity/Response FGFR2 p.P253R mutation detected in patient with head and neck SCC. Mutation initially detected by RNA-Seq and confirmed by Sanger sequencing. Patient is 52 y/o male with initial diagnosis of SCC of right tongue in 2008. Recurrences treated with surgery, radiotherapy and chemotherapy including carboplatin, paclitaxel, cisplatin, and cetuximab. In 2012, progression was detected in right neck and left axilla. Patient was treated with 800 mg of pazopanib daily. At 12 day follow up patient had marked reduction in tumor size. Patient continued treatment for 2 months until he presented with right carotid hemorrhage. Last follow up shows patient is alive 11 months after beginning pazopanib treatment. 23786770 PubMed Liao et al., 2013, Cancer Res. 3 accepted 7833 2905 22 Somatic 2022-07-13 23:18:15 UTC https://civicdb.org/links/evidence_items/7833 https://civicdb.org/links/variants/2905 https://civicdb.org/links/genes/22 false ABL1 25 BCR::ABL Chronic Myeloid Leukemia 8552 Bafetinib,Nilotinib,Dasatinib Substitutes Predictive Supports D Sensitivity/Response In an in vitro study, six CML cell lines expressing the BCR-ABL1 fusion protein showed sensitivity to nilotinib (IC50: 24.3-84.5 nM), dasatinib (IC50: 1.5-10.9 nM), and bafetinib (IC50: 11.8-87.7 nM). When comparing potency of these treatments against the 6 CML cell lines, dasatinib, nilotinib and bafetinib were on average 98.6, 9.85 and 16.4 times more potent than imatinib. Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 7838 1 4 22 23522397 23632600 ENST00000305877.8 9 133729451 133763063 ENST00000318560.5 75 GRCh37 The BCR-ABL fusion protein, commonly referred to as the Philadelphia chromosome, is one of the most studied fusion genes in cancer. It has widely been considered the initiating event in chronic myelogenous leukemia (CML). However, despite its ability to initiate disease in mice, its status as an initiating mutation is in dispute. In what is commonly used as the poster-child for targeted therapeutics, the development and use of imatinib in the clinic has led to profound improvements in the prognosis of the disease. However, imatinib resistance is still seen in patients with mutations in the ABL kinase domain of the fusion, most notably the T315I variant. In patients resistant to imatinib, either acquired or otherwise, second generation BCR-ABL TKI's (dasatinib and nilotinib) have seen some success in delivering a tumor response. Third generation ABL1 inhibitor ponatinib is the only FDA approved drug with activity against T315I . However due to risk of life-threatening blood clots and severe narrowing of blood vessels ponatinib is ONLY approved for T315I-positive CML or T315I-positive Ph+ ALL or in cases of CML, Ph+ ALL with resistance or intolerance to other approved ABL1 inhibitors. Somatic 2021-02-18 00:10:29 UTC https://civicdb.org/links/evidence_items/7838 https://civicdb.org/links/variants/1 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Cancer 162 Dasatinib,Imatinib Substitutes Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the F317L mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to imatinib and dasatinib treatment (IC50: > 2000.0 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 1712 nM and 87.6 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 7839 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2021-02-17 23:58:47 UTC https://civicdb.org/links/evidence_items/7839 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M351T Cancer 162 Imatinib Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the M351T mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to imatinib treatment (IC50: >2000.0 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 1712 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 7841 1029 4 9 133748391 133748391 T C ENST00000318560.5 75 GRCh37 Somatic 2021-02-18 00:01:23 UTC https://civicdb.org/links/evidence_items/7841 https://civicdb.org/links/variants/1029 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315A Cancer 162 Nilotinib,Bafetinib Substitutes Predictive Does Not Support D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the dasatinib-resistance variant T315A in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to nilotinib and bafetinib (INNO-406) treatment (IC50: 949.2 nM, 422.5 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 642.3 nM and 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 7842 2335 4 9 133748282 133748282 A G ENST00000318560.5 75 GRCh37 Somatic 2021-02-18 00:16:23 UTC https://civicdb.org/links/evidence_items/7842 https://civicdb.org/links/variants/2335 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317V Cancer 162 Imatinib,Bafetinib,Nilotinib Substitutes Predictive Does Not Support D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the dasatinib-resistance variant F317V in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to imatinib, nilotinib and bafetinib (INNO-406) treatment (IC50: 1053.7, 286.9 nM, 284 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 1712 nM, 642.3 nM, and 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 7843 1525 4 9 133748288 133748288 T G ENST00000318560.5 75 GRCh37 Somatic 2021-02-18 00:13:49 UTC https://civicdb.org/links/evidence_items/7843 https://civicdb.org/links/variants/1525 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL T315A Cancer 162 Imatinib,Dasatinib Substitutes Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line stably expressing T315A in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to imatinib and dasatinib treatment (IC50: >2000.0 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 1712 nM and 87.6 nM). Sensitivity was determined by assessing cell proliferation. The authors examined X-ray crystal structure of dasatinib/ABL to determine why dasatinib was ineffective against mutations at amino acid 315, and found that T315A causes decreased steric and hydrogen-bonding interactions with dasatinib. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 7844 2335 4 9 133748282 133748282 A G ENST00000318560.5 75 GRCh37 Somatic 2021-02-26 14:03:00 UTC https://civicdb.org/links/evidence_items/7844 https://civicdb.org/links/variants/2335 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317V Cancer 162 Dasatinib Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line stably expressing F317V in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to dasatinib treatment (IC50: >2000.0 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 87.6 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 7845 1525 4 9 133748288 133748288 T G ENST00000318560.5 75 GRCh37 Somatic 2021-02-26 14:04:52 UTC https://civicdb.org/links/evidence_items/7845 https://civicdb.org/links/variants/1525 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL H396P Cancer 162 Nilotinib,Bafetinib Substitutes Predictive Does Not Support D Resistance In an in vitro study, a Ba/F3 cell line stably expressing H396P in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to nilotinib and bafetinib (INNO-406) treatment (IC50: 986.9 nM and 280.1 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 642.3 nM and 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 7846 1531 4 9 133750356 133750356 A C ENST00000318560.5 75 GRCh37 Somatic 2021-02-26 14:07:33 UTC https://civicdb.org/links/evidence_items/7846 https://civicdb.org/links/variants/1531 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL H396P Cancer 162 Imatinib Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line stably expressing H396P in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to imatinib treatment (IC50: >2000.0 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 1712 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 7847 1531 4 9 133750356 133750356 A C ENST00000318560.5 75 GRCh37 Somatic 2021-02-26 14:08:46 UTC https://civicdb.org/links/evidence_items/7847 https://civicdb.org/links/variants/1531 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253F Cancer 162 Imatinib Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the Y253F mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to imatinib treatment (IC50: > 2000.0 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 1712 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 7848 2909 4 Somatic 2021-02-26 14:11:07 UTC https://civicdb.org/links/evidence_items/7848 https://civicdb.org/links/variants/2909 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Q252H Cancer 162 Imatinib,Bafetinib Substitutes Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the Q252H mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to imatinib and bafetinib (INNO-406) treatment (IC50: > 2000.0 nM and 888.1 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 1712 nM and 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 7849 1024 4 9 133738356 133738356 G C ENST00000318560.5 75 GRCh37 Somatic 2021-02-26 14:13:18 UTC https://civicdb.org/links/evidence_items/7849 https://civicdb.org/links/variants/1024 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M244V Cancer 162 Bafetinib,Imatinib Substitutes Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the M244V mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to imatinib and bafetinib (INNO-406) treatment (IC50: > 2000.0 nM and 874.2 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 1712 nM and 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 7850 1021 4 9 133738330 133738330 A G ENST00000318560.5 75 GRCh37 Somatic 2021-02-26 14:16:58 UTC https://civicdb.org/links/evidence_items/7850 https://civicdb.org/links/variants/1021 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G250E Cancer 162 Bafetinib,Imatinib Substitutes Predictive Supports D Resistance In an in vitro study, a Ba/F3 cell line stably expressing the G250E mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to imatinib and bafetinib (INNO-406) treatment (IC50: > 2000.0 nM and 852 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 1712 nM and 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 7853 1023 4 9 133738349 133738349 G A ENST00000318560.5 75 GRCh37 Somatic 2021-02-26 14:17:52 UTC https://civicdb.org/links/evidence_items/7853 https://civicdb.org/links/variants/1023 https://civicdb.org/links/genes/4 false BRAF 673 Non-V600 Solid Tumor Trametinib Predictive Does Not Support B Sensitivity/Response In a phase II basket trial (NCI-MATCH), patients with solid tumors or hematologic malignancies harboring BRAF non-V600 mutations were treated with trametinib. Among 50 patients assigned, 32 were eligible and received therapy with trametinib. Most common tumor histopathologic subtypes were GI cancers (n=8, of which 7 were colorectal adenocarcinoma), lung adenocarcinoma (n=9), prostate adenocarcinoma (n=4), gynecologic cancer (n=4), BRAF alterations included BRAF fusion (n=1), G464 (n=2), G466 (n=4), G469 (n=7), N581 (n=3), D594 (n=11), L597 (n=2) and K601 (n=1). Of the 32 patients evaluable for efficacy endpoints, the response rate was 3% (3/32). The patient with a partial response had invasive breast cancer with a BRAF G469E mutation. The median PFS was 1.8 months and the median OS was 5.7 months. 31924734 PubMed Johnson et al., 2020, Clin. Cancer Res. 4 accepted 7855 2408 5 Somatic 2021-03-02 19:09:19 UTC https://civicdb.org/links/evidence_items/7855 https://civicdb.org/links/variants/2408 https://civicdb.org/links/genes/5 false NT5C2 22978 R367Q Childhood Acute Lymphocytic Leukemia 0080144 Mercaptopurine,Thioguanine Substitutes Predictive Supports D Resistance Lentiviral-mediated overexpression of NT5C2 R367Q in Reh cells resulted in significant resistance against thiopurines (mercaptopurine and thioguanine) versus wildtype and GFP controls, as indicated by reduced apoptosis. Compared to controls, overexpression cells also displayed reduced intercellular thioguanoside nucleotides after 24 hours of drug exposure, as measured by HPLC. Additionally, recombinant protein expression of R367Q led to increased 5’ nucleotidase activity. 23377183 PubMed Meyer et al., 2013, Nat. Genet. 4 accepted 7862 238 9189 10 104852955 104852955 C T ENST00000343289.5 75 GRCh37 Somatic 2020-01-23 23:21:17 UTC https://civicdb.org/links/evidence_items/7862 https://civicdb.org/links/variants/238 https://civicdb.org/links/genes/9189 false NT5C2 22978 R238W Childhood Acute Lymphocytic Leukemia 0080144 Pediatric onset Prognostic Supports C Poor Outcome 71 Childhood B-cell acute lymphocytic leukemia relapse patients had their diagnosis and relapse samples sequenced for NT5C2 mutations. Sequencing revealed 3 early relapse cases with NT5C2 R238W enriched at relapse at variant allele frequencies (VAF) of 27%, 18%, and 31% and only a VAF of .01%, 0%, and 0% at diagnosis. R238W could drive clonal outgrowth through the promotion of drug resistance, specifically to thiopurines, which are a staple of ALL maintenance therapy that are administered daily. 23377183 PubMed Meyer et al., 2013, Nat. Genet. 2 accepted 7863 2896 9189 10 104857107 104857107 G A ENST00000343289.5 75 GRCh37 Somatic 2020-01-23 23:50:03 UTC https://civicdb.org/links/evidence_items/7863 https://civicdb.org/links/variants/2896 https://civicdb.org/links/genes/9189 false NT5C2 22978 S445F Childhood Acute Lymphocytic Leukemia 0080144 Prognostic Supports C Poor Outcome 71 Childhood B-cell acute lymphocytic leukemia relapse patients had their diagnosis and relapse samples sequenced for NT5C2 mutations. Sequencing revealed an early relapse case with NT5C2 S445F enriched to a variant allele frequency (VAF) of 25% at relapse and was undetected at diagnosis. S445F could drive clonal outgrowth through the promotion of drug resistance, specifically to thiopurines, which are a staple of ALL maintenance therapy that are administered daily. 23377183 PubMed Meyer et al., 2013, Nat. Genet. 2 accepted 7864 2897 9189 10 104850483 104850483 G A ENST00000343289.5 75 GRCh37 Somatic 2020-01-23 23:50:36 UTC https://civicdb.org/links/evidence_items/7864 https://civicdb.org/links/variants/2897 https://civicdb.org/links/genes/9189 false PRPS1 5631 PRPS1 MUTATION Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Prognostic Supports B Poor Outcome Sequencing revealed relapse specific PRPS1 mutations in 24/358 (6.7%) relapsed childhood B-ALL cases derived from multiple cohorts. In the Chinese cohort, 18/138 (13%) cases harbored relapse specific PRPS1 mutations. In the German cohort, 6/220 (6.7%) cases harbored relapse specific PRPS1 mutations. All patients with PRPS1 mutations relapsed early (< 36 months after initial diagnosis) (Chinese: 18/18 PRPS1 vs. 77/120 (64.2%) wildtype, p=.002; German: 6/6 PRPS1 vs. 79/214 (36.9%) wildtype, p<.001). All patients with PRPS1 mutations also relapsed while on therapy (Chinese: 18/18 PRPS1 vs. 77/120 (64.2%) wildtype, p<.001; German: 6/6 PRPS1 vs. 51/214 (23.8%) ( p<.001). Of the 24 cases, there were 17 unique PRPS1 mutations. Further experimental data demonstrated 12/17 mutations conferred resistance to thiopurines. 25962120 PubMed Li et al., 2015, Nat. Med. 4 accepted 7871 2916 4566 Somatic 2020-11-20 15:58:07 UTC https://civicdb.org/links/evidence_items/7871 https://civicdb.org/links/variants/2916 https://civicdb.org/links/genes/4566 false LYN 4067 OVEREXPRESSION Chronic Myeloid Leukemia 8552 Bafetinib,Dasatinib Substitutes Predictive Does Not Support D Resistance The BCR-ABL1 expressing imatinib-resistant cell line MYL-R overexpresses LYN, an SRC family kinase. Dasatinib showed the most potency against MYL-R compared to the non-resistant MYL cell line (IC50: 6.4nM vs. 6.5 nM), while bafetinib (INNO-406) showed 3.1 times more potency than nilotinib against MYL-R (IC50: 324.1 nM vs. 993.6 nM) as compared to MYL (IC50: 87.7 nM and 84.5 nM). The authors state that this is in line with experiments showing INNO-406 specifically inhibits LYN and LCK, which may provide a more favorable side effect profile than dasatinib, that was shown to strongly inhibit all 8 SRC family kinases. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 7874 2917 3359 Somatic 2021-02-18 01:14:10 UTC https://civicdb.org/links/evidence_items/7874 https://civicdb.org/links/variants/2917 https://civicdb.org/links/genes/3359 false LYN 4067 OVEREXPRESSION Chronic Myeloid Leukemia 8552 Nilotinib Predictive Supports D Resistance The BCR-ABL1 expressing imatinib-resistant cell line MYL-R overexpresses LYN, an SRC family kinase. Nilotinib showed 3.1 times less potency than bafetinib (INNO-406) against MYL-R (IC50: 993.6 nM vs. 324.1 nM) as compared to MYL cell lines (IC50: 84.5nM and 87.7 nM). The authors state bafetinib may overcome resistance to inhibitor treatment in these cells due to the presence of LYN overexpression, suggesting LYN overexpression may be contributing to Nilotinib resistance. Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 1 accepted 7875 2917 3359 Somatic 2021-02-18 01:22:41 UTC https://civicdb.org/links/evidence_items/7875 https://civicdb.org/links/variants/2917 https://civicdb.org/links/genes/3359 false PRPS1 5631 A190T Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Prognostic Supports B Poor Outcome PRPS1 exons were sequenced in the diagnosis and relapse samples of 358 B-Cell Childhood Acute Lymphoblastic Leukemia relapse patients (138 Chinese and 220 German). PRPS1 A190T was detected only at relapse in 10 (8 Chinese; 2 German) cases, which all relapsed early while on therapy (Chinese 8/8, 100% vs. WT PRPS1 77/120 (64%); German 2/2 (100%) vs. WT PRPS1 79/214 (37%)). Based on protocols cited and the time to relapse, all 10 relapses harboring PRPS1 A190T were exposed to maintenance therapy that consisted of daily doses of thiopurine (mercaptopurine or thioguanine) treatment. A190T could drive clonal outgrowth through the promotion of thiopurine resistance. 25962120 PubMed Li et al., 2015, Nat. Med. 3 accepted 7888 2929 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7888 https://civicdb.org/links/variants/2929 https://civicdb.org/links/genes/4566 false VHL 7428 L188V (c.562C>G) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing N/A C N/A 36 VHL-related pheochromocytomas (from 21 patients) and 10 VHL-related CNS hemangioblastomas (from 6 patients) were studied using comparative genomic hybridization (CGH) to detect genetic imbalances. The study identified selective loss of chromosome 11 in pheochromocytomas associated with VHL. Patient XVI, XX and XXI in VHL-associated pheochromocytoma were found with germline missense mutation (c.562C>G) in the VHL gene. ACMG evidence codes: 'PP4' because the patients' phenotypes are highly specific for a disease with single genetic etiology. 11850829 PubMed Lui et al., 2002, Oncogene 3 accepted 7889 1836 58 3 10191569 10191569 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/7889 https://civicdb.org/links/variants/1836 https://civicdb.org/links/genes/58 false VHL 7428 L178Q (c.533T>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing N/A C N/A 36 VHL-related pheochromocytomas (from 21 patients) and 10 VHL-related CNS hemangioblastomas (from 6 patients) were studied using comparative genomic hybridization (CGH) to detect genetic imbalances. The study identified selective loss of chromosome 11 in pheochromocytomas associated with VHL. Patient XVII and XVIII in VHL-associated pheochromocytoma were found with a germline missense mutation (c.533T>A) in the VHL gene. ACMG evidence codes: 'PP4' because the patients' phenotypes are highly specific for a disease with single genetic etiology. 11850829 PubMed Lui et al., 2002, Oncogene 3 accepted 7890 1997 58 3 10191540 10191540 T A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/7890 https://civicdb.org/links/variants/1997 https://civicdb.org/links/genes/58 false VHL 7428 R161Q (c.482G>A) Von Hippel-Lindau Disease 14175 Pheochromocytoma Predisposing N/A C N/A 36 VHL-related pheochromocytomas (from 21 patients) and 10 VHL-related CNS hemangioblastomas (from 6 patients) were studied using comparative genomic hybridization (CGH) to detect genetic imbalances. The study identified selective loss of chromosome 11 in pheochromocytomas associated with VHL. Patient XIX with VHL-associated pheochromocytoma was found with a germline missense mutation (c.482G>A) in the VHL gene. ACMG evidence codes: 'PP4' because the patients' phenotypes are highly specific for a disease with single genetic etiology. 11850829 PubMed Lui et al., 2002, Oncogene 3 accepted 7891 1746 58 3 10191489 10191489 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/7891 https://civicdb.org/links/variants/1746 https://civicdb.org/links/genes/58 false VHL 7428 106insR (c.316insGCC) Von Hippel-Lindau Disease 14175 Hemangioblastoma Predisposing N/A C N/A 36 VHL-related pheochromocytomas (from 21 patients) and 10 VHL-related CNS hemangioblastomas (from 6 patients) were studied using comparative genomic hybridization (CGH) to detect genetic imbalances. Patient I with VHL-Associated hemangioblastoma was found with a germline insertion mutation (c.316insGCC) in the VHL gene. ACMG evidence codes: 'PP4' because the patients' phenotypes are highly specific for a disease with single genetic etiology. 11850829 PubMed Lui et al., 2002, Oncogene 3 accepted 7892 2930 58 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/7892 https://civicdb.org/links/variants/2930 https://civicdb.org/links/genes/58 false VHL 7428 N78S (c.233A>G) Von Hippel-Lindau Disease 14175 Hemangioblastoma Predisposing N/A C N/A 36 VHL-related pheochromocytomas (from 21 patients) and 10 VHL-related CNS hemangioblastomas (from 6 patients) were studied using comparative genomic hybridization (CGH) to detect genetic imbalances. Patient II in VHL-Associated hemangioblastoma was found with germline missense mutation (c.233A>G) in the VHL gene. ACMG evidence codes: 'PP4' because the patients' phenotypes are highly specific for a disease with single genetic etiology. 11850829 PubMed Lui et al., 2002, Oncogene 3 accepted 7893 1755 58 3 10183764 10183764 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/7893 https://civicdb.org/links/variants/1755 https://civicdb.org/links/genes/58 false VHL 7428 C77_N78insL (c.230_231insTCT) Von Hippel-Lindau Disease 14175 Hemangioblastoma Predisposing N/A C N/A 36 VHL-related pheochromocytomas (from 21 patients) and 10 VHL-related CNS hemangioblastomas (from 6 patients) were studied using comparative genomic hybridization (CGH) to detect genetic imbalances. Patient III in VHL-Associated hemangioblastoma was found with germline insertion mutation (c.230insTCT) in the VHL gene. ACMG evidence codes: 'PP4' because the patients' phenotypes are highly specific for a disease with single genetic etiology. 11850829 PubMed Lui et al., 2002, Oncogene 3 accepted 7894 3096 58 3 10183761 10183762 TCT ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/7894 https://civicdb.org/links/variants/3096 https://civicdb.org/links/genes/58 false VHL 7428 C162W (c.486C>G) Von Hippel-Lindau Disease 14175 Hemangioblastoma Predisposing N/A C N/A 36 VHL-related pheochromocytomas (from 21 patients) and 10 VHL-related CNS hemangioblastomas (from 6 patients) were studied using comparative genomic hybridization (CGH) to detect genetic imbalances. Patient IV with VHL-Associated hemangioblastoma was found with a germline missense mutation (c.486C>G) in the VHL gene. ACMG evidence codes: 'PP4' because the patients' phenotypes are highly specific for a disease with single genetic etiology. 11850829 PubMed Lui et al., 2002, Oncogene 3 accepted 7895 1774 58 3 10191493 10191493 C G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:41 UTC https://civicdb.org/links/evidence_items/7895 https://civicdb.org/links/variants/1774 https://civicdb.org/links/genes/58 false PRPS1 5631 T303S Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Thioguanine,Mercaptopurine Substitutes Predictive Supports D Resistance Lentiviral-mediated overexpression of PRPS1 T303S in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed T303S cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. T303S cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, T303S cells display reduced levels of DNA damage response and apoptosis protein markers. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition. 25962120 PubMed Li et al., 2015, Nat. Med. 4 accepted 7898 2918 4566 Somatic 2020-11-20 15:58:07 UTC https://civicdb.org/links/evidence_items/7898 https://civicdb.org/links/variants/2918 https://civicdb.org/links/genes/4566 false PRPS1 5631 L191F Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Thioguanine,Mercaptopurine Substitutes Predictive Supports D Resistance Lentiviral-mediated overexpression of PRPS1 L191F in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed L191F cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. L191F cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, L191F cells display reduced levels of DNA damage response and apoptosis protein markers. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition. 25962120 PubMed Li et al., 2015, Nat. Med. 4 accepted 7899 2919 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7899 https://civicdb.org/links/variants/2919 https://civicdb.org/links/genes/4566 false PRPS1 5631 D183E Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Thioguanine,Mercaptopurine Substitutes Predictive Supports D Resistance Lentiviral-mediated overexpression of PRPS1 D183E in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed D183E cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. D183E cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, D183E cells display reduced levels of DNA damage response and apoptosis protein markers. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition. 25962120 PubMed Li et al., 2015, Nat. Med. 4 accepted 7900 2920 4566 Somatic 2020-11-20 15:58:07 UTC https://civicdb.org/links/evidence_items/7900 https://civicdb.org/links/variants/2920 https://civicdb.org/links/genes/4566 false PRPS1 5631 K176N Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Mercaptopurine,Thioguanine Substitutes Predictive Supports D Resistance Lentiviral-mediated overexpression of PRPS1 K176N in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed K176N cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. K176N cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, K176N cells display reduced levels of DNA damage response and apoptosis protein markers. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition. 25962120 PubMed Li et al., 2015, Nat. Med. 4 accepted 7901 2921 4566 Somatic 2020-11-20 15:58:07 UTC https://civicdb.org/links/evidence_items/7901 https://civicdb.org/links/variants/2921 https://civicdb.org/links/genes/4566 false PRPS1 5631 N144S Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Mercaptopurine,Thioguanine Substitutes Predictive Supports D Resistance Lentiviral-mediated overexpression of PRPS1 N144S in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed N144S cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. N144S cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, N144S cells display reduced levels of DNA damage response and apoptosis protein markers. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition. 25962120 PubMed Li et al., 2015, Nat. Med. 4 accepted 7903 2923 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7903 https://civicdb.org/links/variants/2923 https://civicdb.org/links/genes/4566 false PRPS1 5631 S103I Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Thioguanine,Mercaptopurine Substitutes Predictive Supports D Resistance Lentiviral-mediated overexpression of PRPS1 S103I in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). After 6-MP exposure, mass spectrometry revealed S103I cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. S103I cells produce increased intracellular concentrations of hypoxanthine and IMP. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition. 25962120 PubMed Li et al., 2015, Nat. Med. 4 accepted 7905 2925 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7905 https://civicdb.org/links/variants/2925 https://civicdb.org/links/genes/4566 false PRPS1 5631 S103N Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Mercaptopurine,Thioguanine Substitutes Predictive Supports D Resistance Lentiviral-mediated overexpression of PRPS1 S103N in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed S103N cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. S103N cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, S103N cells display reduced levels of DNA damage response and apoptosis protein markers. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition. 25962120 PubMed Li et al., 2015, Nat. Med. 4 accepted 7906 2926 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7906 https://civicdb.org/links/variants/2926 https://civicdb.org/links/genes/4566 false PRPS1 5631 S103T Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Thioguanine,Mercaptopurine Substitutes Predictive Supports D Resistance Lentiviral-mediated overexpression of PRPS1 S103T in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed S103T cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. S103T cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, S103T cells display reduced levels of DNA damage response and apoptosis protein markers. S103T results in the activation of the de novo purine synthesis pathway by reducing feedback inhibition, allowing the cell to continue to create nucleotides even when concentrations are elevated. This overactivation creates increased hypoxanthine levels, which likely competitively inhibit thiopurine conversion. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition. 25962120 PubMed Li et al., 2015, Nat. Med. 5 accepted 7907 2927 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7907 https://civicdb.org/links/variants/2927 https://civicdb.org/links/genes/4566 false PRPS1 5631 A190T Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Mercaptopurine,Thioguanine Substitutes Predictive Supports D Resistance Lentiviral-mediated overexpression of PRPS1 A190T in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed A190T cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. A190T cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, A190T cells display reduced levels of DNA damage response and apoptosis protein markers. A190T results in the activation of the de novo purine synthesis pathway by reducing feedback inhibition, allowing the cell to continue to create nucleotides even when concentrations are elevated. This overactivation creates increased hypoxanthine levels, which likely competitively inhibits the conversion of the thiopurines to their active form. 25962120 PubMed Li et al., 2015, Nat. Med. 5 accepted 7909 2929 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7909 https://civicdb.org/links/variants/2929 https://civicdb.org/links/genes/4566 false PRPS1 5631 N144S Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Cytarabine Predictive Supports D Sensitivity/Response Lentiviral-mediated overexpression of PRPS1 N144S in Reh cells resulted in sensitivity to cytarabine (Ara-C) treatment as indicated by reduced cell viability and IC50 compared to empty vector and wildtype PRPS1 overexpression controls. 25962120 PubMed Li et al., 2015, Nat. Med. 2 accepted 7910 2923 4566 Somatic 2020-11-20 15:58:07 UTC https://civicdb.org/links/evidence_items/7910 https://civicdb.org/links/variants/2923 https://civicdb.org/links/genes/4566 false PRPS1 5631 L191F Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Cytarabine Predictive Supports D Sensitivity/Response Lentiviral-mediated overexpression of PRPS1 L191F in Reh cells resulted in sensitivity to cytarabine (Ara-C) treatment as indicated by reduced cell viability and IC50 compared to empty vector and wildtype PRPS1 overexpression controls. 25962120 PubMed Li et al., 2015, Nat. Med. 2 accepted 7911 2919 4566 Somatic 2020-11-20 15:58:07 UTC https://civicdb.org/links/evidence_items/7911 https://civicdb.org/links/variants/2919 https://civicdb.org/links/genes/4566 false PRPS1 5631 A190T Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Lometrexol,Mercaptopurine Combination Predictive Supports D Sensitivity/Response Treatment with the GART inhibitor, Lometrexol (de novo purine synthesis inhibitor), sensitized Reh cells overexpressing PRPS1 A190T to mercaptopurine (6-MP) as evidenced by significant reduction of the cell line's 6-MP IC50 and the significant increase of intracellular levels of TIMP. TIMP is one of the first metabolites 6-MP is converted to during activation. 25962120 PubMed Li et al., 2015, Nat. Med. 3 accepted 7913 2929 4566 Somatic 2020-11-20 15:58:07 UTC https://civicdb.org/links/evidence_items/7913 https://civicdb.org/links/variants/2929 https://civicdb.org/links/genes/4566 false PRPS1 5631 D139G Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Thioguanine,Mercaptopurine Substitutes Predictive Does Not Support D Resistance Lentiviral-mediated overexpression of PRPS1 D139G in Reh cells resulted in similar cytotoxic response to controls (empty vector and overexpression of known reduced-function PRPS1 mutants) after exposure to mercaptopurine or thioguanine. Based on the crystal structure of PRPS1, D139G is not in or near the allosteric site or dimer interface, which likely impedes the ability of the variant to impact thiopurine processing. 25962120 PubMed Li et al., 2015, Nat. Med. 3 accepted 7915 2935 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7915 https://civicdb.org/links/variants/2935 https://civicdb.org/links/genes/4566 false PRPS1 5631 C77S Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Thioguanine,Mercaptopurine Substitutes Predictive Does Not Support D Resistance Lentiviral-mediated overexpression of PRPS1 C77S in Reh cells resulted in similar cytotoxic response to controls (empty vector and overexpression of known reduced-function PRPS1 mutants) after exposure to mercaptopurine or thioguanine. Based on the crystal structure of PRPS1, C77S is not in or near the allosteric site or dimer interface, which likely impedes the ability of the variant to impact thiopurine processing. 25962120 PubMed Li et al., 2015, Nat. Med. 3 accepted 7916 2936 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7916 https://civicdb.org/links/variants/2936 https://civicdb.org/links/genes/4566 false PRPS1 5631 I72V Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Mercaptopurine,Thioguanine Substitutes Predictive Does Not Support D Resistance Lentiviral-mediated overexpression of PRPS1 I72V in Reh cells resulted in similar cytotoxic response to controls (empty vector and overexpression of known reduced-function PRPS1 mutants) after exposure to mercaptopurine or thioguanine. Based on the crystal structure of PRPS1, I72V is not in or near the allosteric site or dimer interface, which likely impedes the ability of the variant to impact thiopurine processing. 25962120 PubMed Li et al., 2015, Nat. Med. 3 accepted 7917 2937 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7917 https://civicdb.org/links/variants/2937 https://civicdb.org/links/genes/4566 false PRPS1 5631 V53A Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Mercaptopurine,Thioguanine Substitutes Predictive Does Not Support D Resistance Lentiviral-mediated overexpression of PRPS1 V53A in Reh cells resulted in similar cytotoxic response to controls (empty vector and overexpression of known reduced-function PRPS1 mutants) after exposure to mercaptopurine or thioguanine. Based on the crystal structure of PRPS1, V53A is not in or near the allosteric site or dimer interface, which likely impedes the ability of the variant to impact thiopurine processing. 25962120 PubMed Li et al., 2015, Nat. Med. 3 accepted 7918 2938 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7918 https://civicdb.org/links/variants/2938 https://civicdb.org/links/genes/4566 false PRPS1 5631 A87T Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Mercaptopurine,Thioguanine Substitutes Predictive Does Not Support D Resistance Lentiviral-mediated overexpression of PRPS1 A87T in Reh cells resulted in similar cytotoxic response (IC50 and apoptosis %) compared to controls (empty vector and wildtype PRPS1 overexpression) after treatment with mercaptopurine (6-MP) or thioguanine (6-TG). After 6-MP exposure, mass spectrometry revealed A87T cells possessed similar concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. Intracellular concentrations of hypoxanthine and IMP were similar in A87T cells and controls. After 6-MP exposure, no difference in DNA damage response and apoptosis protein markers were observed between A87T cells and controls. 25962120 PubMed Li et al., 2015, Nat. Med. 4 accepted 7919 2939 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7919 https://civicdb.org/links/variants/2939 https://civicdb.org/links/genes/4566 false PRPS1 5631 M115T Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Mercaptopurine,Thioguanine Substitutes Predictive Does Not Support D Resistance Lentiviral-mediated overexpression of PRPS1 M115T in Reh cells resulted in similar cytotoxic response (IC50 and apoptosis %) compared to controls (empty vector and wildtype PRPS1 overexpression) after treatment with mercaptopurine (6-MP) or thioguanine (6-TG). After 6-MP exposure, mass spectrometry revealed M115T cells possessed similar concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. Intracellular concentrations of hypoxanthine and IMP were similar in M115T cells and controls. After 6-MP exposure, no difference in DNA damage response and apoptosis protein markers were observed between M115T cells and controls. 25962120 PubMed Li et al., 2015, Nat. Med. 4 accepted 7920 2940 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7920 https://civicdb.org/links/variants/2940 https://civicdb.org/links/genes/4566 false PRPS1 5631 L191F Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Methotrexate,Daunorubicin,Asparaginase Substitutes Predictive Does Not Support D Resistance Lentiviral-mediated overexpression of PRPS1 L191F in Reh cells resulted no difference in response to Methotrexate, Daunorubicin, or L-Asparginase compared to empty vector and wildtype PRPS1 overexpression controls as indicated similar cytotoxicity curves and IC50s. 25962120 PubMed Li et al., 2015, Nat. Med. 3 accepted 7923 2919 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7923 https://civicdb.org/links/variants/2919 https://civicdb.org/links/genes/4566 false PRPS1 5631 S103T Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Asparaginase,Methotrexate,Cytarabine,Daunorubicin Substitutes Predictive Does Not Support D Resistance Lentiviral-mediated overexpression of PRPS1 S103T in Reh cells resulted no difference in response to Methotrexate, Cytarabine, Daunorubicin, or L-Asparginase compared to empty vector and wildtype PRPS1 overexpression controls as indicated similar cytotoxicity curves and IC50s. 25962120 PubMed Li et al., 2015, Nat. Med. 3 accepted 7924 2927 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7924 https://civicdb.org/links/variants/2927 https://civicdb.org/links/genes/4566 false PRPS1 5631 S103N Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Daunorubicin,Methotrexate,Cytarabine,Asparaginase Substitutes Predictive Does Not Support D Resistance Lentiviral-mediated overexpression of PRPS1 S103N in Reh cells resulted no difference in response to Methotrexate, Cytarabine, Daunorubicin, or L-Asparginase compared to empty vector and wildtype PRPS1 overexpression controls as indicated similar cytotoxicity curves and IC50s. 25962120 PubMed Li et al., 2015, Nat. Med. 3 accepted 7925 2926 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7925 https://civicdb.org/links/variants/2926 https://civicdb.org/links/genes/4566 false PRPS1 5631 K176N Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Daunorubicin,Methotrexate,Cytarabine,Asparaginase Substitutes Predictive Does Not Support D Resistance Lentiviral-mediated overexpression of PRPS1 K176N in Reh cells resulted no difference in response to Methotrexate, Cytarabine, Daunorubicin, or L-Asparginase compared to empty vector and wildtype PRPS1 overexpression controls as indicated similar cytotoxicity curves and IC50s. 25962120 PubMed Li et al., 2015, Nat. Med. 3 accepted 7926 2921 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7926 https://civicdb.org/links/variants/2921 https://civicdb.org/links/genes/4566 false PRPS1 5631 D183E Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Daunorubicin,Methotrexate,Cytarabine,Asparaginase Substitutes Predictive Does Not Support D Resistance Lentiviral-mediated overexpression of PRPS1 D183E in Reh cells resulted no difference in response to Methotrexate, Cytarabine, Daunorubicin, or L-Asparginase compared to empty vector and wildtype PRPS1 overexpression controls as indicated similar cytotoxicity curves and IC50s. 25962120 PubMed Li et al., 2015, Nat. Med. 3 accepted 7927 2920 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7927 https://civicdb.org/links/variants/2920 https://civicdb.org/links/genes/4566 false PRPS1 5631 A190T Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Cytarabine,Asparaginase,Daunorubicin,Methotrexate Substitutes Predictive Does Not Support D Resistance Lentiviral-mediated overexpression of PRPS1 A190T in Reh cells resulted no difference in response to Methotrexate, Cytarabine, Daunorubicin, or L-Asparginase compared to empty vector and wildtype PRPS1 overexpression controls as indicated similar cytotoxicity curves and IC50s. 25962120 PubMed Li et al., 2015, Nat. Med. 3 accepted 7928 2929 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7928 https://civicdb.org/links/variants/2929 https://civicdb.org/links/genes/4566 false PRPS1 5631 T303S Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Asparaginase,Daunorubicin,Cytarabine,Methotrexate Substitutes Predictive Does Not Support D Resistance Lentiviral-mediated overexpression of PRPS1 T303S in Reh cells resulted no difference in response to Methotrexate, Cytarabine, Daunorubicin, or L-Asparginase compared to empty vector and wildtype PRPS1 overexpression controls as indicated similar cytotoxicity curves and IC50s. 25962120 PubMed Li et al., 2015, Nat. Med. 3 accepted 7929 2918 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7929 https://civicdb.org/links/variants/2918 https://civicdb.org/links/genes/4566 false PRPS1 5631 N144S Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Methotrexate,Daunorubicin,Asparaginase Substitutes Predictive Does Not Support D Resistance Lentiviral-mediated overexpression of PRPS1 N144S in Reh cells resulted no difference in response to Methotrexate, Daunorubicin, or L-Asparginase compared to empty vector and wildtype PRPS1 overexpression controls as indicated similar cytotoxicity curves and IC50s. 25962120 PubMed Li et al., 2015, Nat. Med. 3 accepted 7930 2923 4566 Somatic 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/7930 https://civicdb.org/links/variants/2923 https://civicdb.org/links/genes/4566 false ROS1 6098 Rearrangement Lung Non-small Cell Carcinoma 3908 Crizotinib Predictive Supports A Sensitivity/Response A phase 2 clinical trial studied the efficacy of Crizotinib in East Asian NSCLC patients positive for ROS1 rearrangements (detected by RT-PCR AmoyDx assay) and negative for ALK1 rearrangements. Of the 127 patients enrolled, 17 achieved complete response and 74 achieved partial response. Overall response rate by independent radiology review was 71.7% (95% CI 63-79.3%) Time to response was rapid (median 1.9 months) and durable (Duration of response median 19.7 months). Median progression free survival was 15.9 months. Crizotinib was clinically beneficial regardless of demographics and prior therapy. Based on these results, Crizotinib was approved for the treatment of ROS1 positive NSCLC in 2017 in Japan, Taiwan, China, and Korea. 29596029 PubMed Wu et al., 2018, J. Clin. Oncol. NCT01945021 4 accepted 7933 269 4941 6 117609463 117747018 ENST00000368508.3 75 GRCh37 ROS1 is a receptor tyrosine kinase that frequently forms gene fusions in several cancer types. Approximately 2% of NSCLC patients harbor a ROS1 gene fusion. Several fusion partners have been described with a constant ROS1-breakpoint, maintaining the kinase domain (Solomon B, 2015). Following case-studies and retrospective analyses, an expansion cohort of a phase-1 study showed clinical benefit of crizotinib in ROS1 rearranged NSCLC. The benefit was independent of the type of ROS1-rearrangement (Shaw et. al.,2014). Somatic 2020-05-12 03:39:32 UTC https://civicdb.org/links/evidence_items/7933 https://civicdb.org/links/variants/269 https://civicdb.org/links/genes/4941 false KRAS 3845 R164Q Cancer 162 Oncogenic N/A D N/A NIH3T3 cells were transfected with control or KRAS R164Q plasmid and focus formation assays were performed. R164Q cells formed 0 foci > 5mm diameter per well, which was the same as wt cells. In contrast, known gain of function mutations KRAS G12V and G12D formed over 70 foci > 5mm diameter average per well. In conclusion, these data suggest that R164Q does not promote oncogenic transformation of NIH3T3 cells by loss of contact inhibition. 20147967 PubMed Smith et al., 2010, Br. J. Cancer 3 accepted 7935 1207 30 12 25368454 25368454 C T ENST00000256078.4 75 GRCh37 Somatic 2021-06-21 17:59:33 UTC https://civicdb.org/links/evidence_items/7935 https://civicdb.org/links/variants/1207 https://civicdb.org/links/genes/30 false KRAS 3845 Q61H Cancer 162 Oncogenic N/A D N/A NIH3T3 cells were transfected with control or KRAS Q61H plasmid and focus formation assays were performed. Q61H cells formed approximately 50 foci > 5mm diameter per well, where wt cells formed none, demonstrating Q61H promotes loss of contact inhibition suggestive of oncogenic transformation of NIH3T3 cells. 20147967 PubMed Smith et al., 2010, Br. J. Cancer 3 accepted 7936 907 30 12 25380275 25380275 T G ENST00000256078.4 75 GRCh37 Somatic 2021-06-21 17:00:46 UTC https://civicdb.org/links/evidence_items/7936 https://civicdb.org/links/variants/907 https://civicdb.org/links/genes/30 false ABL1 25 BCR::ABL E450Q Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with E450Q/M351T and E450Q variants in 1/10 and 9/10 clones, respectively. Clones were generated using peripheral blood RNA. The patient had complete best cytogenetic and complete best hematologic responses to dasatinib which were improved compared to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 4 accepted 7942 2948 4 Somatic 2020-03-11 20:48:42 UTC https://civicdb.org/links/evidence_items/7942 https://civicdb.org/links/variants/2948 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M244V and L364I Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in myeloid blast crisis had the BCR-ABL1 fusion with M244V/L364I, M244V/L364I/N53S, M244V/L364I/M458T, L364I/M458T, and L364I variants in 5/11, 2/11, 1/11, 1/11, and 2/11 clones, respectively. Clones were generated using peripheral blood RNA. The patient had no best cytogenetic response and no evidence of leukemia as best hematologic response to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 7943 2949 4 Somatic 2020-07-31 22:23:10 UTC https://civicdb.org/links/evidence_items/7943 https://civicdb.org/links/variants/2949 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL N146S Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in accelerated phase had the BCR-ABL1 fusion with G250E/E138G/I242T/K271R/V338M, G250E/E138G/I242T/K271R, G250E/I242T/K271R/V338M/N146S, and N146S variants in 3/12, 1/12, 1/12, and 7/12 clones, respectively. Clones were generated using peripheral blood RNA. The patient had no response as best cytogenetic response and complete response as best hematologic response to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 7945 2951 4 Somatic 2020-07-31 22:39:13 UTC https://civicdb.org/links/evidence_items/7945 https://civicdb.org/links/variants/2951 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL V298I Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with V289I, V289I/M388L, and G250E variants in 8/11, 1/11, and 1/11 clones, respectively. Clones were generated using peripheral blood RNA. The patient had minimal response as best cytogenetic response and complete response as best hematologic response to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 7946 2952 4 Somatic 2020-07-31 22:48:51 UTC https://civicdb.org/links/evidence_items/7946 https://civicdb.org/links/variants/2952 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253H Acute Lymphoblastic Leukemia 9952 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with acute lymphoblastic leukemia had the BCR-ABL1 fusion with Y253H and Y253H/Q252R variants in 9/10 and 1/10 clones, respectively. Clones were generated using peripheral blood RNA. The patient had complete response as best cytogenetic response and complete response as best hematologic response to dasatinib which were improved compared to responses in a patient with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 7947 1025 4 9 133738357 133738357 T C ENST00000318560.5 75 GRCh37 Somatic 2020-07-31 22:55:08 UTC https://civicdb.org/links/evidence_items/7947 https://civicdb.org/links/variants/1025 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL S438C Chronic Myeloid Leukemia 8552 Dasatinib Predictive Supports C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the S438C, K466E, and K466R secondary variants in 6/10, 1/10. and 1/10 bacterial clones generated using peripheral blood RNA. They had no best hematologic and no best cytogenetic responses to dasatinib which were poor compared to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 7948 2953 4 Somatic 2020-07-31 22:58:25 UTC https://civicdb.org/links/evidence_items/7948 https://civicdb.org/links/variants/2953 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL Y253H Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with Y253H, M388L, and M388L/M244V variants in 4/10, 5/10, and 1/10 clones, respectively. Clones were generated using peripheral blood RNA. The patient had no response as best cytogenetic response and complete response as best hematologic response to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 7949 1025 4 9 133738357 133738357 T C ENST00000318560.5 75 GRCh37 Somatic 2020-07-31 23:02:00 UTC https://civicdb.org/links/evidence_items/7949 https://civicdb.org/links/variants/1025 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL M388L Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with Y253H, M388L, and M388L/M244V variants in 4/10, 5/10, and 1/10 clones, respectively. Clones were generated using peripheral blood RNA. The patient had no response as best cytogenetic response and complete response as best hematologic response to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 3 accepted 7950 2954 4 Somatic 2020-07-31 23:03:53 UTC https://civicdb.org/links/evidence_items/7950 https://civicdb.org/links/variants/2954 https://civicdb.org/links/genes/4 false IL6 3569 Overexpression Rhabdomyosarcoma 3247 Bazedoxifene Predictive Supports D Resistance Treatment with bazedoxifene inhibited cell colony formation in rhabdomyosarcoma cell lines RH30 and RD. Addition of excess IL6 reduced the inhibitory effect of bazedoxifene on colony formation. 28672024 PubMed Xiao et al., 2017, PLoS ONE 2 accepted 7956 2911 2970 N/A 2020-02-14 19:26:43 UTC https://civicdb.org/links/evidence_items/7956 https://civicdb.org/links/variants/2911 https://civicdb.org/links/genes/2970 false CHEK2 11200 R474C c.1420C>T Cancer 162 Predisposing N/A C N/A Siblings (brother and sister) each were diagnosed with multiple primary lung cancer at the age of 60, along with various other cancers in their lifetimes. Homozygosity mapping revealed their parents (who also had cancer) had a consanguineous union. Each sibling was homozygous for CHEK2 R474C. The brother also had a son who died of neuroblastoma at 22 months of age. Amino acid R474 is highly conserved (98%) and forms a salt bridge in both the inactive and active CHEK2 homodimer. Modeling reveals R474C likely negatively affects the saltbridge and destabilizes the protein. Calcium phosphate DNA precipitation to overexpress CHEK2 WT or R474C in NIH3T3 cells revealed limited expression of R474C and limited activation through phosphorylation after UV exposure compared to the WT CHEK2 controls. ACMG codes as follows: Mutation in critical and well established functional domain (saltbridge) (PM1). Absent from control databases (ESP, dnSNP) except 1000 genomes with 1/2503 cases (.02%)(PM2). Predicted deleterious/damaging by multiple (4; SIFT, PolyPhen, MutationTaster2, Align GCGD) in silico algorithms (PP3). 27900359 PubMed Kukita et al., 2016, Cold Spring Harb Mol Case Stud 3 accepted 7962 2959 8950 Rare Germline 2020-06-17 05:20:13 UTC https://civicdb.org/links/evidence_items/7962 https://civicdb.org/links/variants/2959 https://civicdb.org/links/genes/8950 false CTNNB1 1499 Exon 3 Mutation Childhood Medulloblastoma 3869 Juvenile onset Diagnostic Supports B Positive A series of 72 pediatric medulloblastomas were evaluated for CTNNB1 mutations (by direct sequencing), copy number alterations (by array-comparative genomic hybridization), and beta-catenin protein expression (by immunohistochemistry). CTNNB1 mutations were detected in all six cases with extensive (>50% of the tumor cells) nuclear staining of beta-catenin. Remarkably, five out of these six tumors demonstrated a loss of chromosome 6, a cytogenetic event that is absent in CTNNB1-wildtype tumors (p <0.0001, Fisher’s exact test). 19197950 PubMed Fattet et al., 2009, J. Pathol. 3 accepted 7965 2892 1290 3 41266017 41266244 ENST00000349496.5 75 GRCh37 Somatic 2021-01-26 01:55:32 UTC https://civicdb.org/links/evidence_items/7965 https://civicdb.org/links/variants/2892 https://civicdb.org/links/genes/1290 false CTNNB1 1499 Exon 3 Mutation Childhood Medulloblastoma 3869 Juvenile onset Diagnostic Supports B Positive A total of 51 medulloblastomas from two independent cohorts (19 and 32 cases) were assessed for evidence of Wnt/Wg pathway activation, alongside a genome-wide analysis of associated copy-number aberrations. Cases displaying evidence of Wnt/Wg activation (CTNNB1 mutation and/or beta-catenin nuclear stabilization) were exclusively associated with a distinct genomic signature involving loss of an entire copy of chromosome 6 but few other aberrations. Loss of chromosome 6 was exclusively observed in Wnt/Wg-activated medulloblastoma, as evidenced by 3 of 3 cases with nuclear immune-positivity for b-catenin in the first cohort (19 cases). In the second cohort (32 cases), loss of chromosome 6 is observed in Wnt/Wg-active tumors and absence in Wnt/Wg-negative cases (8/13 vs. 0/19; p=0.0001). 17172831 PubMed Clifford et al., 2006, Cell Cycle 4 accepted 7967 2892 1290 3 41266017 41266244 ENST00000349496.5 75 GRCh37 Somatic 2021-01-26 02:20:38 UTC https://civicdb.org/links/evidence_items/7967 https://civicdb.org/links/variants/2892 https://civicdb.org/links/genes/1290 false DDIT3 1649 FUS::DDIT3 Liposarcoma 3382 Diagnostic Supports B Positive Both RT-PCR and PCR were used to detect and confirm the presence of fusion transcripts in RNA extracted from the surgical resections of 74 liposarcomas and 98 lipomas. FUS-DDIT3 (TLS-CHOP) was found in 22/74 (30%) liposarcomas, but not detected in any of the 98 noncancerous lipomas. Within the liposarcomas FUS-DDIT3 was found in 1/12 (8%) well-differentiated, 1/4 (25%) de-differentiated, 1/17 (6%) unclassified, and 19/41 (46%) myxoid subtypes. The results demonstrate the specificity of FUS-DDIT3 fusions to liposarcomas. 20332486 PubMed Kubo et al., 2010, Anticancer Res. 4 accepted 7981 722 1413 Somatic 2020-03-06 18:44:45 UTC https://civicdb.org/links/evidence_items/7981 https://civicdb.org/links/variants/722 https://civicdb.org/links/genes/1413 false CDKN2A 1029 Loss Acute Lymphoblastic Leukemia 9952 Prognostic Supports B Poor Outcome A total of thirteen studies including 2857 patients were combined in a meta-analysis. Combined HRs suggested that CDKN2A/B deletions were poor prognostic factors for both overall survival (OS) (HR = 2.15, 95% CI 1.82-2.54) and event-free survival (EFS)/disease-free survival (DFS)/relapse-free survival (RFS) (HR = 2.16, 95% CI 1.73-2.69). 30592434 PubMed Zhang et al., 2019, Ann. Med. 4 accepted 7986 554 14 9 21967752 21994623 ENST00000579755.1 75 GRCh37 Somatic 2020-12-04 15:57:33 UTC https://civicdb.org/links/evidence_items/7986 https://civicdb.org/links/variants/554 https://civicdb.org/links/genes/14 false PDGFRA 5156 Overexpression Rhabdomyosarcoma 3247 Sunitinib Predictive Supports D Sensitivity/Response A high-throughput screen of 637 cancer cell lines revealed 2 to be sensitive to the multiple tyrosine kinase inhibitor, sunitinib. The most highly sensitive line was A-204, a rhabdomyosarcoma cell line. A-204 was then compared to a panel of 6 other rhabdomyosarcoma cell lines and was the only one of the 7 with detectable PDGFRA protein (Western) and to demonstrate sensitivity to sunitinib. In A-204, no PDGFRA gene amplification was detected by FISH, but qPCR revealed a an increased PDGFRA mRNA expression. Reduction of PDFGRA expression by shRNA decreased cell number similarly to sunitinib treatment. Additionally, targeting the PDGFRA ligand, PDGFC, with shRNA or antibody decreased cell number similarly to sunitinib treatment. 19366796 PubMed McDermott et al., 2009, Cancer Res. 3 accepted 7988 2944 38 N/A 2020-05-11 23:09:08 UTC https://civicdb.org/links/evidence_items/7988 https://civicdb.org/links/variants/2944 https://civicdb.org/links/genes/38 false PDGFRA 5156 BCR::PDGFRA B-cell Acute Lymphoblastic Leukemia 0080638 Imatinib Predictive Supports C Sensitivity/Response A 47-year-old man was diagnosed with pre-B-cell acute lymphoblastic leukemia. FISH and nested PCR revealed the patient had a t(4;22)(q12;11) translocation that created an in-frame BCR-PDGFRA fusion. The constitutively activating coiled-coil domain and serine/threonine kinase encoded by BCR exon 1 fused with exon 13 of PDGFRA, which retained both tyrosine kinase domains. During initial therapy, intensification, and consolidation, hyperleukocytosis persisted. Based on the presence of the BCR-PDGFRA fusion, single agent imatinib (Glivec) was administered. A complete hematological response was observed within 6 weeks as the presence of t(4;22) in the bone marrow went from a 70% down to 15%. However, the patient had a relapse in the central nervous system. Continued treatment with imatinib along with intrathecal chemotherapy achieved a meningeal remission after 2 weeks. According to the authors, this patient’s response implicates PDGFRA as a clinically actionable imatinib target. 12944919 PubMed Trempat et al., 2003, Oncogene 3 accepted 7990 2971 38 Somatic 2020-04-21 17:18:23 UTC https://civicdb.org/links/evidence_items/7990 https://civicdb.org/links/variants/2971 https://civicdb.org/links/genes/38 false PDGFB 5155 COL1A1::PDGFB Dermatofibrosarcoma Protuberans 3507 Sunitinib Predictive Supports C Sensitivity/Response A 37-year-old man presented with dermatofibrosarcoma protuberans (DFSP). Post resection, multiple nodular metastases were found in both lungs and the disease progressed following treatments with cytotoxic agents and microwave ablation. Overexpression of PDGFRB was detected by IHC and a COL1A1-PDGFB fusion was detected by RT-PCR. Increased PDGFRB is activated by the COL1A1-PDGFB fusion product, which promotes the overactivation of downstream PDGFRB signaling pathways. Imatinib treatment failed as stable disease was followed by disease spread and progression. The patient was then treated with a daily oral dose of sunitinib (a multi-tyrosine kinase inhibitor) for 4 consecutive weeks, followed by a 2-week rest period. After 2 months on sunitinib, the patient experienced overall shrinkage of the body’s tumor mass (reduction of tumor in arm and partial response in lung and pancreas metastases). Sunitinib resulted in 9 months of progression free survival and improved quality of life. Ultimately, the disease progressed and the patient died 46 months after diagnosis. 29760553 PubMed Xiao et al., 2018, Onco Targets Ther 3 accepted 7991 2972 4173 Somatic 2020-05-11 23:23:58 UTC https://civicdb.org/links/evidence_items/7991 https://civicdb.org/links/variants/2972 https://civicdb.org/links/genes/4173 false PDGFRB 5159 Overexpression Dermatofibrosarcoma Protuberans 3507 Sunitinib Predictive Supports C Sensitivity/Response A 37-year-old man presented with dermatofibrosarcoma protuberans (DFSP). Post resection, multiple nodular metastases were found in both lungs and the disease progressed following treatments with cytotoxic agents and microwave ablation. Overexpression of PDGFRB was detected by IHC and a COL1A1-PDGFB fusion was detected by RT-PCR. Increased PDGFRB is activated by the COL1A1-PDGFB fusion product, which promotes the overactivation of downstream PDGFRB signaling pathways. Imatinib treatment failed as stable disease was followed by disease spread and progression. The patient was then treated with a daily oral dose of sunitinib (a multi-tyrosine kinase inhibitor) for 4 consecutive weeks, followed by a 2-week rest period. After 2 months on sunitinib, the patient experienced overall shrinkage of the body’s tumor mass (reduction of tumor in arm and partial response in lung and pancreas metastases). Sunitinib resulted in 9 months of progression free survival and improved quality of life. Ultimately, the disease progressed and the patient died 46 months after diagnosis. 29760553 PubMed Xiao et al., 2018, Onco Targets Ther 3 accepted 7992 2973 4176 N/A 2020-05-11 23:30:55 UTC https://civicdb.org/links/evidence_items/7992 https://civicdb.org/links/variants/2973 https://civicdb.org/links/genes/4176 false NTRK3 4916 ETV6::NTRK3 B-lymphoblastic Leukemia/lymphoma 0080630 Late onset Larotrectinib Predictive Supports C Sensitivity/Response Case report of a 61-year-old man with B-ALL. An initial analysis detected the ETV6-NTRK3 fusion and a NRASGly12Asp mutation. Initial therapies included chemotherapy and CAR-T infusion. Relapse 6 weeks after initial complete response to these therapies found a large increase in fusion transcripts and NTRK3 rearrangements were detectable by FISH in 50/50 blast nuclei whereas NRAS mutations were no longer detectable. The patient was treated with oral monotherapy larotrectinib (100mg twice per day). After 4 days on treatment peripheral blood blasts became undetectable; after 6 days on treatment lymphadenopathy and leukemia cutis resolved and a biopsy revealed an ablated bone marrow with only a few scattered blasts. The patient experienced clinical benefit with no apparent side effects during 42 days of larotrectinib treatment, however, patient eventually succumbed to multifocal angioinvasive aspergillosis because of insufficient recovery of normal hematopoiesis. Later sequencing of the NTRK3 kinase domain did not detect any larotrectinib resistance mutations (p.G623R, p.G696A). 31905241 PubMed Nardi et al., 2020, Blood Adv 3 accepted 7993 801 3985 12 11802788 12022903 ENST00000396373.4 15 88483984 88418230 ENST00000394480.2 75 GRCh37 Somatic 2021-07-24 02:22:01 UTC https://civicdb.org/links/evidence_items/7993 https://civicdb.org/links/variants/801 https://civicdb.org/links/genes/3985 false NTRK3 4916 ETV6::NTRK3 Acute Myeloid Leukemia 9119 Entrectinib Predictive Supports D Sensitivity/Response Two AML cell lines, IMS-M2 and M0-91, with the ETV6-NTRK3 fusion were treated with entrectinib. Sequencing of these cell lines found no other driver mutations in 265 other cancer genes suggesting the ETV6-NTRK3 fusion is the oncogenic driver. The IC50 for the IMS-M2 and M0-91 cell lines was 0.47 and 0.65 nmol/L, respectively. Mouse xenografts treated with entrectinib at 10 or 30 mg/kg had complete remission while treatment with 3 mg/kg caused significant reduction in tumor growth. Testing of the bone marrow of IMS-M2 xenografts after 3 weeks of treatment found no human CD45-positive cells in the 3, 10, and 30 mg/kg treatment groups; all vehicle treated mice had some human CD45-positive cells in their bone marrow. Zebrafish xenotransplantation of M0-91 cells were sensitive to entrectinib treatment. 29237803 PubMed Smith et al., 2018, Mol. Cancer Ther. 3 accepted 7994 801 3985 12 11802788 12022903 ENST00000396373.4 15 88483984 88418230 ENST00000394480.2 75 GRCh37 Somatic 2020-03-05 17:08:56 UTC https://civicdb.org/links/evidence_items/7994 https://civicdb.org/links/variants/801 https://civicdb.org/links/genes/3985 false JAK2 3717 SMU1::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. The SMU1-JAK2 fusion is rare; in this study involving 798 B-ALL patients of which 194 had clinical characteristics of Ph-like ALL, only one case with the SMU1-JAK2 fusion was observed. SMU1 was detected as a novel JAK2 partner in Ph-like B-ALL. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). 27870571 PubMed Roberts et al., 2017, J. Clin. Oncol. 3 accepted 7996 2975 28 The SMU1-JAK2 fusion is composed of part of the SMU1 (SMU1 DNA Replication Regulator and Splicesomal Factor) gene at the 5’ end (N-terminus of the fusion protein), and part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 18 of SMU1 to exon 12 of JAK2 (SMU1-JAK2 18-12). The fusion is hypothesized to result from an intrachromosomal translocation, inversion, or deletion of chromosome 9 (involving loci p21 and p24), and has been identified by RNA sequencing in an older adult patient with BCR-ABL1-like B-lymphoblastic leukemia. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the LisH, CTLH, HisP, and Wd40 domains from SMU1 and the JH2 pseudokinase and JH1 kinase domains from JAK2. Pre-clinical data demonstrates increased JH1 kinase expression as a result of the SMU1-JAK2 fusion event, which is hypothesized to upregulate the pathway shared with signal transducers and activators of transcription (STATs). Clinical significance: The novel SMU1-JAK2 fusion has been documented in one case for which specific clinical information is unavailable. However, the presence of the JAK2 JH1 kinase domain in the fusion protein may offer a target for therapeutic inhibition. Prospective clinical trials are ongoing to evaluate the efficacy of adding JAK2 inhibitors to the treatment of B-lymphoblastic leukemia patients with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2020-09-07 22:19:56 UTC https://civicdb.org/links/evidence_items/7996 https://civicdb.org/links/variants/2975 https://civicdb.org/links/genes/28 false JAK2 3717 OFD1::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive To identify potentially druggable kinase fusions, this study of 278 B-ALL patients (all BCR-ABL1 negative), 34 (12.2%) harbored an IKZF1 deletion as determined by MLPA. Sufficient RNA from 16/34 of these IKZF1 deleted patients underwent mRNA sequencing and detected fusions were validated with RT-PCR and Sanger. Seven patients with clinical characteristics of Ph-like ALL were confirmed to harbor kinase fusions. The novel in-frame OFD1-JAK2 fusion (Exon 22 to Exon 13) was detected in an 11-year-old boy with hyperleukocytosis (185.8e9/l), no response to prednisolone therapy, and classified as NCI high risk. The authors hypothesize this fusion could constitutively activate the JAK-STAT pathway. 26404892 PubMed Yano et al., 2015, Br. J. Haematol. 2 accepted 7997 2974 28 The OFD1-JAK2 fusion is composed of part of the OFD1 (Oral-Facial-Digital Syndrome 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. OFD1 is a centrosomal protein of primary cilia implicated in Oral-Facial-Digital Syndrome type 1, but it has not been previously described in hematologic malignancies. The published breakpoint joins exon 22 of OFD1 to exon 13 of JAK2 (OFD1-JAK2 22-13). This fusion is predicted to result from a reciprocal translocation t(X;9)(p22;p24), and has been identified in two patients by RNA sequencing, one of which demonstrated the abnormal karyotype 46,XY,-17+mar[11]/46,XY[9]. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the FERM and SH2 domains from OFD1 and the JH2 pseudokinase and JH1 kinase domains from JAK2. The inclusion of the JH1 kinase domain is hypothesized to upregulate the pathway shared with signal transducers and activators of transcription (STATs). Functional analysis of the OFD1-JAK2 fusion protein is reportedly underway. Clinical significance: The novel OFD1-JAK2 fusion has been documented in one 3-year-old and one 11-year-old boy with BCR-ABL1-like B-lymphoblastic leukemia. Both children successfully maintained first complete remission following induction chemotherapy and allogeneic hematopoietic stem cell transplantation, with as long as 6 years of follow up. While neither patient was treated with a JAK2 inhibitor, the JH1 kinase domain present within the OFD1-JAK2 fusion protein may offer a target for therapeutic inhibition. Prospective clinical trials are ongoing to evaluate the efficacy of adding JAK2 inhibitors to the treatment of pediatric B-lymphoblastic leukemia patients with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2020-09-25 19:21:33 UTC https://civicdb.org/links/evidence_items/7997 https://civicdb.org/links/variants/2974 https://civicdb.org/links/genes/28 false JAK2 3717 SNX29::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. The SNX29-JAK2 fusion is rare; in this study involving 383 B-ALL patients (179 adult and 204 pediatric) of which 13 (8 adult, 5 pediatric) had Ph-like expression signature, only one case (adult) with the SNX29-JAK2 fusion was observed. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). 27428428 PubMed Liu et al., 2016, EBioMedicine 3 accepted 7998 2976 28 The SNX29-JAK2 fusion is composed of part of the SNX29 (Sorting Nexin 29) gene at the 5’ end (N-terminus of the fusion protein), and a part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion. The published breakpoint joins exon 18 of SNX29 to exon 13 of JAK2 (SNX29 -JAK2 18-13). It is predicted to result from a reciprocal translocation t(9;16) (p24;q13.13), and has been identified by RNA sequencing in one normal-karyotype adult patient with BCR-ABL1-like B-lymphoblastic leukemia. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the RUN and PX_RUN domains from SNX29 and the JH2 pseudokinase and JH1 kinase domains from JAK2. The inclusion of the JH1 kinase domain is hypothesized to upregulate the pathway shared with signal transducers and activators of transcription (STATs). Functional analysis of the SNX29-JAK2 fusion protein has not been performed. Clinical significance: The novel SNX29-JAK2 fusion has been documented in a single case that successfully maintained complete remission without relapse following induction chemotherapy. While the patient was not treated with a JAK2 inhibitor, the JH1 kinase domain present within the SNX29-JAK2 fusion protein may offer a target for therapeutic inhibition. Prospective clinical trials are ongoing to evaluate the efficacy of adding JAK2 inhibitors to the treatment of B-lymphoblastic leukemia patients with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2020-09-07 22:24:01 UTC https://civicdb.org/links/evidence_items/7998 https://civicdb.org/links/variants/2976 https://civicdb.org/links/genes/28 false JAK2 3717 ZNF430::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. The ZNF430-JAK2 fusion is rare; in this study involving 798 adult B-ALL patients of which 194 had Ph-like expression signature, only one case with the ZNF430-JAK2 fusion was observed. ZNF430 was detected as a novel JAK2 partner in Ph-like B-ALL. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). 27870571 PubMed Roberts et al., 2017, J. Clin. Oncol. 3 accepted 7999 2977 28 The ZNF430-JAK2 fusion is composed of part of the ZNF430 (Zinc Finger Protein 430) gene at the 5’ end (N-terminus of the fusion protein), and part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 4 of ZNF430 to exon 19 of JAK2 (ZNF430-JAK2 4-19). The fusion is predicted to result from a reciprocal translocation t(9;19)(p24;p12), and has been identified by RNA sequencing in one adult patient with BCR-ABL1-like B-lymphoblastic leukemia. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the KRAB_A-box domain from ZNF430 and the JH1 kinase domain from JAK2. The inclusion of the JH1 kinase domain is hypothesized to upregulate the pathway shared with signal transducers and activators of transcription (STATs). Functional analysis of the ZNF430-JAK2 fusion protein has not been performed. Clinical significance: The novel ZNF430-JAK2 fusion has been documented in one case for which clinical information is unavailable. However, the presence of the JAK2 JH1 kinase domain in the fusion protein may offer a target for therapeutic inhibition. Prospective clinical trials are ongoing to evaluate the efficacy of adding JAK2 inhibitors to the treatment of pediatric B-lymphoblastic leukemia patients with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2021-01-05 01:52:28 UTC https://civicdb.org/links/evidence_items/7999 https://civicdb.org/links/variants/2977 https://civicdb.org/links/genes/28 false ABL1 25 BCR::ABL F359V Chronic Myeloid Leukemia 8552 Dasatinib Predictive Does Not Support C Resistance Prior to dasatinib treatment, one imatinib-resistant patients with chronic myeloid leukemia (CML) in myeloid blast crisis had the BCR-ABL1 fusion with F359V, F359V/Q252R, and L273M secondary variants in 9/12, 1/12, and 2/12 clones, respectively. Clones were generated using peripheral blood RNA. The patient had complete best cytogenetic and no evidence of leukemia best hematologic responses to dasatinib which were better outcomes in comparison to those seen in patients with unmutated BCR-ABL in this phase. 16775234 PubMed Talpaz et al., 2006, N. Engl. J. Med. NCT00064233 1 accepted 8002 892 4 9 133748414 133748414 T G ENST00000318560.5 75 GRCh37 Somatic 2020-03-11 21:03:46 UTC https://civicdb.org/links/evidence_items/8002 https://civicdb.org/links/variants/892 https://civicdb.org/links/genes/4 false PIK3CA 5290 E542K Breast Cancer 1612 PI-103 Predictive Supports D Resistance As part of a preclinical study, the efficacy of PI-103 was evaluated for several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. KPL1 is a luminal-like breast cancer cell line harboring PIK3CA E542K, and it had an IC50 of 7.62uM. 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 1 accepted 8007 103 37 3 178936082 178936082 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K variants are the second most recurrent PIK3CA mutations in breast cancer and are highly recurrent mutations in many other cancer types. Colorectal cancer patients with the PIK3CA E545K variant, and possibly other variants in the E545 region, may indicate poor prognosis relative to patients with other PIK3CA variants or wild-type PIK3CA. The literature also suggests that E545/E542 variants may confer resistance to EGFR inhibitors (e.g., cetuximab). An FDA approved treatment regimen including a targeted PIK3CA inhibitor is available for specific subtypes of breast cancer. While PIK3CA variants are highly prevalent in many other cancer types, targeted therapies for PIK3CA variants are still in early clinical trial phases in other cancer types. Somatic 2022-01-26 00:13:05 UTC https://civicdb.org/links/evidence_items/8007 https://civicdb.org/links/variants/103 https://civicdb.org/links/genes/37 false PIK3CA 5290 E545K Breast Cancer 1612 PI-103 Predictive Supports D Resistance As part of a preclinical study, the efficacy of PI-103 was evaluated for several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. MCF7 is a luminal-like breast cancer cell line harboring PIK3CA E545K, and it had an IC50 of 1.53uM. 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 1 accepted 8008 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2022-01-26 00:13:49 UTC https://civicdb.org/links/evidence_items/8008 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047L Breast Cancer 1612 PI-103 Predictive Supports D Sensitivity/Response As part of a preclinical study, the efficacy of PI-103 was evaluated for several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. EFM-19 is a luminal-like breast cancer cell line harboring PIK3CA H1047L, and it had an IC50 of 0.16uM. 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 1 accepted 8009 1151 37 3 178952085 178952085 A T ENST00000263967.3 75 GRCh37 Somatic 2022-01-26 00:14:34 UTC https://civicdb.org/links/evidence_items/8009 https://civicdb.org/links/variants/1151 https://civicdb.org/links/genes/37 false PIK3CA 5290 K111N Her2-receptor Positive Breast Cancer 0060079 PI-103 Predictive Supports D Sensitivity/Response As part of a preclinical study, the efficacy of PI-103 was evaluated for several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. BT-474 is a HER2 receptor amplified breast cancer cell line harboring PIK3CA K111N, and it had an IC50 of 0.60uM. 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 1 accepted 8011 1234 37 3 178916946 178916946 G C ENST00000263967.3 75 GRCh37 Somatic 2022-01-26 00:18:12 UTC https://civicdb.org/links/evidence_items/8011 https://civicdb.org/links/variants/1234 https://civicdb.org/links/genes/37 false PTEN 5728 Loss Her2-receptor Positive Breast Cancer 0060079 PI-103 Predictive Supports D Sensitivity/Response As part of a preclinical study, the efficacy of PI-103 was evaluated for several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. HCC-1569 is a HER2 receptor amplified breast cancer cell line harboring PTEN Loss, and it had an IC50 of 0.40uM. 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 1 accepted 8012 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2022-01-26 00:21:20 UTC https://civicdb.org/links/evidence_items/8012 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PIK3CA 5290 E542K Her2-receptor Positive Breast Cancer 0060079 PI3Ka/Di Predictive Supports D Sensitivity/Response As part of a preclinical study, the efficacy of PI3KA/Di—a selective inhibitor for the α and δ subunits of class I PI3K—was evaluated for several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. HCC-202 is a HER2 receptor amplified breast cancer cell line harboring PIK3CA E542K and it had an IC50 of 0.62uM. 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 1 accepted 8013 103 37 3 178936082 178936082 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K variants are the second most recurrent PIK3CA mutations in breast cancer and are highly recurrent mutations in many other cancer types. Colorectal cancer patients with the PIK3CA E545K variant, and possibly other variants in the E545 region, may indicate poor prognosis relative to patients with other PIK3CA variants or wild-type PIK3CA. The literature also suggests that E545/E542 variants may confer resistance to EGFR inhibitors (e.g., cetuximab). An FDA approved treatment regimen including a targeted PIK3CA inhibitor is available for specific subtypes of breast cancer. While PIK3CA variants are highly prevalent in many other cancer types, targeted therapies for PIK3CA variants are still in early clinical trial phases in other cancer types. Somatic 2022-01-26 00:22:28 UTC https://civicdb.org/links/evidence_items/8013 https://civicdb.org/links/variants/103 https://civicdb.org/links/genes/37 false PIK3CA 5290 E542K Breast Cancer 1612 PI3Ka/Di Predictive Supports D Sensitivity/Response As part of a preclinical study, the efficacy of PI3KA/Di—a selective inhibitor for the α (IC50 for p100α: 3nM) and δ (IC50 for p100δ: 20nM) subunits of class I PI3K—was evaluated for several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. KPL-1 is a luminal-type breast cancer cell line harboring PIK3CA E542K and it had an IC50 of 0.55uM. 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 1 accepted 8016 103 37 3 178936082 178936082 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K variants are the second most recurrent PIK3CA mutations in breast cancer and are highly recurrent mutations in many other cancer types. Colorectal cancer patients with the PIK3CA E545K variant, and possibly other variants in the E545 region, may indicate poor prognosis relative to patients with other PIK3CA variants or wild-type PIK3CA. The literature also suggests that E545/E542 variants may confer resistance to EGFR inhibitors (e.g., cetuximab). An FDA approved treatment regimen including a targeted PIK3CA inhibitor is available for specific subtypes of breast cancer. While PIK3CA variants are highly prevalent in many other cancer types, targeted therapies for PIK3CA variants are still in early clinical trial phases in other cancer types. Somatic 2022-01-26 00:28:42 UTC https://civicdb.org/links/evidence_items/8016 https://civicdb.org/links/variants/103 https://civicdb.org/links/genes/37 false PIK3CA 5290 E545K Her2-receptor Positive Breast Cancer 0060079 PI3Ka/Di Predictive Supports D Sensitivity/Response As part of a preclinical study, the efficacy of PI3KA/Di—a selective inhibitor for the α (IC50 for p100α: 3nM) and δ (IC50 for p100δ: 20nM) subunits of class I PI3K—was evaluated for several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. MDA-MB-361 is a HER2 amplified breast cancer cell line harboring PIK3CA E545K and it had an IC50 of 0.16uM. 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 1 accepted 8017 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2022-01-26 00:30:36 UTC https://civicdb.org/links/evidence_items/8017 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false PIK3CA 5290 E545K Breast Cancer 1612 PI3Ka/Di Predictive Supports D Sensitivity/Response As part of a preclinical study, the efficacy of PI3KA/Di—a selective inhibitor for the α (IC50 for p100α: 3nM) and δ (IC50 for p100δ: 20nM) subunits of class I PI3K—was evaluated for several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. MCF7 is a luminal-type breast cancer cell line harboring PIK3CA E545K and it had an IC50 of 0.84uM. 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 1 accepted 8018 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2022-01-26 00:32:06 UTC https://civicdb.org/links/evidence_items/8018 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047L Breast Cancer 1612 PI3Ka/Di Predictive Supports D Sensitivity/Response As part of a preclinical study, the efficacy of PI3KA/Di—a selective inhibitor for the α and δ subunits of class I PI3K—was evaluated for several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. EFM-19 is a luminal-type breast cancer cell line harboring PIK3CA H1047L and it had an IC50 of 0.17uM. 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 1 accepted 8019 1151 37 3 178952085 178952085 A T ENST00000263967.3 75 GRCh37 Somatic 2022-01-26 00:32:42 UTC https://civicdb.org/links/evidence_items/8019 https://civicdb.org/links/variants/1151 https://civicdb.org/links/genes/37 false PIK3CA 5290 K111N Her2-receptor Positive Breast Cancer 0060079 PI3Ka/Di Predictive Supports D Sensitivity/Response As part of a preclinical study, the efficacy of PI3KA/Di—a selective inhibitor for the α and δ subunits of class I PI3K—was evaluated for several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. BT-474 is a HER2 amplified breast cancer cell line harboring PIK3CA K111N and it had an IC50 of 0.52uM. 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 1 accepted 8020 1234 37 3 178916946 178916946 G C ENST00000263967.3 75 GRCh37 Somatic 2022-01-26 00:33:40 UTC https://civicdb.org/links/evidence_items/8020 https://civicdb.org/links/variants/1234 https://civicdb.org/links/genes/37 false PTEN 5728 Loss Her2-receptor Positive Breast Cancer 0060079 PI3Ka/Di Predictive Supports D Resistance As part of a preclinical study, the efficacy of PI3KA/Di—a selective inhibitor for the α and δ subunits of class I PI3K—was evaluated for several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. HCC-1569 is a HER2 amplified breast cancer cell line harboring PTEN loss and it had an IC50 of 2.82uM. 20453058 PubMed O'Brien et al., 2010, Clin. Cancer Res. 1 accepted 8022 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2022-01-26 00:35:50 UTC https://civicdb.org/links/evidence_items/8022 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PIK3CA 5290 V955I Colorectal Cancer 9256 Cetuximab Predictive Supports C Resistance Among 32 colorectal cancer patients with acquired resistance (PFS > 12 weeks) to cetuximab, one was determined to have V955I mutation. V995I allelic fractions low at start of treatment but increased in frequency during treatment. PolyPhen-2 and SIFT functional predict folding changes to activation-loop domain. DiFi cells transfected with PIK3CA V955I plasmid assayed with western blot for pAKT (phosphorylated AKT) and pERK showed increased phosphorylation, which was not affected by the addition of cetuximab. PIK3CA V955I transfected cells also promoted cell viability in the presence of cetuximab. 28424201 PubMed Xu et al., 2017, Clin. Cancer Res. 4 accepted 8063 3001 37 3 178948091 178948091 G A ENST00000263967.3 75 GRCh37 Somatic 2021-01-06 19:13:42 UTC https://civicdb.org/links/evidence_items/8063 https://civicdb.org/links/variants/3001 https://civicdb.org/links/genes/37 false NF2 4771 c.1396C>T Adult Spinal Cord Ependymoma 7788 Predisposing N/A C N/A Blood or tumor specimens of 37 unrelated adult patients with ependymomas related to neurofibromatosis Type 2 (NF2) underwent sequencing of the NF2 gene to reveal germline variants. Overall, 64% were found to harbor truncating mutations of NF2, which the authors conclude supports previous reports of truncating mutations in NF2 associate with more severe phenotypes. Three unrelated patients harbored NF2 R466* (c.1396C>T). It's unclear whether these three patients were symptomatic, but none of them underwent surgical resection of the ependymomas during the study period. 21294614 PubMed Plotkin et al., 2011, J Neurosurg Spine 2 accepted 8067 3002 3870 Rare Germline 2021-04-16 22:42:46 UTC https://civicdb.org/links/evidence_items/8067 https://civicdb.org/links/variants/3002 https://civicdb.org/links/genes/3870 false ABL1 25 BCR::ABL E355G Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. An acute-phase patient achieved complete hematologic response but progressed to chronic phase with detection of the E355G mutation and then to accelerated phase. After allograft, this patient relapsed into chronic phase and the E355G mutation was again detected in 100% of transcripts. 12623848 PubMed Branford et al., 2003, Blood 3 accepted 8090 1487 4 9 133748403 133748403 A G ENST00000318560.5 75 GRCh37 Somatic 2020-07-11 00:14:56 UTC https://civicdb.org/links/evidence_items/8090 https://civicdb.org/links/variants/1487 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F486S Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. An accelerate-phase patient had a complete cytogenetic response until progressing to major cytogenetic response (MCyR) at month 17 and then losing MCyR at month 24 despite dose escalation. At month 9, the F486S variant was found in ~25% of transcripts increasing to ~50% at month 16 and then remaining at a stable proportion. 12623848 PubMed Branford et al., 2003, Blood 2 accepted 8091 1152 4 9 133755488 133755488 T C ENST00000318560.5 75 GRCh37 Somatic 2020-07-24 23:03:00 UTC https://civicdb.org/links/evidence_items/8091 https://civicdb.org/links/variants/1152 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL E459K Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A late-chronic phase (CP) patient had a complete hematologic response but acquired resistance 7 months after treatment initiation. At month 11, the L248V, G250E, S417Y, and E459K variants were present in approximately 25, 25, 25, and 50% of transcripts, respectively. The patient died in accelerated phase at month 14. 12623848 PubMed Branford et al., 2003, Blood 2 accepted 8092 2370 4 9 133753906 133753906 G A ENST00000318560.5 75 GRCh37 Somatic 2020-07-11 00:22:04 UTC https://civicdb.org/links/evidence_items/8092 https://civicdb.org/links/variants/2370 https://civicdb.org/links/genes/4 false ABL1 25 Double Ph Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A chronic-phase patient had a partial hematologic response with the Q252H and M351T variants present. The patient progressed to myeloid blast crisis (MBC) and was then negative for secondary variants. However, they had cytogenetic evidence of double Ph-chromosomes and later died. Another CP patient achieved a complete hematologic response (CHR). The Q252H variant was later detected but was absent when the patient progressed to myeloid blast crisis (MBC) at which time cytogenetic evidence of double Ph-chromosomes were present. The patient later died. An accelerated-phase patient had a complete hematologic response with the F359V and M351T variants present. The patient progressed to myeloid blast crisis at which point there were no secondary variants but cytogenetic evidence of double Ph-chromosomes. 12623848 PubMed Branford et al., 2003, Blood 4 accepted 8093 3009 4 Somatic 2020-07-24 22:36:16 UTC https://civicdb.org/links/evidence_items/8093 https://civicdb.org/links/variants/3009 https://civicdb.org/links/genes/4 false ABL1 25 P-Loop Mutation Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. Of 14 patients who started the study in late chronic phase and had p-loop or non-p-loop mutations, 6/6 with p-loop mutations died compared to no deaths during the course of the study for those with non-p-loop mutations (P=0.0013). 14 patients who started the study in accelerated phase and had p-loop or non-p-loop mutations, 6/7 with p-loop mutations died and 3/6 with non-p-loop mutations died (P=0.14). Overall, this data suggests p-loop mutations that arise during late-chronic phase support resistance to imatinib. 12623848 PubMed Branford et al., 2003, Blood 2 accepted 8094 2375 4 Somatic 2020-07-24 23:18:46 UTC https://civicdb.org/links/evidence_items/8094 https://civicdb.org/links/variants/2375 https://civicdb.org/links/genes/4 false JAK2 3717 ATF7IP::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. The ATF7IP-JAK2 fusion is rare; in this study involving 798 B-ALL patients of which 194 had clinical characteristics of Ph-like ALL, two cases with the ATF7IP-JAK2 fusion were observed. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). 27870571 PubMed Roberts et al., 2017, J. Clin. Oncol. 3 accepted 8095 2846 28 The ATF7IP-JAK2 fusion is composed of part of the ATF7IP (Activating Transcription Factor 7 Interacting Protein) gene at the 5’ end (N-terminus of the fusion protein), and a part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion. Known breakpoint/splice variants join exon 10 of ATF7IP to exon 8 of JAK2 (ATF7IP-JAK2 10-8), exon 13 of ATF7IP to exon 16 of JAK2 (ATF7IP-JAK2 13-16), or exon 13 of ATF7IP to exon 17 of JAK2 (ATF7IP-JAK2 13-17). The fusion is predicted to result from a reciprocal translocation t(9;12) (p24;p13.1), and has been identified by RNA sequencing and Sanger sequencing in three adult patients with BCR-ABL1-like B-lymphoblastic leukemia. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the coiled coil and MDN1 domains from ATF7IP and the JH2 pseudokinase and JH1 kinase domains from JAK2. The coiled coil domain is hypothesized to constitutively activate the JAK2 kinase domain, thereby upregulating the pathway shared with signal transducers and activators of transcription (STATs). Clinical significance: The novel ATF7IP-JAK2 fusion has been documented in three cases for which specific clinical information is unavailable. A pre-clinical xenograft model containing the fusion was sensitive to exposure to the JAK2 inhibitor, ruxolitinib. Therefore, the presence of the JAK2 JH1 kinase domain in the fusion protein may offer a target for therapeutic inhibition. Prospective clinical trials are ongoing to evaluate the efficacy of adding JAK2 inhibitors to the treatment of B-lymphoblastic leukemia patients with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2020-09-07 21:34:01 UTC https://civicdb.org/links/evidence_items/8095 https://civicdb.org/links/variants/2846 https://civicdb.org/links/genes/28 false JAK2 3717 BCR::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. In this study involving 798 B-ALL patients of which 194 had clinical characteristics of Ph-like ALL, only one case with the BCR-JAK2 fusion was observed. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). 27870571 PubMed Roberts et al., 2017, J. Clin. Oncol. 3 accepted 8096 2860 28 The BCR-JAK2 fusion is composed of part of the BCR (Breakpoint Cluster Region) gene at the 5’ end (N-terminus of the fusion protein), and part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion. Known breakpoint/splice variants join exon 14 of BCR to exon 17 of JAK2 (BCR-JAK2 4-17) and exon 1 of BCR to exons 15 (BCR-JAK2 1-15), 17 (BCR-JAK2 1-17), or 19 (BCR-JAK2 1-19). The fusion results from the reciprocal translocation t(9;22)(p24;p11.2), and has been identified by karyotype analysis, FISH, RT-PCR, targeted ligation amplification (TLA), and RNA sequencing. The fusion gene is expressed from the der(9) chromosome. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the coiled coil domain from BCR and the JH1 kinase domain from JAK2. Depending on the breakpoint variant, the fusion protein may also contain the JAK2 JH2 pseudokinase domain. In pre-clinical studies, the coiled coil domain of BCR has been shown to mediate oligomeric activation of the JAK2 kinase domain, thereby promoting downstream signaling by signal transducers and activators of transcription (STATs). The BCR-JAK2 fusion is associated with hematologic malignancies and has been observed in myeloproliferative neoplasms with eosinophilia (multiple cases), B-lymphoblastic leukemia (multiple cases), acute myeloid leukemia (a rare case), and B-cell lymphoma (rare case of Burkitt lymphoma). Clinical significance: As a diagnostic biomarker in B-lymphoblastic leukemia, the BCR-JAK2 fusion is frequently observed in the BCR-ABL1-like subtype. As a prognostic marker, the fusion appears to be associated with high-risk disease in pediatric and adult populations. As a predictive marker, patients whose diseases exhibit the BCR-JAK2 fusion have experienced partial responses or even complete remission with hydroxyurea and/or interferon alfa. Case reports have demonstrated the limited utility of tyrosine kinase inhibitors. One patient diagnosed with a myeloid neoplasm initially responded to the JAK2 inhibitor ruxolitinib, but relapsed after 18 months. Current research has suggested a survival advantage following allogeneic or autologous stem cell transplantation. Somatic 2020-09-07 21:39:59 UTC https://civicdb.org/links/evidence_items/8096 https://civicdb.org/links/variants/2860 https://civicdb.org/links/genes/28 false JAK2 3717 ETV6::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. In this study involving 798 B-ALL patients of which 194 had clinical characteristics of Ph-like ALL, only one case with the ETV6-JAK2 fusion was observed. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). 27870571 PubMed Roberts et al., 2017, J. Clin. Oncol. 3 accepted 8097 2859 28 The ETV6-JAK2 fusion is composed of part of the ETV6 (ETS Variant Transcription Factor 6) gene at the 5’ end (N-terminus of the fusion protein), and part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion. Known breakpoint/splice variants join exon 4 of ETV6 to exon 17 of JAK2 (ETV6-JAK2 4-17), exon 5 of ETV6 to exon 12 of JAK2 (ETV6-JAK2 5-12), or exon 5 of ETV6 to exon 19 of JAK2 (ETV6-JAK2 5-19). The fusion results from the reciprocal translocation t(9;12)(p24;p13), cytogenetically cryptic, and has been identified by FISH and RNA sequencing. The fusion gene is expressed from the der(9) chromosome. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the PNT domain from ETV6 and JH1 kinase domain from JAK2. The ETV6 PNT domain is hypothesized to result in dimerization, which leads to aberrant JAK2 kinase domain activation. Depending on the breakpoint variant, the fusion protein may also contain the JAK2 JH2 pseudokinase domain. The inclusion of the JH1 domain may affect functional effects and disease specificity of the abnormal fusion. Functionally, the fusion results in aberrant activation of JAK2 kinase, leading to activation of downstream signaling through the signal transducers and activators of transcription (STATs). The ETV6-JAK2 fusion is associated with hematologic malignancies and has been observed in B-lymphoblastic leukemia (~10%), T-lymphoblastic leukemia (isolated cases), and myeloid/lymphoid neoplasms with eosinophilia and gene rearrangements (rare cases). Clinical significance: As a diagnostic biomarker, the ETV6-JAK2 fusion in B-lymphoblastic leukemia is associated with the BCR-ABL1-like subtype. As a prognostic marker, the ETV6-JAK2 fusion has been associated with high-risk disease. As a predictive marker, the ETV6-JAK2 fusion has been shown by limited pre-clinical data and case reports to predict response to treatment with JAK2 inhibitors. Prospective clinical trials are ongoing to evaluate the efficacy of adding JAK2 inhibitors to treatment of pediatric B-lymphoblastic leukemia patients with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2020-09-07 21:47:23 UTC https://civicdb.org/links/evidence_items/8097 https://civicdb.org/links/variants/2859 https://civicdb.org/links/genes/28 false JAK2 3717 PPFIBP1::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease.The PPFIBP1-JAK2 fusion is rare; In this study involving 798 B-ALL patients of which 194 had clinical characteristics of Ph-like ALL, only one case with the PPFIBP1-JAK2 fusion was observed. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). 27870571 PubMed Roberts et al., 2017, J. Clin. Oncol. 3 accepted 8099 2848 28 Somatic 2020-09-07 21:57:58 UTC https://civicdb.org/links/evidence_items/8099 https://civicdb.org/links/variants/2848 https://civicdb.org/links/genes/28 false JAK2 3717 SSBP2::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease.The SSBP2-JAK2 fusion is rare; In this study involving 798 B-ALL patients of which 194 had clinical characteristics of Ph-like ALL, two cases with the SSBP2-JAK2 fusion were observed. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). 27870571 PubMed Roberts et al., 2017, J. Clin. Oncol. 3 accepted 8100 2661 28 Somatic 2020-09-07 22:32:27 UTC https://civicdb.org/links/evidence_items/8100 https://civicdb.org/links/variants/2661 https://civicdb.org/links/genes/28 false JAK2 3717 BCR::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In this study involving 574 pediatric B-ALL patients (from a Dutch/German cohort), 77 were shown to be Ph-like cases identified by hierarchical clustering of gene expression data. In one male patient with Ph-like disease, an in-frame BCR-JAK2 fusion involving exon 1 of BCR and exon 17 of JAK2 was identified. This fusion was confirmed by RT-PCR and targeted ligation amplification (TLA). A concurrent IKZF1 exon 2-3 deletion was detected. The patient experienced complete remission after induction but relapsed shortly after. . 27894077 PubMed Boer et al., 2017, Oncotarget 4 accepted 8101 2860 28 The BCR-JAK2 fusion is composed of part of the BCR (Breakpoint Cluster Region) gene at the 5’ end (N-terminus of the fusion protein), and part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion. Known breakpoint/splice variants join exon 14 of BCR to exon 17 of JAK2 (BCR-JAK2 4-17) and exon 1 of BCR to exons 15 (BCR-JAK2 1-15), 17 (BCR-JAK2 1-17), or 19 (BCR-JAK2 1-19). The fusion results from the reciprocal translocation t(9;22)(p24;p11.2), and has been identified by karyotype analysis, FISH, RT-PCR, targeted ligation amplification (TLA), and RNA sequencing. The fusion gene is expressed from the der(9) chromosome. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the coiled coil domain from BCR and the JH1 kinase domain from JAK2. Depending on the breakpoint variant, the fusion protein may also contain the JAK2 JH2 pseudokinase domain. In pre-clinical studies, the coiled coil domain of BCR has been shown to mediate oligomeric activation of the JAK2 kinase domain, thereby promoting downstream signaling by signal transducers and activators of transcription (STATs). The BCR-JAK2 fusion is associated with hematologic malignancies and has been observed in myeloproliferative neoplasms with eosinophilia (multiple cases), B-lymphoblastic leukemia (multiple cases), acute myeloid leukemia (a rare case), and B-cell lymphoma (rare case of Burkitt lymphoma). Clinical significance: As a diagnostic biomarker in B-lymphoblastic leukemia, the BCR-JAK2 fusion is frequently observed in the BCR-ABL1-like subtype. As a prognostic marker, the fusion appears to be associated with high-risk disease in pediatric and adult populations. As a predictive marker, patients whose diseases exhibit the BCR-JAK2 fusion have experienced partial responses or even complete remission with hydroxyurea and/or interferon alfa. Case reports have demonstrated the limited utility of tyrosine kinase inhibitors. One patient diagnosed with a myeloid neoplasm initially responded to the JAK2 inhibitor ruxolitinib, but relapsed after 18 months. Current research has suggested a survival advantage following allogeneic or autologous stem cell transplantation. Somatic 2020-10-19 20:45:03 UTC https://civicdb.org/links/evidence_items/8101 https://civicdb.org/links/variants/2860 https://civicdb.org/links/genes/28 false JAK2 3717 ETV6::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In this study which included 1389 cases of high-risk pediatric B-ALL, 284 were identified by TaqMan Low Density Array to have a Ph-like gene expression signature. RT-PCR or RNAseq performed on CRLF2 negative patients revealed 4.9% had JAK2 rearrangements including one individual who had an ETV6-JAK2 fusion that was confirmed by Sanger sequencing. This patient was designated PH-like non CRLF2. 28408464 PubMed Reshmi et al., 2017, Blood 4 accepted 8102 2859 28 The ETV6-JAK2 fusion is composed of part of the ETV6 (ETS Variant Transcription Factor 6) gene at the 5’ end (N-terminus of the fusion protein), and part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion. Known breakpoint/splice variants join exon 4 of ETV6 to exon 17 of JAK2 (ETV6-JAK2 4-17), exon 5 of ETV6 to exon 12 of JAK2 (ETV6-JAK2 5-12), or exon 5 of ETV6 to exon 19 of JAK2 (ETV6-JAK2 5-19). The fusion results from the reciprocal translocation t(9;12)(p24;p13), cytogenetically cryptic, and has been identified by FISH and RNA sequencing. The fusion gene is expressed from the der(9) chromosome. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the PNT domain from ETV6 and JH1 kinase domain from JAK2. The ETV6 PNT domain is hypothesized to result in dimerization, which leads to aberrant JAK2 kinase domain activation. Depending on the breakpoint variant, the fusion protein may also contain the JAK2 JH2 pseudokinase domain. The inclusion of the JH1 domain may affect functional effects and disease specificity of the abnormal fusion. Functionally, the fusion results in aberrant activation of JAK2 kinase, leading to activation of downstream signaling through the signal transducers and activators of transcription (STATs). The ETV6-JAK2 fusion is associated with hematologic malignancies and has been observed in B-lymphoblastic leukemia (~10%), T-lymphoblastic leukemia (isolated cases), and myeloid/lymphoid neoplasms with eosinophilia and gene rearrangements (rare cases). Clinical significance: As a diagnostic biomarker, the ETV6-JAK2 fusion in B-lymphoblastic leukemia is associated with the BCR-ABL1-like subtype. As a prognostic marker, the ETV6-JAK2 fusion has been associated with high-risk disease. As a predictive marker, the ETV6-JAK2 fusion has been shown by limited pre-clinical data and case reports to predict response to treatment with JAK2 inhibitors. Prospective clinical trials are ongoing to evaluate the efficacy of adding JAK2 inhibitors to treatment of pediatric B-lymphoblastic leukemia patients with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2020-10-19 20:08:03 UTC https://civicdb.org/links/evidence_items/8102 https://civicdb.org/links/variants/2859 https://civicdb.org/links/genes/28 false JAK2 3717 SSBP2::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In this study which included 1389 cases of high-risk pediatric B-ALL, 284 were identified by TaqMan Low Density Array to have a Ph-like gene expression signature. RT-PCR or RNAseq performed on CRLF2 negative patients revealed 4.9% had JAK2 rearrangements including two individuals that had an SSBP2-JAK2 fusion that were confirmed by Sanger sequencing. These patients were designated PH-like non CRLF2. 28408464 PubMed Reshmi et al., 2017, Blood 4 accepted 8103 2661 28 Somatic 2020-10-19 20:11:28 UTC https://civicdb.org/links/evidence_items/8103 https://civicdb.org/links/variants/2661 https://civicdb.org/links/genes/28 false JAK2 3717 OFD1::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In this study involving 373 high risk pediatric B-ALL cases with no recurrent fusions, 29 were kinase-fusion positive as determined by mRNA-seq or mRT-PCR and validated by RT-PCR and Sanger. One case, a 3-year-old male harbored the in-frame OFD1-JAK2 fusion (exon 22 and exon 13) and had an IZKF1 deletion as determined by MLPA. This patient had a high white blood cell count (185,000/ul) and failed induction along with a poor response to prednisolone. Following stem cell transplant, the patient remained in continuous complete remission. Gene set enrichment analysis revealed a positive enrichment score (.48) indicating this patient’s expression signature was similar to the signature of BCR-ABL1 positive patients. 27176795 PubMed Imamura et al., 2016, Blood Cancer J 2 accepted 8104 2974 28 The OFD1-JAK2 fusion is composed of part of the OFD1 (Oral-Facial-Digital Syndrome 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. OFD1 is a centrosomal protein of primary cilia implicated in Oral-Facial-Digital Syndrome type 1, but it has not been previously described in hematologic malignancies. The published breakpoint joins exon 22 of OFD1 to exon 13 of JAK2 (OFD1-JAK2 22-13). This fusion is predicted to result from a reciprocal translocation t(X;9)(p22;p24), and has been identified in two patients by RNA sequencing, one of which demonstrated the abnormal karyotype 46,XY,-17+mar[11]/46,XY[9]. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the FERM and SH2 domains from OFD1 and the JH2 pseudokinase and JH1 kinase domains from JAK2. The inclusion of the JH1 kinase domain is hypothesized to upregulate the pathway shared with signal transducers and activators of transcription (STATs). Functional analysis of the OFD1-JAK2 fusion protein is reportedly underway. Clinical significance: The novel OFD1-JAK2 fusion has been documented in one 3-year-old and one 11-year-old boy with BCR-ABL1-like B-lymphoblastic leukemia. Both children successfully maintained first complete remission following induction chemotherapy and allogeneic hematopoietic stem cell transplantation, with as long as 6 years of follow up. While neither patient was treated with a JAK2 inhibitor, the JH1 kinase domain present within the OFD1-JAK2 fusion protein may offer a target for therapeutic inhibition. Prospective clinical trials are ongoing to evaluate the efficacy of adding JAK2 inhibitors to the treatment of pediatric B-lymphoblastic leukemia patients with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2021-05-25 23:20:47 UTC https://civicdb.org/links/evidence_items/8104 https://civicdb.org/links/variants/2974 https://civicdb.org/links/genes/28 false JAK2 3717 PAX5::JAK2 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports C Positive In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. In this study involving 373 high risk pediatric B-ALL cases of which 29 were kinase-fusion positive patients, only one case with the PAX5-JAK2 fusion was observed. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). 27176795 PubMed Imamura et al., 2016, Blood Cancer J 3 accepted 8105 2861 28 The PAX5-JAK2 fusion is composed of part of the PAX5 (Paired Box 5) gene at the 5’ end (N-terminus of the fusion protein), and part of the JAK2 (Janus Kinase 2) gene at the 3’ end (C-terminus of the fusion protein). JAK2 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 5 of PAX5 to exon 19 of JAK2 (PAX5-JAK2 5-19). The fusion is hypothesized to result from an intrachromosomal translocation, inversion, or deletion of chromosome 9 (involving loci p13 and p24), and has been identified by RNA sequencing, RT-PCR, Sanger sequencing, and FISH in patients B-lymphoblastic leukemia. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the DNA-binding paired domain from PAX5 and the JH1 kinase domain from JAK2. A pre-clinical study has revealed that this fusion protein deregulates the PAX5 transcriptional pathway while also autophosphorylating the JAK2 kinase domain, thereby promoting downstream signaling by signal transducers and activators of transcription (STATs). Clinical significance: As a diagnostic biomarker, the PAX5-JAK2 fusion in B-lymphoblastic leukemia is frequently associated with the BCR-ABL1-like subtype. As a prognostic marker, the fusion has been associated with intermediate to high-risk disease. As a predictive marker, the PAX5-JAK2 fusion has been shown in pre-clinical data to predict response to treatment with JAK2 inhibitors. Prospective clinical trials are ongoing to evaluate the efficacy of adding JAK2 inhibitors to treatment of B-lymphoblastic leukemia patients with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). Somatic 2020-09-07 21:51:13 UTC https://civicdb.org/links/evidence_items/8105 https://civicdb.org/links/variants/2861 https://civicdb.org/links/genes/28 false FLT3 2322 D835Y Cancer 162 Gilteritinib Predictive Supports D Sensitivity/Response Gilteritinib inhibited the cell growth of Ba/F3 cells expressing D835Y (IC50 1.6 nM; 95% CI: 1.1–2.4 nM) compared to controls (IC50 420nM; 95% CI: 350–500 nM). Additionally, immunoblots showed gliteritinib reduced phosphorylation of FLT3 and downstream targets in Ba/F3 D835Y cells in a dose dependent manner. Furthermore, in nude mice xenografted with Ba/F3 cells expressing D835Y, gilteritinib showed antitumor efficacy at 10 mg/kg and 30 mg/kg, and induced tumor regression at 30 mg/k. Computational modelling demonstrated that gilteritinib interacts with activated FLT3 at the ATP-binding site, which is distant from the D835 containing activation loop. This inhibitory mechanism allows for kinase inhibition to occur in the face of D835 mutation. 28516360 PubMed Mori et al., 2017, Invest New Drugs 4 accepted 8106 3011 24 Somatic 2020-07-14 01:24:00 UTC https://civicdb.org/links/evidence_items/8106 https://civicdb.org/links/variants/3011 https://civicdb.org/links/genes/24 false FLT3 2322 D835Y Acute Myeloid Leukemia 9119 Gilteritinib Predictive Supports D Sensitivity/Response A 35 year-old male patient (AML4) presented with a FLT3-ITD mutation at diagnosis and was refractory to induction and salvage chemotherapy. He then received quizartinib and underwent allogenic transplant, but relapsed after 6 months. He then responded to sorafenib, but had disease progression with a FLT3-D835Y mutation. The patient derived relapse sample containing ITD and D835Y mutations was sensitive to gilteritinib based on cytotoxicity assays using MTT. Additionally, immunoblot demonstrated gilteritinib reduced FLT3 phosphorylation in Ba/F3 cells expressing only D835Y with an IC50 of 1.4 nM. 27908881 PubMed Lee et al., 2017, Blood 2 accepted 8108 3011 24 Somatic 2020-12-03 18:41:16 UTC https://civicdb.org/links/evidence_items/8108 https://civicdb.org/links/variants/3011 https://civicdb.org/links/genes/24 false PIK3CA 5290 E545K Cervical Cancer 4362 Cisplatin,Radiation Ionizing Radiotherapy Sequential Predictive Supports D Resistance Cervical cancer cell lines were treated with 1uM cisplatin followed by 1-6Gy ionizing radiation (IR). CaSki cells with PIK3CA E545K mutation show resistance to cisplatin plus IR when compared with HeLa or SiHa cells that express only wild-type PIK3CA. Transfection of HeLa cells with PIK3CA E545K resulted in resistance to cisplatin plus IR compared to cells expressing only wild-type PIK3CA or with PIK3CA depleted. 27489350 PubMed Arjumand et al., 2016, Oncotarget 3 accepted 8112 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2021-01-07 23:58:13 UTC https://civicdb.org/links/evidence_items/8112 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false CCND1 595 Overexpression Childhood B-cell Acute Lymphoblastic Leukemia 0080146 Prognostic Supports B Poor Outcome Reverse phase protein array (RPPA) revealed upregulation of CCND1 at diagnosis in B-ALL relapse patients (n=27) versus patients that did not relapse (n=86, p>.01). 5-year cumulative incidence of relapse analysis showed B-ALL patients within this cohort with CCND1 expression at diagnosis above the 75th percentile had a higher incidence of relapse versus those below the 75th percentile. CCND1 upregulation appears to impact relapse 500 days post initial diagnosis. 29408328 PubMed Bortolozzi et al., 2018, Biochem. Pharmacol. 2 accepted 8115 20 8 11 69455855 69469242 ENST00000227507.2 75 GRCh37 Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK's) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, and range from genomic amplification to promoter methylation changes. While Cyclin D2 has only been found to be significantly misregulated in glioma, Cyclin D1 in particular seems to be a pan-cancer actor. Cyclin D misregulation has been shown to lead to poorer outcomes in a number of studies, and currently there are no FDA-approved targeted therapies. N/A 2020-11-20 15:58:08 UTC https://civicdb.org/links/evidence_items/8115 https://civicdb.org/links/variants/20 https://civicdb.org/links/genes/8 false PML 5371 PML::RARA A216V Acute Promyelocytic Leukemia 0060318 Arsenic Trioxide Predictive Supports B Resistance Five point mutations were identified in the PML B2 domain of PML-RARA transcripts in 9 patients diagnosed with APL and resistant to arsenic. DNA from these 9 patients was cloned into flag-tagged pCag expression vectors. Immunoblotting analyses demonstrated that after the addition of arsenic, the A216V, S214L, and A216T mutants experienced no change in expression or degradation when compared to wild type cells, indicating that these mutants were not inhibited by arsenic and demonstrate resistance. Immunofluorescent measurements indicated arsenic treatment did not alter the nuclear localization pattern of mutants A216V, S214L, or A216T, but had an effect on the localization of other mutants as well as wild type cells. 26537301 PubMed Liu et al., 2016, Blood 4 accepted 8177 462 39 15 74315213 74315213 C T ENST00000268058.3 75 GRCh37 A216V in the B2 domain of PML is one of the variants found in a patient with ATRA-resistant APL. Somatic 2021-01-13 20:59:03 UTC https://civicdb.org/links/evidence_items/8177 https://civicdb.org/links/variants/462 https://civicdb.org/links/genes/39 false PIK3CA 5290 K111N Her2-receptor Positive Breast Cancer 0060079 Trastuzumab,Lapatinib,Dactolisib Substitutes Predictive Does Not Support D Resistance The BT-474 HER2 positive human breast cancer cell line, which is heterozygous for the PIK3CA K111N mutation, demonstrated strongly reduced colony formation when treated with lapatinib, trastuzumab or dactolisib alone or in combination, suggesting that K111N does not induce resistance to these drugs. 19010894 PubMed Eichhorn et al., 2008, Cancer Res. 2 accepted 8183 1234 37 3 178916946 178916946 G C ENST00000263967.3 75 GRCh37 Somatic 2021-01-28 21:30:42 UTC https://civicdb.org/links/evidence_items/8183 https://civicdb.org/links/variants/1234 https://civicdb.org/links/genes/37 false BCL2 596 G101V Chronic Lymphocytic Leukemia/small Lymphocytic Lymphoma 6354 Venetoclax Predictive Supports C Resistance The effective cohort in this study was 11 CLL patients who were first treated with ibrutinib and then on progression treated with venetoclax until progression. Patient samples were sequenced before and after progression on venetoclax. The previously described BCL2 G101V mutation was observed in 1 patient at progression 32232486 PubMed Lucas et al., 2020, Blood 2 accepted 8185 2960 59 18 60985598 60985598 C A ENST00000398117.1 75 GRCh37 Somatic 2022-05-06 04:58:07 UTC https://civicdb.org/links/evidence_items/8185 https://civicdb.org/links/variants/2960 https://civicdb.org/links/genes/59 false MYOD1 4654 L122R Spindle Cell Rhabdomyosarcoma 3260 Diagnostic Supports B Positive This study evaluated forty-nine cases of rhabdomyosarcoma (RMS) (17 cases of alveolar RMS, 10 of embryonal RMS, 21 of spindle cell and sclerosing RMS, and a single case of a pleomorphic RMS) for MYOD1 (L122R), PIK3CA (H1047), and PIK3CA (E542/E545) variants. All 10 cases that were positive for the MYOD1 (L122R) variant were either the spindle cell (3/12) or the sclerosing (7/9) subtypes of RMS, while all 10 cases of the embryonal subtype of RMS were negative for the MYOD1 (L122R) variant. The study suggests that the MYOD1 L122R variant is specific for spindle cell and sclerosing subtype of RMS (where it was detected in 10/21 cases or 48%). The study also confirmed the positive relationship between the spindle cell and the sclerosing subtypes of RMS, which both can have the same molecular abnormality (MYOD1 L122R variant) and are now considered to be the same subtype. Finally, the study confirmed the negative correlation between the aforementioned subtypes with the embryonal subtype of rhabdomyosarcoma. 27562493 PubMed Rekhi et al., 2016, Mod. Pathol. 4 accepted 8193 3032 3777 11 17741694 17741694 T G ENST00000250003.3 75 GRCh37 Somatic 2020-06-16 17:23:07 UTC https://civicdb.org/links/evidence_items/8193 https://civicdb.org/links/variants/3032 https://civicdb.org/links/genes/3777 false MYOD1 4654 L122R Spindle Cell Rhabdomyosarcoma 3260 Prognostic Supports B Poor Outcome This study evaluated forty-nine cases of rhabdomyosarcoma (RMS) (17 cases of alveolar RMS, 10 of embryonal RMS, 21 of spindle cell and sclerosing RMS, and a single case of a pleomorphic RMS) for MYOD1 (L122R), PIK3CA (H1047), and PIK3CA (E542/E545) mutations. 10/49 cases were positive for the MYOD1 (L122R) variant, and all the positive cases belonged to either spindle cell or sclerosing RMS subtype. None of the embryonal RMS cases was positive for the MYOD1 L122R variant. All cases were treated with surgical resection and either adjuvant chemotherapy, adjuvant radiotherapy, or both. On patient follow-up, the alive-with-disease ratio was higher in the adult than in the pediatric population. Furthermore, the patients positive for MYOD1 mutation showed a higher number of disease-positive states on follow-up, while the patients negative for MYOD1 mutation showed a higher number of disease-free states on follow-up. This suggests that the MYOD1 L122R variant is associated with a more aggressive clinical course, although the difference did not reach statistical significance (P=0.34). 27562493 PubMed Rekhi et al., 2016, Mod. Pathol. 2 accepted 8194 3032 3777 11 17741694 17741694 T G ENST00000250003.3 75 GRCh37 Somatic 2020-06-24 16:48:02 UTC https://civicdb.org/links/evidence_items/8194 https://civicdb.org/links/variants/3032 https://civicdb.org/links/genes/3777 false VHL 7428 Splice Site (c.340+1G>A) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma Predisposing N/A C N/A 41 non-related patients with retinal capillary hemangioma presenting in the Benjamin Franklin University Eye Clinic between 1988 to 1999 Germany were evaluated for the presence of other VHL lesions. VHL disease was diagnosed in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cyst, renal carcinoma, and pheochromocytoma), molecular genetic testing, and/or family history. VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. One patient with VHL-related retinal angiomatosis was found to have germline splicing (c.340+1G>A) mutation in the VHL gene. The other VHL lesions harbored by this patient were not specified. ACMG evidence codes: 'PP4' because the patient's phenotype is highly specific for a disease with single genetic etiology. 11148816 PubMed Kreusel et al., 2000, Graefes Arch. Clin. Exp. Ophthalmol. 3 accepted 8215 2114 58 3 10183872 10183872 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:42 UTC https://civicdb.org/links/evidence_items/8215 https://civicdb.org/links/variants/2114 https://civicdb.org/links/genes/58 false VHL 7428 Q132P (c.395A>C) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma Predisposing N/A C N/A 41 non-related patients with retinal capillary hemangioma presenting in the Benjamin Franklin University Eye Clinic between 1988 to 1999 Germany were evaluated for the presence of other VHL lesions. VHL disease was diagnosed in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cyst, renal carcinoma, and pheochromocytoma), molecular genetic testing, and/or family history. VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. One patient with VHL-related retinal capillary hemangioma was found to have germline missense VHL Q132P (c.395A>C). 3 other affected relatives were also evaluated. It's unclear which other VHL-related lesions were identified in this patient. ACMG evidence codes: 'PP4' because the patients' phenotypes and family history are highly specific for a disease with single genetic etiology. 11148816 PubMed Kreusel et al., 2000, Graefes Arch. Clin. Exp. Ophthalmol. 3 accepted 8218 2125 58 3 10188252 10188252 A C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/8218 https://civicdb.org/links/variants/2125 https://civicdb.org/links/genes/58 false VHL 7428 R161* (c.481C>T) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma Predisposing N/A C N/A 41 non-related patients with retinal capillary hemangioma presenting in the Benjamin Franklin University Eye Clinic between 1988 to 1999 Germany were evaluated for the presence of other VHL lesions. VHL disease was diagnosed in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cyst, renal carcinoma, and pheochromocytoma), molecular genetic testing, and/or family history. VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. Two patients with VHL-related retinal capillary hemangioma were found to have germline missense VHL R161* (c.481C>T). 1 other affected relative was also evaluated for one of the patients. Other VHL lesions harbored by the patients were not specified. ACMG evidence codes: 'PP4' because the patients' phenotypes and family history are highly specific for a disease with single genetic etiology. 11148816 PubMed Kreusel et al., 2000, Graefes Arch. Clin. Exp. Ophthalmol. 3 accepted 8222 1804 58 3 10191488 10191488 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:48 UTC https://civicdb.org/links/evidence_items/8222 https://civicdb.org/links/variants/1804 https://civicdb.org/links/genes/58 false PDGFRB 5159 EBF1::PDGFRB B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Chemotherapy,Imatinib Combination Predictive Supports C Sensitivity/Response A 9 year old girl with B-lymphoblastic leukemia/ lymphoma (2016 WHO) relapsed 15 months post-maintenance chemotherapy. FISH and genomic analysis detected the EBF1-PDGFRB fusion (exon 11 with Exon14). The patient was treated with induction [fludarabine, idarubicin and cytarabine] therapy followed by additional chemotherapy (cyclophosphamide, adriamycin, vincristine, and dexamethasone followed by high-dose methotrexate and cytarabine) plus tyrosine kinase inhibitor (TKI, imatinib). Imatinib was stopped 10 days before cord blood transplant (CBT) with reduced intensity conditional and re-initiated on day 47 until 12 months post-transplant. The EBF1-PDGFRB transcript level measured using reverse-transcriptase polymerase chain reaction remained below detection limit (<2.5x102 copies/ microgram RNA) for 36 months post CBT. Furthermore, the patient maintained molecular remission during the 24 months post-CBT and the 12 months following completion of TKI administration, based on minimal residual disease (MRD) testing conducted every 6 months. 32068648 PubMed Sakurai et al., 2020, J. Pediatr. Hematol. Oncol. 3 accepted 8260 535 4176 5 158134987 158526769 ENST00000517373.1 5 149493400 149505140 ENST00000261799.4 75 GRCh37 EBF1-PDGFRB fusions are associated with Ph-like acute lymphoblastic leukemia lacking the BCR-ABL fusion. Case reports have shown positive responses to imatinib treatment. Somatic 2020-08-24 21:56:32 UTC https://civicdb.org/links/evidence_items/8260 https://civicdb.org/links/variants/535 https://civicdb.org/links/genes/4176 false PIK3CA 5290 Amplification Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Supports D Resistance HER2-positive breast cancer cell line BT-474 (heterozygous for PIK3CA K111N) was retrovirally transduced with wildtype PIK3CA and treated with trastuzumab. PIK3CA amplification diminished the growth inhibitory effects of trastuzumab monotherapy in comparison to the inhibition of controls without PIK3CA overexpression. 19010894 PubMed Eichhorn et al., 2008, Cancer Res. 2 accepted 8267 212 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 Somatic 2021-01-28 21:56:50 UTC https://civicdb.org/links/evidence_items/8267 https://civicdb.org/links/variants/212 https://civicdb.org/links/genes/37 false PIK3CA 5290 Amplification Her2-receptor Positive Breast Cancer 0060079 Lapatinib,Dactolisib Substitutes Predictive Supports D Sensitivity/Response This preclinical study tested the sensitivity of HER2-positive breast cancer cell line BT-474 (heterozygous for PIK3CA K111N) retrovirally transduced with wildtype PIK3CA to NVP-BEZ235 (dactolisib; a dual PI3K/mTOR inhibitor), lapatinib and trastuzumab. The study found that dactolisib and lapatinib were effective in inhibiting outgrowth of PIK3CA amplified cells as monotherapies. Combination therapy produced similar abrogation of growth for PIK3CA amplified cells. Additionally, growth of untransduced BT-474 control cells was prevented by treatment with any monotherapy or combination of lapatinib or dactolisib. 19010894 PubMed Eichhorn et al., 2008, Cancer Res. 2 accepted 8271 212 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 Somatic 2021-01-28 21:46:45 UTC https://civicdb.org/links/evidence_items/8271 https://civicdb.org/links/variants/212 https://civicdb.org/links/genes/37 false PTEN 5728 Loss Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Supports D Resistance In a preclinical study, efficacy of trastuzumab monotherapy was evaluated in vitro against HER2 amplified human breast cancer cell line BT474 (heterozygous for PIK3CA K111N) with shRNA-induced PTEN expression loss. Authors found that loss of PTEN expression induced resistance to trastuzumab as assessed by colony formation assay compared to PTEN expressing control cells. Among trastuzumab treated cells, concentration of phosphorylated AKT (S473 and T308) was higher in PTEN knockdown cells compared to PTEN expression cells, by western blot. 19010894 PubMed Eichhorn et al., 2008, Cancer Res. 2 accepted 8274 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2021-01-28 22:33:26 UTC https://civicdb.org/links/evidence_items/8274 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PTEN 5728 Loss Her2-receptor Positive Breast Cancer 0060079 Lapatinib Predictive Supports D Resistance In a preclinical study, efficacy of trastuzumab monotherapy was evaluated in vitro against HER2 amplified human breast cancer cell line BT474 (heterozygous for PIK3CA K111N) with shRNA-induced PTEN expression loss. Authors found that loss of PTEN expression induced resistance to lapatinib as assessed by colony formation assay compared to PTEN expressing control cells. Among lapatinib treated cells, concentration of phosphorylated AKT and ERK was substantially higher in cells with PTEN loss compared to PTEN expressing cells, by western blot. Furthermore, athymic nude mice injected with PTEN non-expressing BT474 cells had significantly higher mean tumor volume following lapatinib monotherapy compared to mice injected with PTEN expressing BT474. Authors conclude that loss of PTEN expression confers resistance to lapatinib in HER2 positive breast cancer cells. 19010894 PubMed Eichhorn et al., 2008, Cancer Res. 4 accepted 8275 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2021-01-28 22:39:00 UTC https://civicdb.org/links/evidence_items/8275 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PTEN 5728 Loss Her2-receptor Positive Breast Cancer 0060079 Dactolisib Predictive Supports D Resistance In a preclinical study, efficacy of dactolisib monotherapy was evaluated in vitro against HER2 amplified human breast cancer cell line BT474 (heterozygous for PIK3CA K111N) with shRNA-induced PTEN expression loss. PTEN loss resulted in partial rescue from the strong dactolisib induced reduction of colony formation that was seen in BT474 cells with unperturbed PTEN. Among cells treated with dactolisib (100nmol/L), those lacking PTEN expression demonstrated higher concentrations of phosphorylated AKT (S473) and phosphorylated ERK compared to PTEN expressing cells. 19010894 PubMed Eichhorn et al., 2008, Cancer Res. 2 accepted 8276 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2021-01-28 22:53:18 UTC https://civicdb.org/links/evidence_items/8276 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PTEN 5728 Loss Her2-receptor Positive Breast Cancer 0060079 Dactolisib,Lapatinib Combination Predictive Does Not Support D Resistance In a preclinical study, efficacy of NVP-BEZ235 (dactolisib; a dual PI3K/mTOR inhibitor) and lapatinib combination therapy was evaluated in vitro against HER2 amplified breast cancer cell line BT474 (heterozygous for PIK3CA K111N) with shRNA-induced PTEN expression loss. Authors found that while PTEN loss induced resistance to lapatinib, combination with dactolisib produced an additive anti-proliferation effect. Western blot analysis of lapatinib and dactolisib combination treated cells showed a decrease in phosphorylated AKT and S6 relative to untreated and lapatinib treated control cells. Authors concluded that addition of dactolisib to lapatinib overcame PTEN loss induced lapatinib resistance in HER-2 positive breast cancer cells. 19010894 PubMed Eichhorn et al., 2008, Cancer Res. 2 accepted 8278 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2021-01-28 22:11:05 UTC https://civicdb.org/links/evidence_items/8278 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false PTEN 5728 Loss Her2-receptor Positive Breast Cancer 0060079 Trastuzumab,Dactolisib Combination Predictive Does Not Support D Resistance In a preclinical study, efficacy of NVP-BEZ235 (dactolisib; a dual PI3K/mTOR inhibitor) and trastuzumab combination therapy was evaluated in vitro against HER2 amplified human breast cancer cell line BT474 (heterozygous for PIK3CA K111N) with shRNA-induced PTEN expression loss. Authors found that while PTEN loss induced resistance to trastuzumab, combination with dactolisib produced an additive anti-proliferation effect. 19010894 PubMed Eichhorn et al., 2008, Cancer Res. 2 accepted 8279 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2021-01-28 21:59:30 UTC https://civicdb.org/links/evidence_items/8279 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false MYOD1 4654 L122R Spindle Cell Rhabdomyosarcoma 3260 Prognostic Supports B Poor Outcome This study examined 17 cases of spindle cell/sclerosing rhabdomyosarcoma (SC/SRMS) for the presence of MYOD1 variants. 12 cases harbored a MYOD-1 mutation, of which 8 cases were homozygous for p.L122R, 3 were heterozygous for p.L122R, and 1 was heterozygous for a novel p.E118K variant. There was one case of predominantly spindle cell rhabdomyosarcoma with the MYOD-1 mutation that also contained a PIK3CA mutation. The case with both MYOD-1 and PIK3CA mutations consisted histologically of lipoblasts within focally myxoid stroma, thus demonstrating that the PIK3CA mutation was a secondary aberration while MYOD-1 was the primary neomorphic mutation. On clinical follow-up, seven of the MYOD-1 variant cases experienced local recurrences and/or metastatic disease. In a median of a 13.5 month follow-up, there was 1 patient who passed away, 8 patients who were alive with the disease, and 3 patients who were alive without the disease; there was no correlation with the type of treatment that the patients had received. This supports aggressive clinical course for SC/SRMS positive for MYOD-1 variants, regardless of the presence of a concurrent PIK3CA mutation. 30604891 PubMed Tsai et al., 2019, Histopathology 3 accepted 8313 3032 3777 11 17741694 17741694 T G ENST00000250003.3 75 GRCh37 Somatic 2020-06-24 16:47:21 UTC https://civicdb.org/links/evidence_items/8313 https://civicdb.org/links/variants/3032 https://civicdb.org/links/genes/3777 false FGFR3 2261 R248C Cancer 162 R3Mab Predictive Does Not Support D Resistance In this preclinical study, R3Mab (a monoclonal antibody specific to FGFR3) inhibited ligand-independent proliferation in Ba/F3 cells expressing common bladder carcinoma variant: FGFR3 R248C. Authors note that R3Mab similarly inhibited proliferation of FGF1 stimulated Ba/F3 cells expressing wildtype FGFR3 and bladder carcinoma cell lines expressing wildtype FGFR3 (RT112 and RT4). They conclude that R3Mab inhibits wildtype and mutant FGFR3 by inhibiting receptor dimerization. 19381019 PubMed Qing et al., 2009, J. Clin. Invest. 3 accepted 8321 2403 23 4 1803564 1803564 C T ENST00000340107.4 75 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. Somatic 2022-06-01 17:27:05 UTC https://civicdb.org/links/evidence_items/8321 https://civicdb.org/links/variants/2403 https://civicdb.org/links/genes/23 false NTRK3 4916 ETV6::NTRK3 Congenital Fibrosarcoma 8418 Diagnostic Supports A Positive This is the first study showing the ETV6-NTRK3 gene fusion in congenital fibrosarcoma (CFS). Using cytogenetic and FISH analyses, a novel t(12;15)(p13;q25) rearrangement was identified in CFS cases (3 of 4, including 1 case likely presenting overgrowth of normal fibroblasts). Mapping of breakpoints and mRNA analysis revealed that the translocation gives rise to the ETV6-NTRK3 fusion transcript, consisting of the HLH dimerization domain of ETV6 fused to the kinase domain of NTRK3. This aberration was absent in adult-type fibrosarcoma (ATFS, 2 cases) and infantile fibromatosis (IFB, 15 cases). This is the first study describing the involvement of NTRK proteins in human oncogenesis and ETV6 gene fusion in solid tumors and proposing ETV6-NTRK3 as a diagnostic biomarker for CFS. 9462753 PubMed Knezevich et al., 1998, Nat. Genet. 4 accepted 8332 801 3985 12 11802788 12022903 ENST00000396373.4 15 88483984 88418230 ENST00000394480.2 75 GRCh37 Somatic 2022-07-10 10:53:46 UTC https://civicdb.org/links/evidence_items/8332 https://civicdb.org/links/variants/801 https://civicdb.org/links/genes/3985 false FLT3 2322 Y842C Acute Myeloid Leukemia 9119 FLT3/ABL/Aurora Kinase Inhibitor KW-2449 Predictive Supports D Resistance The authors used saturation mutagenesis of FLT3/ITD followed by selection of transfected cells in FLT3 TKI. The FLT3/ITD Y842C mutation produced high-level resistance to KW2449, sorafenib, sunitinib and AGS324 in vitro but remained sensitive to lestaurtinib and midostaurin. Balb/c mice transplanted with the FLT3/ITD Y842C mutation confirmed resistance to sorafenib in vivo but not to lestaurtinib. 22858906 PubMed Williams et al., 2013, Leukemia 3 accepted 8336 3070 24 Somatic 2020-08-13 05:07:50 UTC https://civicdb.org/links/evidence_items/8336 https://civicdb.org/links/variants/3070 https://civicdb.org/links/genes/24 false FLT3 2322 Y842C Acute Myeloid Leukemia 9119 Sorafenib Predictive Supports D Resistance The authors used saturation mutagenesis of FLT3/ITD followed by selection of transfected cells in FLT3 TKI. The FLT3/ITD Y842C mutation produced high-level resistance to KW2449, sorafenib, sunitinib and AGS324 in vitro but remained sensitive to lestaurtinib and midostaurin. Balb/c mice transplanted with the FLT3/ITD Y842C mutation confirmed resistance to sorafenib in vivo but not to lestaurtinib. 22858906 PubMed Williams et al., 2013, Leukemia 4 accepted 8337 3070 24 Somatic 2020-08-13 05:07:33 UTC https://civicdb.org/links/evidence_items/8337 https://civicdb.org/links/variants/3070 https://civicdb.org/links/genes/24 false FLT3 2322 Y842C Acute Myeloid Leukemia 9119 Sunitinib Predictive Supports D Resistance The authors used saturation mutagenesis of FLT3/ITD followed by selection of transfected cells in FLT3 TKI. The FLT3/ITD Y842C mutation produced high-level resistance to KW2449, sorafenib, sunitinib and AGS324 in vitro but remained sensitive to lestaurtinib and midostaurin. Balb/c mice transplanted with the FLT3/ITD Y842C mutation confirmed resistance to sorafenib in vivo but not to lestaurtinib. 22858906 PubMed Williams et al., 2013, Leukemia 3 accepted 8338 3070 24 Somatic 2020-08-13 05:07:45 UTC https://civicdb.org/links/evidence_items/8338 https://civicdb.org/links/variants/3070 https://civicdb.org/links/genes/24 false FLT3 2322 Y842C Acute Myeloid Leukemia 9119 Lestaurtinib Predictive Supports D Sensitivity/Response A screen using saturation mutagenesis of FLT3/ITD followed by selection of transfected TF1 cells in FLT3 TKIs identified Y842C. Cytotoxicity assessed by MTT demonstrated Ba/F3 cells expressing FLT3/ITD Y842C treated with Lestaurtinib responded similarly to FLT3/ITD control cells (IC50: 2nM). Immunoblotting revealed Lestaurtinib inhibited FLT3 autophosphorylation and the activation of downstream pathways in Ba/F3 FLT3/ITD Y842C and control cells. These FLT3/ITD Y842C cells also responded to Lestaurtinib treatment in vivo after transplantation into Balb/c mice as measured by minimal bioluminescence and reduced spleen weight compared to vehicle and sorafenib treated mice. 22858906 PubMed Williams et al., 2013, Leukemia 4 accepted 8339 3070 24 Somatic 2021-08-28 00:32:22 UTC https://civicdb.org/links/evidence_items/8339 https://civicdb.org/links/variants/3070 https://civicdb.org/links/genes/24 false FLT3 2322 Y842C Acute Myeloid Leukemia 9119 Midostaurin Predictive Supports D Sensitivity/Response A screen using saturation mutagenesis of FLT3/ITD followed by selection of transfected TF1 cells in FLT3 TKIs identified Y842C. Cytotoxicity assessed by MTT demonstrated Ba/F3 cells expressing FLT3/ITD Y842C treated with Midostaurin responded similarly to FLT3/ITD control cells (IC50: 4nM). Like in FLT3/ITD control cells, immunoblotting showed Midostaurin inhibited FLT3 autophosphorylation and the activation of downstream pathways in Ba/F3 FLT3/ITD Y842C cells. 22858906 PubMed Williams et al., 2013, Leukemia 3 accepted 8340 3070 24 Somatic 2021-08-28 00:15:26 UTC https://civicdb.org/links/evidence_items/8340 https://civicdb.org/links/variants/3070 https://civicdb.org/links/genes/24 false FLT3 2322 F691L Acute Myeloid Leukemia 9119 Lestaurtinib Predictive Supports D Resistance A screen using saturation mutagenesis of FLT3/ITD followed by selection of transfected TF1 cells in FLT3 TKIs identified F691L. Cytotoxicity assessed by MTT demonstrated Ba/F3 cells expressing FLT3/ITD F691L conferred moderate resistance to lestaurtinib (IC50: 8nM) compared to FLT3/ITD control cells (IC50: 2nM). Immunoblotting showed lestaurtinib was able to partially inhibit FLT3 autophosphorylation and the activation of downstream pathways in Ba/F3 FLT3/ITD F691L cells. Structural modeling revealed F691 to be located in the ATP binding cleft. The authors hypothesize this amino acid change weakens inhibitor affinity as this residue likely makes direct contact with FLT3 TKIs. 22858906 PubMed Williams et al., 2013, Leukemia 3 accepted 8341 3071 24 Somatic 2021-08-28 00:05:46 UTC https://civicdb.org/links/evidence_items/8341 https://civicdb.org/links/variants/3071 https://civicdb.org/links/genes/24 false FLT3 2322 F691L Acute Myeloid Leukemia 9119 Midostaurin Predictive Supports D Resistance A screen using saturation mutagenesis of FLT3/ITD followed by selection of transfected TF1 cells in the FLT3 TKI midostaurin identified F691L in 1 of 400 clones. Cytotoxicity assessed by MTT demonstrated Ba/F3 cells expressing FLT3/ITD F691L conferred moderate resistance to midostaurin (IC50: 18nM) compared to FLT3/ITD control cells (IC50: 4nM). Immunoblotting showed midostaurin was able to partially inhibit FLT3 autophosphorylation and the activation of downstream pathways in Ba/F3 FLT3/ITD F691L cells. Structural modeling revealed F691 to be located in the ATP binding cleft. The authors hypothesize this amino acid change weakens inhibitor affinity as this residue likely makes direct contact with FLT3 TKIs. 22858906 PubMed Williams et al., 2013, Leukemia 3 accepted 8342 3071 24 Somatic 2021-06-23 22:24:54 UTC https://civicdb.org/links/evidence_items/8342 https://civicdb.org/links/variants/3071 https://civicdb.org/links/genes/24 false TP53 7157 Mutation Medulloblastoma SHH Activated 0080703 Prognostic Supports B Poor Outcome In the childhood (≥4.3 years) SHH-MB subgroup, TP53 mutations (n=13) are associated with shorter progression-free survival (PFS) compared to the no mutation group (n=35) (HR, 3.47; 95% CI, 1.29 to 9.3; p<0.014). 28545823 PubMed Schwalbe et al., 2017, Lancet Oncol. 5 accepted 8347 222 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 N/A 2022-07-22 21:39:15 UTC https://civicdb.org/links/evidence_items/8347 https://civicdb.org/links/variants/222 https://civicdb.org/links/genes/45 false FLT3 2322 D835I Acute Myeloid Leukemia 9119 Gilteritinib Predictive Supports D Sensitivity/Response A 62-year-old female patient (AML5) was refractory to conventional chemotherapy and developed disease progression to quizartinib due to a D835I mutation. Using MTT to measure cytotoxicity, gilteritinib inhibited this patient’s relapse sample. Additionally, immunoblot demonstrated gilteritinib inhibited FLT3 phosphoryaltion at a concentration of 20 nM in the patient dereivd relapse cells. 27908881 PubMed Lee et al., 2017, Blood 2 accepted 8351 3075 24 Somatic 2020-07-15 18:41:06 UTC https://civicdb.org/links/evidence_items/8351 https://civicdb.org/links/variants/3075 https://civicdb.org/links/genes/24 false PIK3CA 5290 H1047R Colorectal Cancer 9256 Vemurafenib,Akt Inhibitor MK2206 Combination Predictive Supports D Sensitivity/Response Resistance of RKO cells, which harbor BRAF V600E (a known vemurafenib sensitizing mutation) and PIK3CA H1047R, to vemurafenib monotherapy was abrogated by the addition of pan-AKT inhibitor MK-2206 in vitro and in vivo. In vitro, vemurafenib and MK-2206 combination treatment of RKO cells resulted in substantially greater proliferation inhibition than either agent in isolation or untreated control cells (combination index score = 0.691 at EC50). Synergistic effects of vemurafenib and MK-2206 on RKO cells was confirmed in vivo via xenografts on an athymic mouse model, where mice treated with vemurafenib monotherapy experienced minimal tumor growth inhibition (25%), mice treated with MK-2206 monotherapy experienced modest tumor growth inhibition (37%), and mice treated with both achieved 87% tumor growth inhibition compared to vehicle treated control mice (P <0.001). 22180495 PubMed Yang et al., 2012, Cancer Res. 3 accepted 8364 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2020-06-18 22:23:05 UTC https://civicdb.org/links/evidence_items/8364 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false KRAS 3845 Exon 2 Mutation Colorectal Cancer 9256 Vemurafenib Predictive Does Not Support D Sensitivity/Response This preclinical study examined vemurafenib efficacy on various colorectal cancer cell lines and in vivo via mouse xenograft experiments. Three cell lines harbored KRAS exon 2 mutations and wt BRAF: HCT 116 (KRAS G13D), SW620 (KRAS G12V), LOVO (KRAS G13D). Cell lines with KRAS exon 2 mutations were insensitive to vemurafenib compare those with wt KRAS and BRAF V600E (a known vemurafenib sensitizing mutation; HT29, Colo205, Colo471, LS411N; IC50s >10uM vs 0.025-0.35 uM). Nude, athymic mice with HCT116 or LoVo xenografts did not experience tumor inhibition when treated with vemurafenib. 22180495 PubMed Yang et al., 2012, Cancer Res. 3 accepted 8367 75 30 12 25398208 25398329 ENST00000256078.4 75 GRCh37 Exon 2 mutations have been associated with reduced response rates or resistance to EGFR inhibitors in non-small cell lung and colorectal cancer. The NCCN guidelines for colorectal cancer contain recommendations that the targeted therapies cetuximab and panitumumab should only be used in the context of wild type KRAS. Somatic 2020-06-18 22:54:11 UTC https://civicdb.org/links/evidence_items/8367 https://civicdb.org/links/variants/75 https://civicdb.org/links/genes/30 false BCL2 596 F104I Follicular Lymphoma 0050873 Venetoclax Predictive Supports C Resistance This study identified BCL2 F104I mutation in one Follicular Lymphoma patient who developed resistance to venetoclax. Codon 104 is located at the venetoclax binding site of BCL2. 31234236 PubMed Blombery et al., 2019, Br. J. Haematol. 2 accepted 8375 3082 59 18 60985590 60985590 A T ENST00000398117.1 75 GRCh37 Somatic 2020-09-02 23:38:09 UTC https://civicdb.org/links/evidence_items/8375 https://civicdb.org/links/variants/3082 https://civicdb.org/links/genes/59 false BCL2 596 F104I Follicular Lymphoma 0050873 Venetoclax Predictive Supports D Resistance Rs4;11 cells overexpressing BCL2 F104I exhibited >40-fold greater resistance to venetoclax after 24-hour treatment (IC50 not reached) than Rs4;11 overexpressing BCL2 WT cells as determined by cell titer glo measured cytotoxicity assays. Plasmon resonance protein binding assays demonstrated marked impairment (300 fold) of venetoclax binding to F104I (Ki=5.9 nM) veresus WT (Ki=.018nM). The authors pointed out reduction in binding was a similar magnitude as that observed previously with the BCL2 G101V and F104L. 31234236 PubMed Blombery et al., 2019, Br. J. Haematol. 3 accepted 8376 3082 59 18 60985590 60985590 A T ENST00000398117.1 75 GRCh37 Somatic 2021-06-15 20:53:24 UTC https://civicdb.org/links/evidence_items/8376 https://civicdb.org/links/variants/3082 https://civicdb.org/links/genes/59 false VHL 7428 R167W (c.499C>T) Von Hippel-Lindau Disease 14175 Neoplasm of the adrenal gland Predisposing N/A C N/A The 10 1/2 year old patient was diagnosed with adrenal incidentaloma. He had intermittent abdominal pain for 6 months. His blood pressure was normal. A CT scan showed a left adrenal solid tumor (3x3cm) with no calcifications and I-MIBG scintiography was normal. He underwent an adrenalectomy. He was found to have a point mutation in exon 3 (Arg167Trp) but neither parent had this mutation. Brain and spinal cord MRI, ophthalmoscopy, whole body CT scan and ultrasonography of the testes, showed no abnormalities. ACMG evidence codes: 'PS2' since both parents are tested and do not present with the variant (de novo), 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology. 16042317 PubMed Pozo et al., 2005, J. Pediatr. Endocrinol. Metab. 3 accepted 8469 1747 58 3 10191506 10191506 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:43 UTC https://civicdb.org/links/evidence_items/8469 https://civicdb.org/links/variants/1747 https://civicdb.org/links/genes/58 false VHL 7428 L184P (c.551T>C) Von Hippel-Lindau Disease 14175 Retinal vascular proliferation,Morphological central nervous system abnormality,Retinal capillary hemangioma,Abnormality of the pancreas,Abnormal renal morphology Predisposing N/A C N/A Of 14 patients with retinal vascular proliferation and known family history of VHL disease, 12 patients were enrolled in an approved study protocol at the National Cancer Institute. 11 of these patients underwent genetic testing and were found to have mutations in the VHL gene. Patient 1 presented with retinal capillary hemangioblastoma (RCH) in her left eye at age the age of 13, which was treated with radiation. At age 62 years, this eye had good visual acuity (20/20) without any RCHs. As of her last visit, patient 1 also presented with abnormalities in the CNS, pancreas and kidney. She was found to have the L184P (c.551T>C) mutation. Her last known age was 69 years old. ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology. 18474773 PubMed Wong et al., 2008, Arch. Ophthalmol. 3 accepted 8491 1776 58 3 10191558 10191558 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/8491 https://civicdb.org/links/variants/1776 https://civicdb.org/links/genes/58 false BRAF 673 V600E Colorectal Cancer 9256 Irinotecan,Vemurafenib,Cetuximab Combination Predictive Supports D Sensitivity/Response This in vivo study examined the efficacy of various treatments on athymic nude mice xenografted with colorectal cancer HT29 cells, which harbor BRAF V600E. The authors sought to understand whether the addition of vemurafenib (a BRAF V600E inhibitor) to agents approved for the treatment of metastatic colorectal cancer increased therapeutic efficacy, and which combinations worked best. Irinotecan, cetuximab and vemurafenib combination therapy resulted in >100% tumor growth inhibition (TGI) and 250% increased lifespan (ILS) compared to vehicle treated controls. Of the ten treated mice, nine experienced partial response and one experienced a complete response. Compared to all doublet and single agent combinations of vemurafenib, irinotecan, and cetuximab, triplet therapy produced the best TGI and ILS (p<0.05, p <0.0001 for all comparisons). 22180495 PubMed Yang et al., 2012, Cancer Res. 3 accepted 8506 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-07-09 21:30:05 UTC https://civicdb.org/links/evidence_items/8506 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false BRAF 673 V600E Colorectal Cancer 9256 Vemurafenib,Erlotinib Combination Predictive Supports D Sensitivity/Response This in vivo study examined the efficacy of various treatments on athymic nude mice xenografted with colorectal cancer HT29 cells, which harbor BRAF V600E. The authors sought to understand whether the addition of vemurafenib (a BRAF V600E inhibitor) to agents approved for the treatment of metastatic colorectal cancer increased therapeutic efficacy, and which combinations worked best. Erlotinib and vemurafenib combination therapy resulted in >100% tumor growth inhibition (TGI) and 142% increased lifespan (ILS) compared to vehicle treated controls. Of ten treated mice, 9 experienced partial response. Doublet therapy produced a greater increase in TGI and ILS than either agent in isolation. 22180495 PubMed Yang et al., 2012, Cancer Res. 3 accepted 8507 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2020-07-09 21:32:43 UTC https://civicdb.org/links/evidence_items/8507 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false ABL1 25 BCR::ABL Y253F Chronic Myeloid Leukemia 8552 Imatinib Predictive Supports C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. An AP patient had a complete hematologic response. After 9 months of therapy, the patient progressed returning to chronic phase. Concurrently, the Y253F and E255V variants were found in ~50% and ~50% of BCR-ABL1 transcripts, respectively. Imatinib was withdrawn at 10 months and the patient died 14 months after treatment initiation. 12623848 PubMed Branford et al., 2003, Blood 3 accepted 8508 2909 4 Somatic 2020-07-10 23:52:37 UTC https://civicdb.org/links/evidence_items/8508 https://civicdb.org/links/variants/2909 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL F317L Chronic Myeloid Leukemia 8552 Imatinib Predictive Does Not Support C Resistance In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A late-chronic phase patient had a complete cytogenetic response which was maintained despite detection of the F317L variant in ~75% of transcripts at month 18. 12623848 PubMed Branford et al., 2003, Blood 2 accepted 8509 241 4 9 133748288 133748288 T C ENST00000318560.5 75 GRCh37 BCR-ABL F317L, like the similar BCR-ABL T315I mutation, is becoming a common clinical marker for resistance to front-line therapies in CML. It has been shown to confer resistance to dasatinib, but responds well to ponatinib and other second generation inhibitors. Somatic 2020-07-11 00:38:59 UTC https://civicdb.org/links/evidence_items/8509 https://civicdb.org/links/variants/241 https://civicdb.org/links/genes/4 false FLT3 2322 D835H Acute Myeloid Leukemia 9119 Gilteritinib Predictive Supports D Sensitivity/Response Ba/F3 cells were transfected to express FLT3-ITD or FLT3 tyrosine kinase domain mutations. Immunoblots revealed gilteritinib IC50s of 2nM, 1.6nM, and 5nM for D835H, FLT3-ITD, and wildtype (cell line: SEMK2) cells, respectively. 27908881 PubMed Lee et al., 2017, Blood 2 accepted 8517 612 24 13 28592642 28592642 C G ENST00000241453.7 75 GRCh37 Somatic 2021-06-08 02:01:39 UTC https://civicdb.org/links/evidence_items/8517 https://civicdb.org/links/variants/612 https://civicdb.org/links/genes/24 false FLT3 2322 D835V Acute Myeloid Leukemia 9119 Gilteritinib Predictive Supports D Sensitivity/Response Ba/F3 cells were transfected to express FLT3-ITD or FLT3 tyrosine kinase domain mutations. Immunoblots revealed gilteritinib IC50s of 0.7nM, 1.6nM, and 5nM for D835H, FLT3-ITD, and wildtype (cell line: SEMK2) cells, respectively. 27908881 PubMed Lee et al., 2017, Blood 2 accepted 8518 1302 24 13 28592641 28592641 T A ENST00000241453.7 75 GRCh37 Somatic 2021-06-08 01:44:12 UTC https://civicdb.org/links/evidence_items/8518 https://civicdb.org/links/variants/1302 https://civicdb.org/links/genes/24 false PIK3CA 5290 Mutation Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Emtansine Predictive Does Not Support B Resistance In a phase 3 clinical trial (NCT00829166), metastatic HER-2 amplified breast cancer patients whose tumors harbored PIK3CA mutations treated with ado-trastuzumab emtansine (T-DM1; n=40) were associated with similar median progression free survival (PFS), overall response rate (ORR), and overall survival (OS) compared to patients whose tumors harbored wild-type PIK3CA (n=93; PFS: 10.9 vs. 9.8 months, ORR: 50% vs 47.4%, OS not reached for either group). Of PIK3CA mutant HER2 patients, those treated with T-DM1 experienced a greater decrease in disease progression than those treated with standard of care capecitabine + lapatinib. In vitro, HER2 amplified cell lines with various PIK3CA mutations were associated with similar sensitivity to T-DM1 as PIK3CA wild-type cell line SK-BR-3. In mouse xenograft models of various PIK3CA mutations (H1047R, E545K, or K111N), tumor regression or complete tumor suppression >20 days was seen following a single dose >10mg/kg for all models. 26920887 PubMed Baselga et al., 2016, Clin. Cancer Res. 3 accepted 8536 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2020-08-20 23:39:37 UTC https://civicdb.org/links/evidence_items/8536 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PIK3CA 5290 E545K Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Supports D Resistance As part of a pre-clinical experiment, the efficacy of trastuzumab was evaluated against various HER2 positive cell lines. MCF7-neo/HER2 cell line harboring PIK3CA E545K was associated with resistance to trastuzumab compared to PIK3CA wild-type cell line SK-BR-3, at all concentrations tested (0-10 ug/mL). 26920887 PubMed Baselga et al., 2016, Clin. Cancer Res. 2 accepted 8547 104 37 3 178936091 178936091 G A ENST00000263967.3 75 GRCh37 PIK3CA E545K/E542K are the second most recurrent PIK3CA mutations in breast cancer, and are highly recurrent mutations in many other cancer types. E545K, and possibly the other mutations in the E545 region, may present patients with a poorer prognosis than patients with either patients with other PIK3CA variant or wild-type PIK3CA. There is also data to suggest that E545/542 mutations may confer resistance to EGFR inhibitors like cetuximab. While very prevalent, targeted therapies for variants in PIK3CA are still in early clinical trial phases. Somatic 2020-08-14 20:55:56 UTC https://civicdb.org/links/evidence_items/8547 https://civicdb.org/links/variants/104 https://civicdb.org/links/genes/37 false PIK3CA 5290 H1047R Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Supports D Resistance As part of a pre-clinical experiment, the efficacy of trastuzumab was evaluated against various HER2 positive cell lines. CC1954 and KPL-4 cell lines expressing PIK3CA H1047R were associated with resistance to trastuzumab compared to PIK3CA wild-type cell line SK-BR-3, at all concentrations tested (0-10 ug/mL). 26920887 PubMed Baselga et al., 2016, Clin. Cancer Res. 2 accepted 8548 107 37 3 178952085 178952085 A G ENST00000263967.3 75 GRCh37 PIK3CA H1047R is one of the most recurrent single nucleotide variants in cancer, especially breast cancer. Of PIK3CA-mutant breast cancers, over half harbor this mutation. Meta-analyses have shown that patients harboring this mutation may have worse overall survival, but other studies have shown no difference between H1047R and other PIK3CA mutants from a prognostic standpoint. While very prevalent, targeted therapies for this particular mutation are still in early clinical trial phases. Somatic 2020-08-14 20:59:19 UTC https://civicdb.org/links/evidence_items/8548 https://civicdb.org/links/variants/107 https://civicdb.org/links/genes/37 false PIK3CA 5290 C420R Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Supports D Resistance As part of a pre-clinical experiment, the efficacy of trastuzumab was evaluated against various HER2 positive cell lines. EFM-192A cell line expressing PIK3CA C420R was associated with resistance to trastuzumab compared to PIK3CA wild-type cell line SK-BR-3, at all concentrations tested (0-10 ug/mL). 26920887 PubMed Baselga et al., 2016, Clin. Cancer Res. 2 accepted 8549 931 37 3 178927980 178927980 T C ENST00000263967.3 75 GRCh37 Somatic 2020-08-14 21:07:19 UTC https://civicdb.org/links/evidence_items/8549 https://civicdb.org/links/variants/931 https://civicdb.org/links/genes/37 false FGFR3 2261 S249C Transitional Cell Carcinoma 2671 Cisplatin Predictive Supports D Resistance Bladder cancer cell line 97-7 expressing endogenous FGFR3 S249C (IC50 44.6ug/ml) was resistant to cisplatin compared to two FGFR3 wild-type cell lines, 5637 (IC50 2.07ug/ml) and T24 (IC50 1.58ug/ml) as shown by a CCK-8 colorimetric cytotoxicity. Western blot revealed the ratio of phosphorylated-Akt/total Akt was higher in the 97-7 cells than in the wild-type cells, which was reversed by siRNA knockdown of FGFR3. Inhibition of Akt signaling by treatment with GDC0068 or LY294002 increased the cisplatin sensitivity of 97-7 cells (IC50 4.17ug/ml & 8.91ug/ml respectively). 31316618 PubMed Xie et al., 2019, Exp Ther Med 3 accepted 8642 628 23 4 1803568 1803568 C G ENST00000340107.4 75 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. Somatic 2020-11-20 15:48:06 UTC https://civicdb.org/links/evidence_items/8642 https://civicdb.org/links/variants/628 https://civicdb.org/links/genes/23 false VHL 7428 F76del (c.227_229del) Von Hippel-Lindau Disease 14175 Pancreatic cysts,Cerebellar hemangioblastoma,Renal cyst Predisposing N/A C N/A Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. A mutation, F76del(c.227_229del) (noted as g.941_943delTCT in the paper originally) was found in a patient with cerebellar hemangioblastomas, renal cyst, and pancreatic cyst, the pateints age on onset was 31 years old. No family history was mentioned. ACMG evidence code: "flag for PP4" because patients phenotype is specific for the disease. 14722919 PubMed Ruiz-Llorente et al., 2004, Hum. Mutat. 2 accepted 8651 3157 58 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8651 https://civicdb.org/links/variants/3157 https://civicdb.org/links/genes/58 false NTRK2 4915 KANK1::NTRK2 Pilocytic Astrocytoma 4851 Diagnostic Supports C Positive A case report showing a two-year-old girl with an unusual pilocytic astrocytoma (PA) with both classic- and anaplastic- appearing tumors. A custom NGS panel identified a novel KANK1-NTRK2 fusion in both the classic and anaplastic regions. The KANK1-NTRK2 fusion was also detected in the resected recurrence, which was histologically similar to the initial anaplastic region. The KIAA1549-BRAF fusion, the most common genetic alteration in PA, was absent in this case. Different from previously known mechanisms underlying the progression to anaplastic PA, this case lacks NF1 alterations and is radiation-naïve. 29804288 PubMed López et al., 2019, Neuropathol. Appl. Neurobiol. 2 accepted 8653 3158 3984 Somatic 2020-08-11 18:29:23 UTC https://civicdb.org/links/evidence_items/8653 https://civicdb.org/links/variants/3158 https://civicdb.org/links/genes/3984 false FLT3 2322 Y842C Acute Myeloid Leukemia 9119 Quizartinib Predictive Supports D Resistance A screen using saturation mutagenesis of FLT3/ITD followed by selection of transfected TF1 cells in FLT3 TKIs identified Y842C. Cytotoxicity assessed by MTT demonstrated Ba/F3 cells expressing FLT3/ITD Y842C conferred high-level resistance to Quizartinib (AC220) (IC50: 20nM) compared to FLT3/ITD control cells (IC50: 1nM). Unlike in FLT3/ITD control cells, immunoblotting showed Quizartinib was unable to inhibit FLT3 autophosphorylation and the activation of downstream pathways in Ba/F3 FLT3/ITD Y842C cells. Structural modeling revealed Y842 to be located in the activation loop. The authors hypothesize altered conformation interferes with drug interaction. 22858906 PubMed Williams et al., 2013, Leukemia 3 accepted 8654 3070 24 Somatic 2021-08-28 00:39:52 UTC https://civicdb.org/links/evidence_items/8654 https://civicdb.org/links/variants/3070 https://civicdb.org/links/genes/24 false ALK 238 Fusion Lung Non-small Cell Carcinoma 3908 Alectinib Predictive Supports A Sensitivity/Response A randomized phase 3 trial (J-ALEX) of 207 Japanese ALK-positive NSCLC patients compared the efficacy and safety of alectinib (300mg twice daily) and crizotinib (250mg twice daily) in the first-line setting. When used as a first line treatment the median progression-free survival of the alectinib group was unreached (95% CI 17.5–not estimated) versus 10.2 months (95% CI 8.3–13.9) in the crizotinib group (HR 0.31; 95% CI 0.17–0·57). In the overall intent to treat population, Alectinib showed improved median PFS (HR 0.34; 99.7% CI 0.17-0.71; stratified log-rank p<0·0001) with an unreached PFS (95% CI 20.3-not estimated) compared to 10.2 months (95% CI 8.2-12.0) for crizotinib. The safety profile of alectinib was favorable relative to crizotinib with fewer dose interruptions (29% vs 74%) and fewer grade 3-4 adverse events (26% vs 52%). 28501140 PubMed Hida et al., 2017, Lancet 5 accepted 8657 499 1 2 29415640 29446394 ENST00000389048.3 75 GRCh37 Following the initial discovery and characterization of NPM-ALK fusion mutation in anaplastic large cell lymphoma (ALCL), EML4-ALK fusions were found to be driver mutations in a subset of lung adenocarcinomas. ALK fusions bring the C-terminal ALK kinase domain together with the N terminal region of the fusion partner, and have since been found in a range of cancers including inflammatory myofibroblastic tumor, renal cell carcinoma, diffuse large B cell lymphoma and colorectal cancer. In a Phase I trial for crizotinib, a 92% response rate was seen in the subset of patients with a specific EML4-ALK variant, which was higher than the 57% rate in the overall ALK-rearranged population, but the subpopulation numbers were insufficient to correlate variant type with patient response. Due to restricted wild-type ALK expression, and also mild phenotypes seen in ALK knockout mice, ALK fusions are desirable targets. ALK inhibitor TAE684 was used in initial characterizations of ALK fusion cancer drivers, and crizotinib – a small molecule ATP-competitor RTK inhibitor which is highly selective for ALK and MET - has been approved as first line therapy in ALK-rearranged NSCLC. ALK-rearrangement defines an NSCLC subtype that makes up 3-5% of NSCLC cases, and is characterized by higher proportions of younger patients and never smokers. EML4-ALK variant 1 is the most common ALK fusion in NSCLC and was the first to be discovered and demonstrate cancer driver properties in vitro and in mouse models. A Phase I study of crizotinib in ALK-rearranged NSCLC demonstrated an increase in overall survival when compared to standard chemotherapy. These and other initial results prompted accelerated approval for crizotinib in NSCLC. Continued clinical work demonstrated benefit with crizotinib over chemotherapy in multi-armed studies, and as first line therapy. Crizotinib was also found to remain beneficial to NSCLC patients who had progressed on crizotinib. Additionally, crizotinib was shown to increase intracranial disease control in brain metastasis occurring from ALK-rearranged NSCLC. Somatic 2020-08-14 19:14:14 UTC https://civicdb.org/links/evidence_items/8657 https://civicdb.org/links/variants/499 https://civicdb.org/links/genes/1 false PIK3CA 5290 K111N Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Does Not Support D Resistance As part of a pre-clinical experiment, the efficacy of trastuzumab was evaluated against various HER2 positive cell lines in cell viability assays. BT-474 cell line expressing PIK3CA K111N was associated with similar sensitivity to trastuzumab as PIK3CA wild-type cell line SK-BR-3, at all concentrations tested (0-10 ug/mL). 26920887 PubMed Baselga et al., 2016, Clin. Cancer Res. 2 accepted 8662 1234 37 3 178916946 178916946 G C ENST00000263967.3 75 GRCh37 Somatic 2020-08-14 21:16:46 UTC https://civicdb.org/links/evidence_items/8662 https://civicdb.org/links/variants/1234 https://civicdb.org/links/genes/37 false PIK3CA 5290 I391M Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Predictive Does Not Support D Resistance As part of a pre-clinical experiment, the efficacy of trastuzumab was evaluated against various HER2 positive cell lines using cell viability assays. ZR-75-30 cell line expressing PIK3CA I391M was associated with similar sensitivity to trastuzumab compared to PIK3CA wild-type cell line SK-BR-3, at all concentrations tested (0-10 ug/mL). 26920887 PubMed Baselga et al., 2016, Clin. Cancer Res. 2 accepted 8663 1235 37 3 178927410 178927410 A G ENST00000263967.3 75 GRCh37 Somatic 2020-08-14 21:19:33 UTC https://civicdb.org/links/evidence_items/8663 https://civicdb.org/links/variants/1235 https://civicdb.org/links/genes/37 false PIK3CA 5290 Mutation Her2-receptor Positive Breast Cancer 0060079 Lapatinib,Capecitabine Combination Predictive Supports B Resistance In a phase 3 clinical trial (NCT00829166), metastatic HER-2 amplified breast cancer patients whose tumors harbored PIK3CA mutations treated with standard of care capecitabine and lapatinib combination chemotherapy (n=39) were associated with lower median progression free survival (PFS), overall response rate (ORR), and overall survival (OS) compared to patients whose tumors harbored wild-type PIK3CA (n=87; PFS: 4.3 vs. 6.4 months, ORR: 17.1% vs 39.7%, OS 17.3 vs 27.8 mo). 26920887 PubMed Baselga et al., 2016, Clin. Cancer Res. 3 accepted 8705 311 37 3 178866311 178957881 ENST00000263967.3 75 GRCh37 PIK3CA mutations are observed in many cancers among the most prevalent are breast cancer, colorectal cancer, and head and neck squamous cell carcinoma. These mutations have been observed in up to 40%, 20%, and 21% respectively for each of these cancer types with mutations commonly occurring within the helical exon 9 and kinase domain of exon 20. In breast cancer PIK3CA mutations have been associated with better prognosis, and a greater survival outcome, however the PI3K pathway is also associated with increased drug resistance (trastuzumab/lapatinib). PIK3CA mutations in both HNSCC and CRC have been associated with resistance to anti-EGFR therapeutic agents and mutations in exon 9 and 20 are associated with a poorer prognosis in CRC. Interestingly PIK3CA mutations in HNSCC have been observed to be absent from a number of ethnic groups including greek, german, and vietnamese populations. Somatic 2020-08-20 23:44:40 UTC https://civicdb.org/links/evidence_items/8705 https://civicdb.org/links/variants/311 https://civicdb.org/links/genes/37 false PTEN 5728 Loss Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Emtansine Predictive Does Not Support B Resistance In a phase 3 clinical trial (NCT00829166), metastatic HER-2 amplified breast cancer patients whose tumors had decreased, slightly decreased, or absent PTEN expression (assessed by IHC) treated with ado-trastuzumab emtansine (T-DM1; n= 113) were associated with similar median progression free survival (PFS) compared to patients whose tumors expressed PTEN normally or greater (n=21; 8.4 vs. 9.9 months). In HER2 patients with decreased or absent PTEN expression, T-DM1 was a more effective treatment than standard of care capecitabine + lapatinib as measured by PFS, although no difference in OS was seen. 26920887 PubMed Baselga et al., 2016, Clin. Cancer Res. 3 accepted 8706 214 41 10 89622870 89731687 ENST00000371953.3 75 GRCh37 Somatic 2020-08-21 00:34:21 UTC https://civicdb.org/links/evidence_items/8706 https://civicdb.org/links/variants/214 https://civicdb.org/links/genes/41 false ERBB3 2065 Overexpression Her2-receptor Positive Breast Cancer 0060079 Trastuzumab Emtansine Predictive Does Not Support B Resistance In a phase 3 clinical trial (NCT00829166), metastatic HER-2 amplified breast cancer patients whose tumors harbored higher than median levels of ERBB3 mRNA treated with ado-trastuzumab emtansine (T-DM1; n=210) were associated with similar median progression free survival (PFS) compared to patients whose tumors harbored the median or lower levels of ERBB3 mRNA (n=214; PFS: 9.8 vs. 9.3 months). 26920887 PubMed Baselga et al., 2016, Clin. Cancer Res. 2 accepted 8707 289 1733 12 56473645 56497289 ENST00000267101.3 75 GRCh37 N/A 2020-10-07 02:44:28 UTC https://civicdb.org/links/evidence_items/8707 https://civicdb.org/links/variants/289 https://civicdb.org/links/genes/1733 false VHL 7428 P86S (c.256C>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma,Pancreatic endocrine tumor,Renal cell carcinoma Predisposing N/A C N/A Among patients prospectively followed by the members of the French VHL Study Group, 35 consecutive patients with well-documented endocrine pancreatic tumour (20 women and 15 men; median age,37 [21Y-57] years) were included. All 35 patients had VHL germline mutations and were assessed for the presence of pheochromocytoma and renal carcinoma in addition to pancreatic tumours. The presence of other phenotypes was not described. DNA was isolated from peripheral blood lymphocytes and mutations were detected using direct sequencing of the 3 exons of VHL and/or southern blot analysis. A germline missense mutation (c.256C>T) was found in 3 patients, 2 of which were related. Patient No 7 from family 503 presented with pancreatic endocrine tumour, pheochromocytoma, and renal carcinoma and patient No 15 from family 503 presented with pancreatic endocrine tumour. Their familial relation was not described. Patient No. 27 from family 11 also had the same mutation and presented with pancreatic endocrine tumour, pheochromocytoma, and renal carcinoma. The patients' phenotypes are highly specific to VHL disease (ACMG PP4). 18580449 PubMed Corcos et al., 2008, Pancreas 3 accepted 8771 1902 58 3 10183787 10183787 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8771 https://civicdb.org/links/variants/1902 https://civicdb.org/links/genes/58 false KRAS 3845 Mutation Ovary Serous Adenocarcinoma 5744 Binimetinib Predictive Supports B Sensitivity/Response Post hoc analysis of a randomized phase 3 trial (MILO/ENGOT-ov11) suggests a possible association between KRAS mutation and response to binimetinib in patients with pretreated (1-3 lines of prior chemotherapy) recurrent or persistent Low-Grade Serous Carcinomas of the Ovary, Fallopian Tube, or Primary Peritoneum. Of 133 binimetinib-treated patients with individual response and molecular data, 46 harbored KRAS mutations. KRAS mutation status was significantly associated with local best response (P=0.004); 44% of patients with KRAS mutation versus 19% of patients with KRAS WT had CR or PR in the binimetinib arm. KRAS mutation was also associated with prolonged PFS in patients treated with binimetinib (median PFS: KRAS mutant: 17.7 months; KRAS wild-type (WT): 10.8 months; P = .006), but not in patients receiving standard chemotherapy (physicians' choice, median PFS: KRAS mutant: 14.6 months; KRAS WT: 11.5 months; P=.502). 32822286 PubMed Monk et al., 2020, J Clin Oncol NCT01849874 3 accepted 8773 336 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2021-03-02 19:22:09 UTC https://civicdb.org/links/evidence_items/8773 https://civicdb.org/links/variants/336 https://civicdb.org/links/genes/30 false KRAS 3845 Wildtype Colorectal Cancer 9256 Regorafenib Predictive Does Not Support D Resistance In an in vitro study, a human colon adenocarcinoma SW48 cell line expressing KRAS wildtype did not demonstrate resistance to regorafenib treatment (IC50: 114.28 nM) compared to SW48 cells expressing various common KRAS G12/G13 mutations. Resistance was determined by assessing cell viability. In vivo, SW48 cells were injected into NOD/SCID mice. Treatment with regorafenib did not lead to a significant delay of tumor growth, although KRAS wt mice trended toward better response than KRAS G12C expressing mice. IHC analysis of mouse tissue revealed more pronounced changes in markers of proliferation (Ki67), angiogenesis (CD31), and apoptosis (TUNEL) in KRAS wt mice treated with regorafenib compared to KRAS G12C mice whose tumors did not display changes in these markers. Authors concluded that KRAS wildtype was not resistant to regorafenib compared to other common KRAS G12/G13 mutations. 26161928 PubMed Camaj et al., 2015, Future Oncol 2 accepted 8840 3200 30 12 25362365 25403737 ENST00000256078.4 75 GRCh37 Somatic 2020-12-03 18:33:03 UTC https://civicdb.org/links/evidence_items/8840 https://civicdb.org/links/variants/3200 https://civicdb.org/links/genes/30 true BCL2 596 G101V Chronic Lymphocytic Leukemia 1040 Venetoclax Predictive Supports D Resistance This study described the similar crystal structures of BCL-2 wild-type and G101V when bound to venetoclax. Steady state competition surface plasmon resonance experiments demonstrated a ~177 fold decrease in venetoclax affinity for G101V (Ki=3.2nM) versus WT (Ki=.018nM). Resistance is acquired by a knock-on effect in the P2 pocket of V101 on an adjacent residue, E152 as affinity for venetoclax was restored in BCL2 G101V through the introduction of an E152A mutation (Ki =.002nM). Additionally, BCL2 G101V maintains similar affinity for apoptotic BH3 peptides, which assists in the prevention of apoptosis. 31160589 PubMed Birkinshaw et al., 2019, Nat Commun 3 accepted 8841 2960 59 18 60985598 60985598 C A ENST00000398117.1 75 GRCh37 Somatic 2021-06-14 23:52:07 UTC https://civicdb.org/links/evidence_items/8841 https://civicdb.org/links/variants/2960 https://civicdb.org/links/genes/59 false RET 5979 Fusion Lung Non-small Cell Carcinoma 3908 Selpercatinib Predictive Supports B Sensitivity/Response Patients with RET-fusion positive non-small cell lung cancer were enrolled in this phase 1-2 trial of RET inhibitor selpercatinib. Among 105 consecutively enrolled patients who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). 32846060 PubMed Drilon et al., 2020, N Engl J Med NCT03157128 4 accepted 8850 1687 42 Somatic 2020-09-03 22:22:52 UTC https://civicdb.org/links/evidence_items/8850 https://civicdb.org/links/variants/1687 https://civicdb.org/links/genes/42 false FGFR3 2261 S249C Bladder Urothelial Carcinoma 4006 Oncogenic N/A D N/A In contrast to controls (empty vector and FGFR3 wildtype overexpression NIH-3T3 cell lines), the stable transfection of NIH-3T3 cells with FGFR3b-S249C led to ligand-independent phosphorylation of FGFR3 and the acquisition of elongated, refractile spindle-shaped morphology like transformed cells. Using a thymidine incorporation assay, S249C expressing cells were shown to lose contact inhibition and grew 3x to 4x more rapidly than controls. Soft agar assays demonstrated increased colony formation and anchorage independent growth in S249C expressing cells versus controls. All nude mice subcutaneously injected with S249C cells rapidly formed tumors, but no tumors were observed in empty vector injected mice. The authors conclude mutated FGFR3b-S249C has transforming properties attributed to oncogenes. 16338952 PubMed Bernard-Pierrot et al., 2006, Carcinogenesis 4 accepted 8853 628 23 4 1803568 1803568 C G ENST00000340107.4 75 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. Somatic 2022-07-30 16:16:17 UTC https://civicdb.org/links/evidence_items/8853 https://civicdb.org/links/variants/628 https://civicdb.org/links/genes/23 false FGFR3 2261 S249C Functional Supports D Gain of Function Forster Resonance Energy Transfer (FRET)-based technique acquired quantitative measurement of the effect of S249C on unliganded mutant FGFR3 dimer stability and structure in plasma membrane vesicles from CHO cells. Dimer stability was modestly increased by S249C (-3.7 kcal/mol) versus wildtype FGFR3 (-3.4 kcal/mol). Intrinsic FRET demonstrated S249C dimers were significantly closer together (45 A) than the wildtype dimer (53 A). The substitution of cysteine was expected to lead to strong covalent bonds, but the authors conclude their data demonstrates S249C does not induce constitutive FGFR3 dimerization, but induces dimer structural modifications. 25606676 PubMed Del Piccolo et al., 2015, Biophys J 3 accepted 8854 628 23 4 1803568 1803568 C G ENST00000340107.4 75 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. N/A 2021-06-11 00:00:51 UTC https://civicdb.org/links/evidence_items/8854 https://civicdb.org/links/variants/628 https://civicdb.org/links/genes/23 false IDH1 3417 Mutation Acute Myeloid Leukemia 9119 Venetoclax Predictive Supports C Sensitivity/Response In this case series, 7 elderly patients with secondary AML (sAML) not eligible for intensive chemotherapy and refractory to HMA (including 1 patient with antecedent myeloproliferative neoplasm) were treated with venetoclax monotherapy. Three of 7 patients showed response. Of these: 2 patients achieved complete remission (1 of which was mutated for IDH2). One patient with IDH1 mutation showed PB blast clearance (derived anti-leukemic benefit) but BM was not performed to evaluate response. Venetoclax responders had high BCL‐2 and/or BIM expression levels in myeloblasts, and the response was significantly associated with OS. BCL-2 and BIM expression levels can potentially identifer venetoclax responders. 30725494 PubMed Huemer et al., 2019, Eur J Haematol 3 accepted 8856 645 26 2 209101803 209116275 ENST00000415913.1 75 GRCh37 Somatic 2022-02-17 23:12:21 UTC https://civicdb.org/links/evidence_items/8856 https://civicdb.org/links/variants/645 https://civicdb.org/links/genes/26 false IDH2 3418 Mutation Acute Myeloid Leukemia 9119 Venetoclax Predictive Supports C Sensitivity/Response In this case series, 7 elderly patients with secondary AML (sAML) not eligible for intensive chemotherapy and refractory to HMA (including 1 patient with antecedent myeloproliferative neoplasm) were treated with venetoclax monotherapy. Three of 7 patients showed response. Of these: 2 patients achieved complete remission (1 of which was mutated for IDH2). One patient with IDH1 mutation showed PB blast clearance (derived anti-leukemic benefit) but BM was not performed to evaluate response. Venetoclax responders had high BCL‐2 and/or BIM expression levels in myeloblasts, and the response was significantly associated with OS. BCL-2 and BIM expression levels can potentially identifer venetoclax responders. 30725494 PubMed Huemer et al., 2019, Eur J Haematol 3 accepted 8857 570 27 15 90626277 90645736 ENST00000330062.3 75 GRCh37 Somatic 2022-02-17 23:38:40 UTC https://civicdb.org/links/evidence_items/8857 https://civicdb.org/links/variants/570 https://civicdb.org/links/genes/27 false SMARCB1 6598 LOSS Atypical Teratoid Rhabdoid Tumor 2129 Diagnostic Supports B Positive 53 pediatric tumors consisting of 20 AT/RT, 10 PNET, and 23 other central nervous system tumors were classified using microscopic diagnosis, and then tested for expression of the SMARCB1 gene product INI1. In the 20 cases of AT/RT, expression of INI1 was not detected in tumor cells using the BAF47/SNF5 monoclonal INI1 antibody. Expression of INI1 was detected in 31 out of the 33 remaining tumors, with one Oligodendroglioma showing no expression, and one pituitary adenoma showing weak expression. The authors conclude that immunohistochemical staining with an INI1 antibody may be useful in confirming histologic diagnosis of AT/RT. 15105654 PubMed Judkins et al., 2004, Am J Surg Pathol 4 accepted 8862 3202 5356 Somatic 2020-12-02 23:18:11 UTC https://civicdb.org/links/evidence_items/8862 https://civicdb.org/links/variants/3202 https://civicdb.org/links/genes/5356 false NTRK1 4914 SQSTM1::NTRK1 Congenital Fibrosarcoma 8418 Larotrectinib Predictive Supports C Sensitivity/Response In a pediatric phase 1 trial (NCT02637687), a 2 year old with infantile fibrosarcoma of the shoulder harbored the SQSTM1-NTRK1 fusion. After two surgical resections and multiple rounds of chemotherapy, Larotrectinib treatment resulted in 93% tumour reduction. An R1 resection was performed followed by adjuvant Larotrectinib. The patient remained on Larotrectinib without evidence of disease progression at the time of last follow-up. 30204247 PubMed DuBois et al., 2018, Cancer NCT02637687 3 accepted 8865 800 3983 Somatic 2020-09-16 04:01:19 UTC https://civicdb.org/links/evidence_items/8865 https://civicdb.org/links/variants/800 https://civicdb.org/links/genes/3983 false ATRX 546 Mutation Malignant Astrocytoma 3069 Brain neoplasm,Glioma Diagnostic Supports B Positive Whole exome sequencing of 4 low grade gliomas (LGGs) and targeted sequencing of 28 LGGs revealed ATRX variants are found exclusively in a subset of IDH1-mutant, 1p/19q intact LGGs. Paired blood samples were sequenced in all cases and mutations were confirmed by Sanger. IDH1mutation was found in 28/32 LGGs and of these 12 possessed an ATRX mutation (~43%). In all 12 ATRX mutated cases 1p/19q was intact (correlation p=0.0003), and ATRX variants were not observed in the 12 1p/19q codeleted cases. Additionally, multiplex mRNA profiling of 28 astrocytic tumors with subclasses assigned based on 75 gene signatures demonstrated ATRX mutations were associated (p=.0044) with the early progenitor-like subclass (EPL) (11/13 EPL cases harbored ATRX mutants). 23104868 PubMed Kannan et al., 2012, Oncotarget 3 accepted 8868 3203 525 X 76760356 77041702 ENST00000373344.5 75 GRCh37 Somatic 2020-09-24 02:29:34 UTC https://civicdb.org/links/evidence_items/8868 https://civicdb.org/links/variants/3203 https://civicdb.org/links/genes/525 false NTRK1 4914 LMNA::NTRK1 e2-e10 Congenital Fibrosarcoma 8418 Childhood onset Crizotinib Predictive Supports C Sensitivity/Response A mass found at birth in a patient’s left arm became enlarged at age 2 and was resected and characterized as a high-grade spindle cell sarcoma. FISH and RT-PCR did not detect any common sarcoma translocations. A recurrence and a new mass formed after 4 months of therapy, so amputation was performed. Metastatic high-grade sarcoma appeared in the lungs 4 months later followed by multiple recurrences 10 months after treatment. Whole exome and transcriptome sequencing of diagnosis and normal samples were performed and the in-frame LMNA-NTRK1 fusion (exon 2 & exon 10) with the kinase domain intact was discovered. Treatment with Crizotinib was started and a chest CT after 2 months revealed partial response. After 22 months of therapy, chest CT revealed a complete response of lung nodules, which has been sustained >18 months beyond the conclusion of treatment at 31 months. 30709876 PubMed Bender et al., 2019, Cold Spring Harb Mol Case Stud 3 accepted 8878 3223 3983 Somatic 2021-06-09 19:46:02 UTC https://civicdb.org/links/evidence_items/8878 https://civicdb.org/links/variants/3223 https://civicdb.org/links/genes/3983 false FGFR3 2261 Y373C Urinary Bladder Cancer 11054 Oncogenic N/A D N/A The authors identified a bladder cancer cell line (MGH-U3) with a homozygous Y373C mutation. With immunoprecipitation (IP) ,and immunoblotting (IB) experiments, they demonstrated constitutional phosphorylation of FGFR3 Y373C protein. Then with SU5492 (an FGFR3 TKI) and FGFR3 siRNA, they also demonstrate that constitutional phosphorylation of the FGFR3 Y373C can be inhibited. Furthermore, cells treated with SU5492 (for inhibition) and FGFR3 siRNA (for depletion) of the mutant FGFR3 Y373C protein show inhibition of cell proliferation and anchorage independent growth. These studies suggest potentially oncogenic properties for the Y373C mutation. 16338952 PubMed Bernard-Pierrot et al., 2006, Carcinogenesis 3 accepted 8881 2404 23 4 1806099 1806099 A G ENST00000440486.2 75 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. Somatic 2022-07-30 19:26:20 UTC https://civicdb.org/links/evidence_items/8881 https://civicdb.org/links/variants/2404 https://civicdb.org/links/genes/23 false FOXO1 2308 PAX3::FOXO1 Alveolar Rhabdomyosarcoma 4051 Prognostic Supports B Poor Outcome In a cohort of 171 uniformly treated pediatric rhabdomyosarcoma (RMS) patients, 78 patients had alveolar rhabdomyosarcoma (ARMS). Of ARMS patients, 55% harbored a PAX3-FOXO1 fusion, 22% harbored a PAX7-FOXO1 fusion, and 23% were fusion negative. Authors found a trend toward worse overall survival (OS) for PAX3-FOXO1 positive ARMS compared to PAX7-FOXO1 ARMS (4 year survival 52% vs 77%, p=0.08); fusion-negative ARMS had an intermediate OS. Among patients with metastatic disease, the PAX3-FOXO1 fusions were associated with significantly worse OS (4-year survival: 8% vs 75% for PAX7-FOXO1 ARMS, p = 0.002). In multivariate analysis, PAX3-FOXO1 fusion was independently associated with failure or death compared to loco-regional embryonal RMS (P=0.033), and among metastatic fusion positive ARMS (for failure: p=0.025, for death: p=0.019). The authors concluded that PAX3-FOXO1 fusion is an independent indicator of poor outcome. 12039929 PubMed Sorensen et al., 2002, J. Clin. Oncol. 3 accepted 8885 2582 1925 Somatic 2020-10-01 22:47:41 UTC https://civicdb.org/links/evidence_items/8885 https://civicdb.org/links/variants/2582 https://civicdb.org/links/genes/1925 false FOXO1 2308 PAX7::FOXO1 Alveolar Rhabdomyosarcoma 4051 Prognostic Supports B Better Outcome In a cohort of 171 uniformly treated pediatric rhabdomyosarcoma (RMS) patients, 78 patients had alveolar rhabdomyosarcoma (ARMS). Of ARMS patients, 55% harbored a PAX3-FOXO1 fusion, 22% harbored a PAX7-FOXO1 fusion, and 23% were fusion negative. Authors found a trend toward better overall survival (OS) for PAX7-FOXO1 positive ARMS compared to PAX3-FOXO1 ARMS (4 year survival 77% vs 52%, p=0.08); fusion-negative ARMS had an intermediate OS. Among patients with metastatic disease, the PAX7-FOXO1 fusions were associated with significantly better OS (4-year survival: 75% vs 8% for PAX3-FOXO1 ARMS, p = 0.002). In multivariate analysis, among metastatic fusion positive ARMS, PAX7-FOXO1 fusion was not significantly associated with increased risk of failure or death. Further, among PAX7-FOXO1 fusion patients, there was little difference in outcome whether patients presented with loco-regional or metastatic disease, in striking contrast with PAX3-FOXO1 fusion positive patients. The authors concluded that PAX7-FOXO1 fusion is an independent indicator of favorable outcome in metastatic ARMS. 12039929 PubMed Sorensen et al., 2002, J. Clin. Oncol. 3 accepted 8886 2583 1925 Somatic 2020-10-01 22:52:08 UTC https://civicdb.org/links/evidence_items/8886 https://civicdb.org/links/variants/2583 https://civicdb.org/links/genes/1925 false NTRK1 4914 LMNA::NTRK1 e11-e10 Colorectal Cancer 9256 Entrectinib Predictive Supports C Sensitivity/Response After disease progression with no objective response to therapy, a 75-year-old with metastatic colorectal cancer that spread to the liver displayed elevated NTRK1 expression in both primary tumor and liver metastasis as measured by immunohistochemistry. FISH of the tumor and patient derived xenograft indicated NTRK1 involvement. 5’RACE PCR discovered a novel LMNA-NTRK1 fusion (exon 11 & exon 10), which resulted in the expression of two different fusion splice transcripts (exons 1-10 with exons 10-16 and exons 1-11 with exons 10-16). Fusion expression of both transcripts was confirmed by western blot, and Sanger sequencing revealed the fusion to be in-frame with the kinase domain intact. After 4 weeks of treatment with Entrectinib, CT scan revealed the patient showed a partial response with a 30% reduction of target lesions. This response was maintained for 5 months. 26563355 PubMed Sartore-Bianchi et al., 2016, J Natl Cancer Inst 4 accepted 8900 3225 3983 1 156084498 156108548 ENST00000368300.4 1 156844363 156851434 ENST00000524377.1 75 GRCh37 Somatic 2021-07-15 14:23:30 UTC https://civicdb.org/links/evidence_items/8900 https://civicdb.org/links/variants/3225 https://civicdb.org/links/genes/3983 false NTRK1 4914 LMNA::NTRK1 e11-e10 Colorectal Cancer 9256 Oncogenic N/A D N/A FISH of the tumor and patient derived xenograft of a 75-year-old with metastatic colorectal cancer that spread to the liver indicated NTRK1 involvement. 5’RACE PCR discovered a novel LMNA-NTRK1 fusion (exon 10 & exon 10), which resulted in the expression of two different fusion splice transcripts (exons 1-10 with exons 10-16 and exons 1-11 with exons 10-16). Expression was confirmed by Western and Sanger sequencing revealed the fusion to be in-frame with the kinase domain intact. Western blot of the tumor also indicated constitutive activation of the fusion based on phosphorylation of the fusion. Additionally, downstream kinase targets (PLCγ1, AKT, and MAPK) were also phosphorylated in the tumor, similar to levels observed in the TPM3-NTRK1 containing KM12 colorectal cancer cell line. 26563355 PubMed Sartore-Bianchi et al., 2016, J Natl Cancer Inst 1 accepted 8901 3225 3983 1 156084498 156108548 ENST00000368300.4 1 156844363 156851434 ENST00000524377.1 75 GRCh37 Somatic 2021-06-09 18:13:38 UTC https://civicdb.org/links/evidence_items/8901 https://civicdb.org/links/variants/3225 https://civicdb.org/links/genes/3983 false NTRK1 4914 LMNA::NTRK1 e2-e11 Spitzoid Melanoma 0070326 Oncogenic N/A D N/A The in-frame LMNA-NTRK1 fusion (exon 2 & exon 11) with intact kinase domain was found and confirmed by next generation sequencing, RT-PCR, FISH, and/or immunohistochemistry in 3 Spitz neoplasm cases. Compared to controls (wildtype NTRK1 overexpression and GFP), lentiviral mediated overexpression of LMNA-NTRK1 in mouse melanocyte cells (melan-a) displayed increased phosphorylation of the fusion and downstream kinase targets, as assessed by Western Blot. Treatment with the NTRK1 inhibitor, AZ-23, quenched fusion and pathway activation. Additionally, injection of LMNA-NTRK1 melan-a cells into immunocompromised mice resulted in the rapid growth of tumors at the injection site within 40 days. Similar results were observed in mice injected with melan-a cells overexpressing NRAS G12V or HRAS G12V, but no tumors were observed in mice injected with GFP control melan-a cells. 24445538 PubMed Wiesner et al., 2014, Nat Commun 3 accepted 8903 3224 3983 Somatic 2021-03-30 20:31:49 UTC https://civicdb.org/links/evidence_items/8903 https://civicdb.org/links/variants/3224 https://civicdb.org/links/genes/3983 false NTRK3 4916 ETV6::NTRK3 B-lymphoblastic Leukemia/lymphoma 0080630 Juvenile onset Larotrectinib,Etoposide,Methotrexate Combination Predictive Supports C Sensitivity/Response All lines of conventional therapy (including allogeneic HSCT, blinatumomab, and CAR T cells) were inefficient for a 6-year-old boy with B-cell ALL and CNS infiltration (National Cancer Institute high risk). Conventional cytogenetics, FISH, and an Abbott break-apart probe of a peripheral blood sample collected at diagnosis revealed an unbalance translocation of the ETV6 locus. The patient relapsed twice and RNA sequencing of the initial diagnosis sample revealed a cytogenetically cryptic ETV6-NTRK3 fusion. Treatment with larotrectinib was initiated in combination with etoposide and methotrexate resulted in molecular remission in 66 days in bone marrow and CNS. A third relapse occurred 45 days after Larotrectinib was paused for CAR-T infusions. Larotrectinib was resumed with a dosage increase and again achieved sustained undetectable minimal residual disease after 66 days, and displayed molecular remission through 39 days. The authors suggest larotrectinib as a potential effective treatment for B-cell ALL patients harboring ETV6-NTRK3, including those with CNS infiltration. 31725893 PubMed Schewe et al., 2019, Blood Adv 4 accepted 8917 801 3985 12 11802788 12022903 ENST00000396373.4 15 88483984 88418230 ENST00000394480.2 75 GRCh37 Somatic 2021-07-21 16:19:30 UTC https://civicdb.org/links/evidence_items/8917 https://civicdb.org/links/variants/801 https://civicdb.org/links/genes/3985 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Gilteritinib Predictive Supports D Sensitivity/Response This study was designed to test the efficacy of FLT3 inhibitors in vitro against FLT3-ITD and other TKD variants clinically observed. IC50s were determined from immunoblots quantifying FLT3 phosphorylation in endogenous (Molm14) or ectopic expression FLT3-ITD cell lines (TF-1, Ba/F3) and the endogenous wildtype FLT3 SEMK2 cell line after gilteritinib treatment. IC50 values ranged from 1.4 to 1.8 nM in the three FLT3-ITD lines compared to 5nM in wildtype cells, suggesting increased sensitivity to the inhibitor. As measured by MTT assay, primary cultures from two AML patients with high allelic FLT3-ITD showed cytotoxic response to gilteritinib. Additionally, plasma taken from 3 patients receiving 120mg of gilteritinib daily was able to inhibit FLT3 phosphorylation in Molm14 cells. 27908881 PubMed Lee et al., 2017, Blood 3 accepted 8923 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2020-12-03 04:01:20 UTC https://civicdb.org/links/evidence_items/8923 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false FLT3 2322 ITD Acute Myeloid Leukemia 9119 Gilteritinib Predictive Supports D Sensitivity/Response In vitro gilteritinib treatment of MV4-11 and MOLM-13 cells, which endogenously express FLT3-ITD, showed growth suppression based on CellTiter GLO cytotoxicity assays with IC50 values of 0.92 nM (95% CI: 0.23–3.6 nM) and 2.9 nM (95% CI: 1.4–5.8 nM), respectively. Phosphorylation of FLT3 and its downstream targets were rapidly inhibited in MV4-11 cells relative to control treatment (DMSO). In a mouse xenograft model using MV4-11 cells, increasing doses of gilteritinib further reduced tumor size and growth and inhibited phosphorylation of both FLT3 and STAT5 (N=6, p<0.05 at lowest dose). Gilteritinib inhibited growth in vitro of Ba/F3 cells expressing FLT3-ITD (IC50 1.8nM; 95% CI: 1.0-3.0 nM) and in vivo as tumor maintenance or shrinkage was also significant in mice xenografted with Ba/F3 FLT3-ITD cells (N=5, p<0.001). Mice receiving an intra-bone marrow injection of MV4-11 cells labelled with luciferase began gilteritinib treatment on day 15. Gilteritinib treated mice showed significantly less widespread disease at day 42 than control counterparts (N=10, p<0.001) and significantly improved survival (log-rank, p<0.001). 28516360 PubMed Mori et al., 2017, Invest New Drugs 4 accepted 8924 55 24 13 28608219 28608351 ENST00000241453.7 75 GRCh37 FLT3-ITD (internal tandem duplications) frequently occur in patients with hematologic malignancies such as chronic myelogenous leukemia, acute myeloid leukemia (AML) and myelodysplastic syndrome, but particularly in cytogenetically normal AML (CN-AML). These duplication events disrupt the juxtamembrane domain of FLT3 and can be the result of a duplication of internal FLT3 sequence or other unrelated sequence resulting in an in-frame duplication event. The length of these duplications can vary widely which may have prognostic consequences, but this has not been conclusively determined. FLT3-ITD mutations overall have generally been associated with poor prognosis. Additional genes associated with CN-AML such as NPM1 may modulate the prognosis associated with this variant. Somatic 2020-12-03 00:06:29 UTC https://civicdb.org/links/evidence_items/8924 https://civicdb.org/links/variants/55 https://civicdb.org/links/genes/24 false NTRK3 4916 ETV6::NTRK3 B-lymphoblastic Leukemia/lymphoma 0080630 Juvenile onset Larotrectinib Predictive Supports D Sensitivity/Response Conventional cytogenetics, FISH, and an Abbott break-apart probe of a peripheral blood sample collected at diagnosis of a 6-year-old boy with B-cell ALL and CNS infiltration (National Cancer Institute high risk) revealed an unbalance translocation of the ETV6 locus. RNA sequencing of detected a cytogenetically cryptic ETV6-NTRK3 fusion. Larotrectinib therapy achieved remission of the patient’s two separate relapses. Patient derived xenografts injected into mice and treated with Larotrectinib demonstrated significant reductions in spleen volume, blasts in spleen, and blast in bone marrow (p < .0001) compared to controls 25 days after injection. Larotrectinib treatment was effective regardless of the day of initiation post xenograft injection (1 day or 8 days after). 31725893 PubMed Schewe et al., 2019, Blood Adv 3 accepted 8930 801 3985 12 11802788 12022903 ENST00000396373.4 15 88483984 88418230 ENST00000394480.2 75 GRCh37 Somatic 2021-07-21 16:20:15 UTC https://civicdb.org/links/evidence_items/8930 https://civicdb.org/links/variants/801 https://civicdb.org/links/genes/3985 false NTRK3 4916 ETV6::NTRK3 B-lymphoblastic Leukemia/lymphoma 0080630 Oncogenic N/A D N/A The tyrosine kinase domain of NTRK3 was inserted into exon 6 of Etv6 to create conditional knock-in Etv6-NTRK3 mice . Expression was induced in pre-b cells during lymphoid development by CD19-Cre. Fusion expression in the bone marrow was confirmed by RT-PCR. Etv6-NTRK3/+ CD19-Cre mice developed aggressive lymphoid leukemia. Compared to controls (Etv6-NTRK3/+; n=28), Etv6-NTRK3/+ CD19-Cre mice (n=27) displayed worse overall survival (p<.0001), decreased body weight (p<.0001), increased spleen weights (p<.05), and increased circulating CD19+/B220+ cells (p=.0008). Over 60% of Etv6-NTRK3 CD19-Cre mice demonstrated extramedullary tumors and over 50% presented with central nervous system infiltration. RNA-sequencing indicated upregulation of the AP1 complex in the Etv6-NTRK3 CD19-Cre mice. The authors conclude this ETV6-NTRK3 Cre-19 mouse model mimics human B-ALL. 29880614 PubMed Roberts et al., 2018, Blood 4 accepted 8931 801 3985 12 11802788 12022903 ENST00000396373.4 15 88483984 88418230 ENST00000394480.2 75 GRCh37 Somatic 2021-07-25 03:59:50 UTC https://civicdb.org/links/evidence_items/8931 https://civicdb.org/links/variants/801 https://civicdb.org/links/genes/3985 false NRAS 4893 Q61K Ovary Serous Adenocarcinoma 5744 Trametinib Predictive Supports C Sensitivity/Response One 56 year old female with advanced recurrent low grade serous ovarian cancer with NRAS Q61K mutation had a partial response to trametinib, with short follow-up. 30809568 PubMed Champer et al., 2019, Gynecol Oncol Rep 2 accepted 8933 427 36 1 115256530 115256530 G T ENST00000369535.4 75 GRCh37 Somatic 2021-03-02 19:22:42 UTC https://civicdb.org/links/evidence_items/8933 https://civicdb.org/links/variants/427 https://civicdb.org/links/genes/36 false BRAF 673 KIAA1549::BRAF Childhood Pilocytic Astrocytoma 6812 Selumetinib Predictive Supports D Sensitivity/Response In this preclinical experiment, a pediatric pilocytic astrocytoma cell line (DKFZ-BT66) harboring KIAA1549:BRAF fusion was generated from a two year old patient. Treatment with selumetinib resulted in a significant decrease in viable cell count at concentrations of 10µM. Treatment with selumetinib fully abrogated ERK activation at concentrations of 0.1μM for as long as 120 hours. Authors note that inhibitory effects were more pronounced in cells treated with trametinib than cells treated with selumetinib. 28002790 PubMed Selt et al., 2017, Oncotarget 3 accepted 8943 618 5 7 138545885 138666064 ENST00000440172.1 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2020-12-01 00:28:53 UTC https://civicdb.org/links/evidence_items/8943 https://civicdb.org/links/variants/618 https://civicdb.org/links/genes/5 false BRAF 673 KIAA1549::BRAF Childhood Pilocytic Astrocytoma 6812 Trametinib Predictive Supports D Sensitivity/Response In this preclinical experiment, a pediatric pilocytic astrocytoma cell line (DKFZ-BT66) harboring KIAA1549:BRAF fusion was generated from a two year old patient. Treatment with trametinib resulted in a significant decrease in viable cell count at concentrations of 100nM and above. Trametinib also fully abrogated ERK activation at concentrations of 0.1μM for as long as 120 hours. Authors note that inhibitory effects were more pronounced in cells treated with trametinib than cells treated with selumetinib. 28002790 PubMed Selt et al., 2017, Oncotarget 3 accepted 8944 618 5 7 138545885 138666064 ENST00000440172.1 7 140434279 140487384 ENST00000288602.6 75 GRCh37 Somatic 2020-12-01 00:28:26 UTC https://civicdb.org/links/evidence_items/8944 https://civicdb.org/links/variants/618 https://civicdb.org/links/genes/5 false TP53 7157 Overexpression Renal Wilms' Tumor 5176 Prognostic Supports B Poor Outcome 44 archival FFPE samples from confirmed cases of Wilms tumor with mean age 3 years 2 months, and taken from the most histologically aggressive parts of each tumor, were stained with p53 monoclonal antibody and the corresponding patient clinical data was analyzed. 24 samples were p53 positive, and did not correlate with age or sex. All tumors with unfavorable histology were p53 positive, in contrast to 13 of 33 tumors with favorable histology, with weak-moderate p53 signal (p<0.001). 2 year overall survival rate was 89.2% in p53 negative, and 55.7% for p53 positive cases (P = .01), and mean survival was 46 months in p53 negative and 26 months in p53 positive cases (P = .02). Compared with p53 negative, tumors with week to moderate p53 signal had HR 3.75 (P = .05), and high signal had HR 8.61 (P = .01). No significant correlation was seen between tumor clinicopathological stage and p53 expression. 21525573 PubMed Jadali et al., 2011, Iran J Kidney Dis 3 accepted 8945 1306 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 N/A 2020-12-10 02:04:51 UTC https://civicdb.org/links/evidence_items/8945 https://civicdb.org/links/variants/1306 https://civicdb.org/links/genes/45 false FGFR3 2261 R248C Functional Supports D Gain of Function In BaF3 cells, the R248C mutant was shown to fully activate FGFR3 with complete independence of the ligand presence. Ligand independent activation was determined by proliferation, phosphorylation, and dimerization assays (via the formation of an intermolecular disulfide bond). 8640234 PubMed Naski et al., 1996, Nat Genet 5 accepted 8946 2403 23 4 1803564 1803564 C T ENST00000340107.4 75 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. Rare Germline 2022-07-30 17:23:34 UTC https://civicdb.org/links/evidence_items/8946 https://civicdb.org/links/variants/2403 https://civicdb.org/links/genes/23 false VHL 7428 R167W (c.499C>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma,Paraganglioma,Meningioma Predisposing N/A C N/A Patients' records in a tertiary care university hospital were reviewed. Fifty-four Black patients presenting with phaeochromocytoma between 1980 and 2009 were included. Two patients had VHL syndrome (submitted for publication). The second diagnosis of VHL syndrome was made in the pregnant woman (Case 9) who had bilateral adrenal phaeochromocytomas. There were no clinical features of VHL syndrome; however, MRI showed a haemangioblastoma in the cervical spine. Genetic testing revealed a missense mutation (c.499C>T) in the VHL gene, located on chromosome 3p26-p25. Her 6-year-old daughter screened positive for the mutation; her 8-year-old son was negative. Both mother and daughter will be investigated further and monitored long-term. ACMG PP4 21382250 PubMed Huddle, 2011, S Afr Med J 3 accepted 8968 1747 58 3 10191506 10191506 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8968 https://civicdb.org/links/variants/1747 https://civicdb.org/links/genes/58 false VHL 7428 F76del (c.227_229del) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Renal cell carcinoma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregared with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS Hb, RCC, and Pheo was available. Case 2 had p.Phe76del mutation and one affected member with hemangioblastoma and renal cell carcinoma. ACMG PP4 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8969 3157 58 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/8969 https://civicdb.org/links/variants/3157 https://civicdb.org/links/genes/58 false VHL 7428 N78S (c.233A>G) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Hemangioblastoma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 9 had p.Asn78Ser (c.233A>G) mutation. Three members were affected, and all had retinal capillary hemangioma and CNS hemangioblastoma. Other demographics of the members were not described. ACMG PP4 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8970 1755 58 3 10183764 10183764 A G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/8970 https://civicdb.org/links/variants/1755 https://civicdb.org/links/genes/58 false VHL 7428 P81S (c.241C>T) Von Hippel-Lindau Disease 14175 Hemangioblastoma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregared with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS Hb, RCC, and Pheo was available. Case 37 had p.Pro81Ser mutation. One member was affected with hemangioblastoma. Other demographics of the members were not described. ACMG PP4 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8971 1837 58 3 10183772 10183772 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8971 https://civicdb.org/links/variants/1837 https://civicdb.org/links/genes/58 false VHL 7428 P86S (c.256C>T) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Retinal capillary hemangioma,Renal cell carcinoma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 42 had p.Pro86Ser (c.256C>T) mutation. One member was affected with hemangioblastoma, retinal angioma, and RCC. Other demographics of the members were not described. ACMG PP4 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8972 1902 58 3 10183787 10183787 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:46 UTC https://civicdb.org/links/evidence_items/8972 https://civicdb.org/links/variants/1902 https://civicdb.org/links/genes/58 false VHL 7428 P86L (c.257C>T) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma, renal cell carcinoma, and pheochromocytoma was available. Case 39 had p.Pro86Leu (c.257C>T) mutation. One member was affected with retinal angioma. Other demographics of the members were not described. ACMG PP4 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8973 1760 58 3 10183788 10183788 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8973 https://civicdb.org/links/variants/1760 https://civicdb.org/links/genes/58 false VHL 7428 W88S (c.263G>C) Von Hippel-Lindau Disease 14175 Renal cell carcinoma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregared with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS Hb, RCC, and Pheo was available. Case 8 had p.Trp88Ser mutation. 5 members were affected with renal cell carcinoma. Other demographics of the members were not described. ACMG PP4 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8985 1966 58 3 10183794 10183794 G C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8985 https://civicdb.org/links/variants/1966 https://civicdb.org/links/genes/58 false VHL 7428 T157I (c.470C>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma,Renal cell carcinoma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma, renal cell carcinoma (RCC), and pheochromocytoma was available. Case 45 had a p.Thr157Ile (c.470C>T) mutation. 2 members were affected: one had RCC and the other had RCC and pheochromocytoma (ACMG PP4). Other demographics of the members were not described. 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8988 1745 58 3 10191477 10191477 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8988 https://civicdb.org/links/variants/1745 https://civicdb.org/links/genes/58 false VHL 7428 C162R (c.484T>C) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 4 had a C162R (c.484T>C) mutation. 2 members were affected: both had RCC, 1 had retinal angioma, and 1 had CNS Hb (ACMG PP4). We were not able to determine which member had more than one phenotype. Other demographics of the members were not described. 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8989 1772 58 3 10191491 10191491 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8989 https://civicdb.org/links/variants/1772 https://civicdb.org/links/genes/58 false VHL 7428 C162Y (c.485G>A) Von Hippel-Lindau Disease 14175 Hemangioblastoma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb), renal cell carcinoma (RCC), and pheochromocytoma was available. Case 11 had a p.Cys162Tyr (c.485G>A) mutation. 4 members were affected with CNS Hb (ACMG PP4). Other demographics of the members were not described. 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8990 1824 58 3 10191492 10191492 G A ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8990 https://civicdb.org/links/variants/1824 https://civicdb.org/links/genes/58 false VHL 7428 R167W (c.499C>T) Von Hippel-Lindau Disease 14175 Pheochromocytoma,Retinal capillary hemangioma,Hemangioblastoma,Renal cell carcinoma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 19 had an R167W (c.499C>T) mutation. 1 member was affected with RCC, pheochromocytoma, CNS Hb, and retinal hemangioma (ACMG PP4). Other demographics of the members were not described. 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8991 1747 58 3 10191506 10191506 C T ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8991 https://civicdb.org/links/variants/1747 https://civicdb.org/links/genes/58 false VHL 7428 R167Q (c.500G>A) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Renal cell carcinoma,Retinal capillary hemangioma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb), renal cell carcinoma (RCC), and pheochromocytoma was available. Case 5 had an R167Q (c.500G>A) mutation. 2 members were affected: 1 had RCC, CNS Hb, and retinal hemangioma. The other had CNS Hb and retinal hemangioma. (ACMG PP4) Other demographics of the members were not described. 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8992 1739 58 3 10191507 10191507 G A ENST00000256474.2 75 GRCh37 R167Q is the most common point mutation in hereditary Von Hippel-Lindau (VHL) disease and disrupts the VHL genes binding to elongin C reducing the levels of the VHL-elongin B-elongin C (VBC) E3 ligase complex and inhibiting the ability of VHL to regulate HIF2α. This partial function in turn leads to an increased risk of tumorgenesis. VHL derived clear cell renal cell carcinoma models however have shown the proteasome inhibitors bortezomib and carfilzomib can act to stabilize mutant VHL-R167Q leading to downregulation of HIF2α and suprressed tumorgenesis. Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8992 https://civicdb.org/links/variants/1739 https://civicdb.org/links/genes/58 false VHL 7428 L178P (c.533T>C) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Renal cell carcinoma,Hemangioblastoma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregared with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS Hb, RCC, and Pheo was available. Case 34 had an c.533T>C mutation. 1 member was affected with RCC, CNS Hb, and retinal hemangioma (ACMG PP4). Other demographics of the members were not described. 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8993 1748 58 3 10191540 10191540 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8993 https://civicdb.org/links/variants/1748 https://civicdb.org/links/genes/58 false VHL 7428 Null (Large deletion) Von Hippel-Lindau Disease 14175 Retinal capillary hemangioma,Renal cell carcinoma,Hemangioblastoma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregared with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS Hb, RCC, and Pheo was available. Case 20, 23, and 30 were found with complete VHL deletions. Phenotypes found in the patients included RCC, retinal capillary hemangioma and hemangioblastoma (ACMG PP4). Other demographics of the members were not described. 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8994 2182 58 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8994 https://civicdb.org/links/variants/2182 https://civicdb.org/links/genes/58 false VHL 7428 R120fs (c.358_359insAC) Von Hippel-Lindau Disease 14175 Renal cell carcinoma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 14 had p.Arg120fs ( c.358insAC) mutation. 2 members were affected with renal cell carcinoma (ACMG PP4). Other demographics of the members were not described. 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8995 3244 58 3 10188215 10188216 AC ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8995 https://civicdb.org/links/variants/3244 https://civicdb.org/links/genes/58 false VHL 7428 S80fs (c.239del) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Retinal capillary hemangioma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 22 had p.Ser80fs (c.239del) mutation. One member was affected with retinal capillary hemangioma and hemangioblastoma (ACMG PP4). Other demographics of the members were not described. 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8996 2511 58 3 10183770 10183770 G ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8996 https://civicdb.org/links/variants/2511 https://civicdb.org/links/genes/58 false VHL 7428 C77fs (c.230del) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Hemangioblastoma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregared with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS Hb, RCC, and Pheo was available. Case 16 had p.Cys77fs mutation and one affected member with hemangioblastoma and renal cell carcinoma. ACMG PP4 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8997 3245 58 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8997 https://civicdb.org/links/variants/3245 https://civicdb.org/links/genes/58 false VHL 7428 L118P (c.353T>C) Von Hippel-Lindau Disease 14175 Renal cell carcinoma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma, renal cell carcinoma (RCC), and pheochromocytoma was available. Case 46 had p.Leu117Pro (c.353T>C) mutation. 1 member was affected with RCC (ACMG PP4). Other demographics of the members were not described. 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8998 1798 58 3 10188210 10188210 T C ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8998 https://civicdb.org/links/variants/1798 https://civicdb.org/links/genes/58 false VHL 7428 Q96_P97delinsH (c.288_290del) Von Hippel-Lindau Disease 14175 Renal cell carcinoma,Retinal capillary hemangioma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma, renal cell carcinoma (RCC), and pheochromocytoma was available. Case 25 had c.288delGCC mutation resulting in the replacement of Q96 and P97 with H. 1 member was affected with retinal angioma and RCC (ACMG PP4). Other demographics of the members were not described. 8634692 PubMed 1995, Hum Mol Genet 3 accepted 8999 3246 58 3 10183819 10183821 GCC ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/8999 https://civicdb.org/links/variants/3246 https://civicdb.org/links/genes/58 false VHL 7428 G144fs (c.429_439del) Von Hippel-Lindau Disease 14175 Hemangioblastoma,Retinal capillary hemangioma,Renal cell carcinoma Predisposing N/A C N/A Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 26 had a G144fs (c.429_439del) frameshift mutation. 1 member was affected with retinal angioma, CNS hemangioblastoma, and renal cell carcinoma (ACMG PP4). Other demographics of the members were not described. 8634692 PubMed 1995, Hum Mol Genet 3 accepted 9000 3247 58 3 10188285 10188295 ACGGACAGCCT ENST00000256474.2 75 GRCh37 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/9000 https://civicdb.org/links/variants/3247 https://civicdb.org/links/genes/58 false BRAF 673 V600E Thyroid Gland Papillary Carcinoma 3969 Vemurafenib Predictive Supports B Sensitivity/Response Open label phase 2 (Clinical Level B) trial including patients from across the globe (USA, Italy, and the Netherlands) investigating sensitivity to Vemurafenib in patients that have BRAF V600E-positive papillary thyroid cancer that have become resistant to radioactive iodine (the standard treatment). There were 116 patients identified for this trial, 51 of which met the conditions to be included. These 51 patients were split into two cohorts: 1) patients that had never been treated with a multikinase inhibitor targeting VEGFR and 2) patients that have previously been treated with a VEGFR multikinase inhibitor. In cohort 1, ten of 26 patients had best overall response. Best overall response was defined as the proportion of patients with a complete or partial response, however these ten patients were all partial response. In the same cohort 1, nine had achieved stable disease control for at least six months; therefore, 19 patients achieved disease control (73% of total cohort 1, 95% CI 52-88). In cohort 2, of 23 eligible patients, six had a partial response as best overall response and six had stable disease control for at least six months; therefore, 12 patients achieved disease control. (55% of total cohort 2, 95% CI 32-76). The authors conclude that vemurafenib is a potential treatment option for late-stage BRAF V600E-positive papillary thyroid cancer for treatment in patients naïve to a multikinase inhibitor (Cohort 1) and to patients that have been previously treated with a multikinase inhibitor (Cohort 2). 27460442 PubMed Brose et al., 2016, Lancet Oncol. NCT01286753 4 accepted 9018 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2021-01-26 23:27:12 UTC https://civicdb.org/links/evidence_items/9018 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false VHL 7428 Null (Large deletion) Von Hippel-Lindau Disease 14175 Pancreatic endocrine tumor Predisposing N/A C N/A 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 6 patients were found to have the large germline deletions in the VHL gene. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP4' because phenotype consistent with VHL disease. 20660572 PubMed Erlic et al., 2010, Endocr. Relat. Cancer 2 accepted 9020 2182 58 Rare Germline 2022-01-12 17:35:47 UTC https://civicdb.org/links/evidence_items/9020 https://civicdb.org/links/variants/2182 https://civicdb.org/links/genes/58 false ABL1 25 ETV6::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Diagnostic Supports B Positive This study determined the incidence, clinical characteristics and associated genetic abnormalities in hematologic malignancies with the ETV6-ABL1 fusion. The total of 44 new and previously published ETV6-ABL1 positive cases were detected and characterized using conventional cytogenetics, FISH, RT-PCR, SNP/copy number arrays, expression arrays and a custom Taqman 'low-density array' (LDA card). Among the 44 cases, there were 22 cases of B-ALL (13 children, 9 adults), and 22 myeloid malignancies (18 myeloproliferative neoplasms, and 4 acute myeloid leukemias). The 9 ETV6-ABL1 positive ALL cases (7 diagnosis and 2 relapse samples) that underwent whole genome expression profiling displayed similar expression profiles to the BCR-ABL1 positive leukemia cohort. Also, 9/10 ETV6-ABL1 BCP-ALL cases were classified by custom Taqman assay (designed to detect BCR-ABL1-like expression signature) as BCR-ABL1-like. The study thus shows that in B-ALL, the presence of the ETV6-ABL1 fusion correlates with the BCR-ABL1 like (Ph-like) subtype of the disease. 27229714 PubMed Zaliova et al., 2016, Haematologica 4 accepted 9073 2575 4 Somatic 2021-05-17 21:29:41 UTC https://civicdb.org/links/evidence_items/9073 https://civicdb.org/links/variants/2575 https://civicdb.org/links/genes/4 false ABL1 25 NUP214::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Young adult onset,Juvenile onset Diagnostic Supports C Positive Transcriptome and whole genome sequencing were performed on 15 cases of B-lymphoblastic leukemia/lymphoma (B-ALL) that were previously shown to have a BCR-ABL1-like (Ph-like) expression signature. Two cases were positive for the NUP214-ABL1 fusion, identified by RNA-seq analysis. In both cases the fusion was generated by a small copy number gain (duplication) in 9q34, with the breakpoints in the two partner genes. Considering the previously shown Ph-like expression signature in the studied cases, the results suggest association of the NUP214-ABL1 fusion in B-ALL with the Ph-like genetic subtype of the disease. 22897847 PubMed Roberts et al., 2012, Cancer Cell 2 accepted 9074 2660 4 9 134000948 134106156 ENST00000359428.5 9 133730188 133763062 ENST00000318560.5 75 GRCh37 The NUP214 -ABL1 fusion is composed of part of the NUP214 (Nucleoporin 214) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 34 of NUP214 to exon 2 of ABL1 (NUP214-ABL1 34-2). In T-ALL, the fusion is typically expressed from amplified extrachromosomal bodies (episomes) that arise when the genomic region from ABL1 to NUP214 circularizes to generate the NUP214-ABL1 fusion. In B-ALL, the fusion commonly results from an intrachromosomal duplication involving chromosome 9, with breakpoints within the NUP214 and ABL1 genes. The fusion has been identified in 6% of cases of T-lymphoblastic leukemia and rare cases of B-lymphoblastic leukemia by multiplex ligation-dependent probe amplification, single nucleotide polymorphism array, real-time polymerase chain reaction, and fluorescence in situ hybridization targeting the ABL1 gene. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the WD40 repeat and coiled-coil domains of NUP214 and the SH2, tyrosine kinase, and F actin binding domains of ABL1, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and MAPK and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The case report that illustrates the clinical significance of the NUP214-ABL1 fusion describes a 6-year-old boy and a 15-year-old girl with BCR-ABL1-like B-lymphoblastic leukemia with normal karyotype. Both patients demonstrated minimal residual disease after induction chemotherapy, and later experienced relapse after either consolidation therapy or bone marrow transplant. Dasatinib was then prescribed and follow-up information is available for the older child, who successfully achieved a complete response for three months before succumbing to the disease. The clinical details of this case could predict response to treatment with tyrosine kinase inhibitors and is the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-05-17 13:24:45 UTC https://civicdb.org/links/evidence_items/9074 https://civicdb.org/links/variants/2660 https://civicdb.org/links/genes/4 false ABL1 25 RCSD1::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Young adult onset,Juvenile onset Diagnostic Supports C Positive This study included 1389 cases of high-risk pediatric B-ALL, of which 284 were identified by TaqMan Low Density Array to have a Ph-like gene expression signature. RT-PCR or RNAseq performed on Ph-like, CRLF2 negative patients revealed 17 cases with ABL1 fusions with 8 different partner genes. There was one case with the RCSD1-ABL1 fusion. Considering the previously confirmed Ph-like signature in the tested cases, the results suggest that the presence of the RCSD1-ABL1 fusion in B-ALL correlates with the BCR-ABL1-like (Ph-like) subtype of the disease. 28408464 PubMed Reshmi et al., 2017, Blood 2 accepted 9075 2681 4 The RCSD1-ABL1 fusion is composed of part of the RCSD1 (RCS Domain Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 2 or, more frequently, exon 3 of RCSD1 to exon 4 of ABL1 (RCSD1-ABL1 3-4). The fusion is the result of a reciprocal translocation t(1;9)(q24.2;q34.12) and has been identified by FISH/karyotype, RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the ABL1 SH2, actin binding domain, and tyrosine kinase domain, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The RCSD1-ABL1 fusion has been documented in greater than fifteen pediatric and adult patients with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. The majority that that were exposed to tyrosine kinase inhibitors (TKIs: imatinib, dasatinib, or ponatinib) experienced durable remissions until the TKIs were discontinued. The clinical details of these cases may predict response to treatment with TKIs and are the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-04-23 17:16:16 UTC https://civicdb.org/links/evidence_items/9075 https://civicdb.org/links/variants/2681 https://civicdb.org/links/genes/4 false ABL1 25 RANBP2::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Juvenile onset,Young adult onset Diagnostic Supports C Positive This study included 1389 cases of high-risk pediatric B-ALL, of which 284 were identified by TaqMan Low Density Array to have a Ph-like gene expression signature. RT-PCR or RNAseq performed on Ph-like, CRLF2 negative patients revealed 17 cases with ABL1 fusions with 8 different partner genes. There were three cases with the RANBP2-ABL1 fusion. Considering the previously confirmed Ph-like expression signature in the tested cases, the results suggest that the presence of the RANBP2-ABL1 fusion in B-ALL indicates the BCR-ABL1-like (Ph-like) subtype of the disease. 28408464 PubMed Reshmi et al., 2017, Blood 2 accepted 9076 3268 4 2 109336063 109375004 ENST00000283195 9 133729451 133763062 ENST00000372348.2 75 GRCh37 The RANBP2-ABL1 fusion is composed of part of the RANBP2 (RAN Binding Protein 2) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 18 of RANBP2 to exon 2 of ABL1 (RANBP2-ABL1 18-2). The fusion is the result of a reciprocal translocation t(2;9)(p12.3;q34.12) and has been identified by FISH/karyotype and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, includes the leucine zipper of RANBP2 and the tyrosine kinase of ABL1, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The RANBP2-ABL1 fusion has been documented in several juvenile and young adult patients with B-lymphoblastic leukemia, some of which were further classified as BCR-ABL1 (Ph)-like subtype. Most of the documented patients were treated with a tyrosine kinase inhibitor (specifically dasatinib) added to their chemotherapy regimens, but they eventually experienced relapse and succumbed to their disease. The use of tyrosine kinase inhibitors is the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-04-22 04:56:45 UTC https://civicdb.org/links/evidence_items/9076 https://civicdb.org/links/variants/3268 https://civicdb.org/links/genes/4 false ABL1 25 ZMIZ1::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Young adult onset,Juvenile onset Diagnostic Supports C Positive This study included 1389 cases of high-risk pediatric B-ALL, of which 284 were identified by TaqMan Low Density Array to have a BCR-ABL1-like (Ph-like) gene expression signature. RT-PCR or RNAseq performed on Ph-like, CRLF2 negative patients revealed 17 cases with ABL1 fusions with 8 different partner genes. There were three cases with the ZMIZ1-ABL1 fusion. Considering the previously confirmed Ph-like expression signature in the tested cases, the results suggest that the presence of the ZMIZ1-ABL1 fusion in B-ALL indicates the BCR-ABL1-like (Ph-like) subtype of the disease. 28408464 PubMed Reshmi et al., 2017, Blood 2 accepted 9077 3269 4 10 80828792 81061969 ENST00000334512.5 9 133729451 133763062 ENST00000318560.5 75 GRCh37 The ZMIZ1-ABL1 fusion is composed of part of the ZMIZ1 (Zinc Finger MIZ-Type Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The most commonly published breakpoint joins exon 18 of ZMIZ1 to exon 2 of ABL1 (ZMIZ1-ABL1 18-2). The fusion is the result of a reciprocal translocation t(9;10)(q34.12;q22.3) and has been identified by FISH/karyotype, RT-PCR, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, which contains one of the proline-rich domains of ZMIZ1 and the ABL1 tyrosine kinase domain. Similar to other oncogenic fusion proteins, the proline-rich domain of ZMIZ1 is involved in protein-protein interactions, and therefore the fusion may encode a constitutively activated tyrosine kinase that upregulates the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Patients harboring the ZMIZ1-ABL1 fusion are hypothesized to be eligible for imatinib therapy. Somatic 2021-04-23 17:19:35 UTC https://civicdb.org/links/evidence_items/9077 https://civicdb.org/links/variants/3269 https://civicdb.org/links/genes/4 false ABL1 25 CENPC::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Juvenile onset Diagnostic Supports C Positive This study included 1389 cases of high-risk pediatric B-ALL, of which 284 were identified by TaqMan Low Density Array to have a BCR-ABL1-like (Ph-like) gene expression signature. RT-PCR or RNAseq performed on Ph-like, CRLF2 negative patients revealed 17 cases with ABL1 fusions with 8 different partner genes. There was one case of the CENPC-ABL1 fusion in a 15-year-old patient. Considering the previously confirmed Ph-like expression signature in the tested cases, the results suggest that the presence of the CENPC-ABL1 fusion in B-ALL indicates the BCR-ABL1-like (Ph-like) subtype of the disease. 28408464 PubMed Reshmi et al., 2017, Blood 2 accepted 9078 3270 4 The CENPC-ABL1 fusion is composed of part of the CENPC (Centromere Protein C) gene at the 5’ end (N-terminus of the fusion protein) and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The CENPC-ABL1 fusion is in-frame and it has been documented in one pediatric patient with high risk BCR-ABL1-like B-lymphoblastic leukemia. Somatic 2021-09-18 22:01:52 UTC https://civicdb.org/links/evidence_items/9078 https://civicdb.org/links/variants/3270 https://civicdb.org/links/genes/4 false ABL1 25 NUP153::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Young adult onset,Juvenile onset Diagnostic Supports C Positive This study included 1389 cases of high-risk pediatric B-ALL, of which 284 were identified by TaqMan Low Density Array to have a BCR-ABL1-like (Ph-like) gene expression signature. RT-PCR or RNAseq performed on Ph-like, CRLF2 negative patients revealed 17 cases with ABL1 fusions with 8 different partner genes. There was one case of the NUP153-ABL1 fusion. Considering the previously confirmed Ph-like expression signature in the tested cases, the results suggest that the presence of the NUP153-ABL1 fusion in B-ALL indicates the BCR-ABL1-like (Ph-like) subtype of the disease. 28408464 PubMed Reshmi et al., 2017, Blood 2 accepted 9079 3271 4 The NUP153-ABL1 fusion is composed of part of the NUP153 (Nucleoporin 153) gene at the 5’ end (N-terminus of the fusion protein) and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein, and the inclusion of the ABL1 tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. The NUP153-ABL1 has been documented in one pediatric patient with BCR-ABL1-like B-lymphoblastic leukemia, as detected by RNA kinome capture and transcriptome sequencing. Somatic 2021-04-22 05:07:50 UTC https://civicdb.org/links/evidence_items/9079 https://civicdb.org/links/variants/3271 https://civicdb.org/links/genes/4 false ABL1 25 LSM14A::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Juvenile onset,Young adult onset Diagnostic Supports C Positive This retrospective study included 1389 cases of high-risk pediatric B-ALL, of which 284 were identified by TaqMan Low Density Array to have a BCR-ABL1-like (Ph-like) gene expression signature. RT-PCR or RNAseq performed on Ph-like, CRLF2 negative patients revealed 17 cases with ABL1 fusions with 8 different partner genes. There was one case of the LSM14A-ABL1 fusion. Considering the previously confirmed Ph-like expression signature in the tested cases, the results suggest that the presence of the LSM14A-ABL1 fusion in B-ALL indicates the BCR-ABL1-like (Ph-like) subtype of the disease. 28408464 PubMed Reshmi et al., 2017, Blood 2 accepted 9080 3272 4 The LSM14A-ABL1 fusion is composed of part of the LSM14A (LSM14A mRNA processing body assembly factor) gene at the 5’ end (N-terminus of the fusion protein) and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The fusion is in-frame and it has been documented in two patients with BCR-ABL1-like B-lymphoblastic leukemia (Ph-like ALL). The first patient was a child with high risk Ph-like ALL and the second patient was a 36 years old male who had a poor prednisone response and did not reach complete remission after vincristine-dexamethasone-rituximab or a combination of dasatinib and chemotherapy. The second patient died early of sepsis in a context of uncontrolled disease (survival 2 months). Somatic 2021-03-22 20:34:21 UTC https://civicdb.org/links/evidence_items/9080 https://civicdb.org/links/variants/3272 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL G250E Cancer 162 Dasatinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line stably expressing the G250E mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with increased sensitivity to dasatinib treatment (IC50: 27.2 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 87.6 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 9083 1023 4 9 133738349 133738349 G A ENST00000318560.5 75 GRCh37 Somatic 2021-02-18 01:25:06 UTC https://civicdb.org/links/evidence_items/9083 https://civicdb.org/links/variants/1023 https://civicdb.org/links/genes/4 false ABL1 25 BCR::ABL H396P Cancer 162 Dasatinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line stably expressing H396P in the ABL1 portion of the BCR-ABL1 fusion protein was associated with increased sensitivity to dasatinib treatment (IC50: 8.9 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 87.6 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. 18191450 PubMed Deguchi et al., 2008, Leuk. Res. 3 accepted 9084 1531 4 9 133750356 133750356 A C ENST00000318560.5 75 GRCh37 Somatic 2021-02-18 01:25:40 UTC https://civicdb.org/links/evidence_items/9084 https://civicdb.org/links/variants/1531 https://civicdb.org/links/genes/4 false ABL1 25 NUP214::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Pediatric onset,Juvenile onset Prognostic Supports B Better Outcome A multicenter, retrospective, cohort study that included 122 pediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukemia who had not received tyrosine-kinase inhibitor treatment as a first-line therapy. ABL-class genes included ABL1, ABL2, CSF1R and PDGFRB. There were 33% of patients (40/122) that harbored an ABL1 fusion, including 7 with a NUP214-ABL1 fusion. For patients that were ABL1 fusion positive the 5-year event-free survival was 68.6% (54.5-86.3), the 5-year overall survival was 82.9% (71.2-96.4) and the 5-year cumulative incidence of relapse was 29.6% (15.0-45.9). Additionally ABL1 fusion positive patients had the lowest levels of MRD at the end of induction therapy (20/29 evaluable patients had less than 10^-2). Of patients with NUP214-ABL1, 4/7 had MRD <10^-2 at the end of induction. 33357483 PubMed den Boer et al., 2021, Lancet Haematol 3 accepted 9148 2660 4 9 134000948 134106156 ENST00000359428.5 9 133730188 133763062 ENST00000318560.5 75 GRCh37 The NUP214 -ABL1 fusion is composed of part of the NUP214 (Nucleoporin 214) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 34 of NUP214 to exon 2 of ABL1 (NUP214-ABL1 34-2). In T-ALL, the fusion is typically expressed from amplified extrachromosomal bodies (episomes) that arise when the genomic region from ABL1 to NUP214 circularizes to generate the NUP214-ABL1 fusion. In B-ALL, the fusion commonly results from an intrachromosomal duplication involving chromosome 9, with breakpoints within the NUP214 and ABL1 genes. The fusion has been identified in 6% of cases of T-lymphoblastic leukemia and rare cases of B-lymphoblastic leukemia by multiplex ligation-dependent probe amplification, single nucleotide polymorphism array, real-time polymerase chain reaction, and fluorescence in situ hybridization targeting the ABL1 gene. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the WD40 repeat and coiled-coil domains of NUP214 and the SH2, tyrosine kinase, and F actin binding domains of ABL1, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and MAPK and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The case report that illustrates the clinical significance of the NUP214-ABL1 fusion describes a 6-year-old boy and a 15-year-old girl with BCR-ABL1-like B-lymphoblastic leukemia with normal karyotype. Both patients demonstrated minimal residual disease after induction chemotherapy, and later experienced relapse after either consolidation therapy or bone marrow transplant. Dasatinib was then prescribed and follow-up information is available for the older child, who successfully achieved a complete response for three months before succumbing to the disease. The clinical details of this case could predict response to treatment with tyrosine kinase inhibitors and is the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-03-31 21:03:39 UTC https://civicdb.org/links/evidence_items/9148 https://civicdb.org/links/variants/2660 https://civicdb.org/links/genes/4 false ABL1 25 ZMIZ1::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Pediatric onset,Young adult onset Prognostic Supports B Better Outcome A multicenter, retrospective, cohort study that included 122 paediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukemia who had not received tyrosine-kinase inhibitor treatment as a first-line therapy. ABL-class genes included ABL1, ABL2, CSF1R and PDGFRB. There were 33% of patients (40/122) that harbored an ABL1 fusion, including 16 with a ZMIZ1-ABL1 fusion. For patients that were ABL1 fusion positive the 5-year event-free survival was 68.6% (54.5-86.3), the 5-year overall survival was 82.9% (71.2-96.4) and the 5-year cumulative incidence of relapse was 29.6% (15.0-45.9). Additionally ABL1 fusion positive patients had the lowest levels of MRD at the end of induction therapy. Patients with ZMIZ1-ABL1 had a median MRD between 10^-3 and <10^4 at the end of induction, but between fusion parters, MRD did not differ significantly. 33357483 PubMed den Boer et al., 2021, Lancet Haematol 4 accepted 9149 3269 4 10 80828792 81061969 ENST00000334512.5 9 133729451 133763062 ENST00000318560.5 75 GRCh37 The ZMIZ1-ABL1 fusion is composed of part of the ZMIZ1 (Zinc Finger MIZ-Type Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The most commonly published breakpoint joins exon 18 of ZMIZ1 to exon 2 of ABL1 (ZMIZ1-ABL1 18-2). The fusion is the result of a reciprocal translocation t(9;10)(q34.12;q22.3) and has been identified by FISH/karyotype, RT-PCR, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, which contains one of the proline-rich domains of ZMIZ1 and the ABL1 tyrosine kinase domain. Similar to other oncogenic fusion proteins, the proline-rich domain of ZMIZ1 is involved in protein-protein interactions, and therefore the fusion may encode a constitutively activated tyrosine kinase that upregulates the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Patients harboring the ZMIZ1-ABL1 fusion are hypothesized to be eligible for imatinib therapy. Somatic 2021-09-19 15:42:02 UTC https://civicdb.org/links/evidence_items/9149 https://civicdb.org/links/variants/3269 https://civicdb.org/links/genes/4 false ABL1 25 NUP214::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Young adult onset Dasatinib,Ponatinib,Imatinib,Nilotinib Substitutes Predictive Does Not Support D Sensitivity/Response A 22-year-old male with B-cell acute lymphoblastic leukemia was treated with induction therapy. FISH using a BCR-ABL1 probe demonstrated 50-80 extrachromosomal copies of ABL1; FISH using probes to the 3' regions of ABL1 and NUP214 confirmed NUP214-ABL1 amplification in ~99% of cells. The NUP214-ABL1 amplification was also confirmed by MLPA and SNP6.0 analysis. Additionally, this patient harbored a focal deletion of IKZF1 (exons 2-7) and CDKN2A/B (exons 1-2). Day 29 marrow showed complete morphological remission; however PCR-based IgVH MRD rearrangement studies revealed clonal IgVH rearrangement (1 in 10^4 cells). Patient underwent sibling donor allogenic stem cell transplant, and at 4 months is in complete remission. NUP214-ABL1 positive patient primary cells were cultured with various tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, and ponatinib). After 72-hour culture there was no significant reduction in viable cell numbers or increase in apoptosis, when compared to the no drug control. The in vitro sensitivity to TKIs may be attributed to variable NUP214-ABL1 copy number and/or focal deletions of IKZF1 and CDKN2A/B. 23175662 PubMed Eyre et al., 2012, Blood 2 accepted 9150 2660 4 9 134000948 134106156 ENST00000359428.5 9 133730188 133763062 ENST00000318560.5 75 GRCh37 The NUP214 -ABL1 fusion is composed of part of the NUP214 (Nucleoporin 214) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 34 of NUP214 to exon 2 of ABL1 (NUP214-ABL1 34-2). In T-ALL, the fusion is typically expressed from amplified extrachromosomal bodies (episomes) that arise when the genomic region from ABL1 to NUP214 circularizes to generate the NUP214-ABL1 fusion. In B-ALL, the fusion commonly results from an intrachromosomal duplication involving chromosome 9, with breakpoints within the NUP214 and ABL1 genes. The fusion has been identified in 6% of cases of T-lymphoblastic leukemia and rare cases of B-lymphoblastic leukemia by multiplex ligation-dependent probe amplification, single nucleotide polymorphism array, real-time polymerase chain reaction, and fluorescence in situ hybridization targeting the ABL1 gene. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the WD40 repeat and coiled-coil domains of NUP214 and the SH2, tyrosine kinase, and F actin binding domains of ABL1, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and MAPK and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The case report that illustrates the clinical significance of the NUP214-ABL1 fusion describes a 6-year-old boy and a 15-year-old girl with BCR-ABL1-like B-lymphoblastic leukemia with normal karyotype. Both patients demonstrated minimal residual disease after induction chemotherapy, and later experienced relapse after either consolidation therapy or bone marrow transplant. Dasatinib was then prescribed and follow-up information is available for the older child, who successfully achieved a complete response for three months before succumbing to the disease. The clinical details of this case could predict response to treatment with tyrosine kinase inhibitors and is the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-06-24 14:47:45 UTC https://civicdb.org/links/evidence_items/9150 https://civicdb.org/links/variants/2660 https://civicdb.org/links/genes/4 false ABL1 25 ZMIZ1::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Childhood onset Oncogenic N/A C N/A A 18-month-old female with B-cell acute lymphoblastic leukemia. Chromosome and FISH analysis using a BCR-ABL1 probe confirmed the involvement of ABL1 in a t(9;10)(q34;q22.3) translocation. Follow-up molecular analysis using RT-PCR confirmed the presence of a ZMIZ1-ABL1 fusion transcript (ZMIZ1 exon 14 and ABL1 exon 2). Patient was treated according to standard risk protocol without kinase inhibitors and is in first complete remission. Authors note that The ZMIZ1-ABL1 fusion transcript predicts the the synthesis of ZMIZ1-ABL fusion protein, which contains one of the proline-rich domains of ZMIZ1 and ABL tyrosine kinase domain. Similar to other oncogenic fusion proteins, the proline-rich domain of ZMIZ1 is involved in protein-protein interactions, and therefore the fusion may encode a constitutively activated tyrosine kinase that promotes cellular transformation. The authors further note that patients with t(9;10) would be eligible for imatinib treatment. 18007576 PubMed Soler et al., 2008, Leukemia 1 accepted 9151 3269 4 10 80828792 81061969 ENST00000334512.5 9 133729451 133763062 ENST00000318560.5 75 GRCh37 The ZMIZ1-ABL1 fusion is composed of part of the ZMIZ1 (Zinc Finger MIZ-Type Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The most commonly published breakpoint joins exon 18 of ZMIZ1 to exon 2 of ABL1 (ZMIZ1-ABL1 18-2). The fusion is the result of a reciprocal translocation t(9;10)(q34.12;q22.3) and has been identified by FISH/karyotype, RT-PCR, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, which contains one of the proline-rich domains of ZMIZ1 and the ABL1 tyrosine kinase domain. Similar to other oncogenic fusion proteins, the proline-rich domain of ZMIZ1 is involved in protein-protein interactions, and therefore the fusion may encode a constitutively activated tyrosine kinase that upregulates the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Patients harboring the ZMIZ1-ABL1 fusion are hypothesized to be eligible for imatinib therapy. Somatic 2021-08-19 19:12:50 UTC https://civicdb.org/links/evidence_items/9151 https://civicdb.org/links/variants/3269 https://civicdb.org/links/genes/4 false ABL1 25 ZMIZ1::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Pediatric onset Diagnostic Supports C Positive Study comprised 574 children with newly diagnosed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and focused on B-other/BCR-ABL-like which were identified by hierarchical clustering of gene expression data. RT-PCR followed by Sanger sequencing for detection of tyrosine kinase fusions was performed for 153 cases. There were 14 fusions found among the BCR-ABL-like cases (14/77=18%), which included one case with a ZMIZ1-ABL1 (exon 18 and exon 2). ZMIZ1-AML1 fusion was among a group of nine fusions found, and characterized by the authors as predictive for activated ABL signaling. The 8-year cumulative incidence of relapse for the fusion-positive BCR-ABL1-like group (35%) was comparable to the fusion-negative BCR-ABL1-like group (35%), and worse than non-BCR-ABL1-like B-other group (17%, p=0.07). 27894077 PubMed Boer et al., 2017, Oncotarget 2 accepted 9152 3269 4 10 80828792 81061969 ENST00000334512.5 9 133729451 133763062 ENST00000318560.5 75 GRCh37 The ZMIZ1-ABL1 fusion is composed of part of the ZMIZ1 (Zinc Finger MIZ-Type Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The most commonly published breakpoint joins exon 18 of ZMIZ1 to exon 2 of ABL1 (ZMIZ1-ABL1 18-2). The fusion is the result of a reciprocal translocation t(9;10)(q34.12;q22.3) and has been identified by FISH/karyotype, RT-PCR, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, which contains one of the proline-rich domains of ZMIZ1 and the ABL1 tyrosine kinase domain. Similar to other oncogenic fusion proteins, the proline-rich domain of ZMIZ1 is involved in protein-protein interactions, and therefore the fusion may encode a constitutively activated tyrosine kinase that upregulates the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Patients harboring the ZMIZ1-ABL1 fusion are hypothesized to be eligible for imatinib therapy. Somatic 2021-09-19 15:41:30 UTC https://civicdb.org/links/evidence_items/9152 https://civicdb.org/links/variants/3269 https://civicdb.org/links/genes/4 false ABL1 25 LSM14A::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Young adult onset Prognostic Supports C Poor Outcome This retrospective study reported the outcome of 24 patients with Ph-like acute lymphoblastic leukemia (Ph-like ALL) harboring ABL-class fusions who were treated with a combination of tyrosine kinase inhibitors (TKIs) and chemotherapy. Of the 24 patients reported, 12 had fusions involving ABL1 including 1 case with LSM14A-ABL1. The patient with LSM14A-ABL1 was a 36 year old male who also had a IKZF1 intragenic deletion. He had a poor prednisone response and did not reach complete remission after vincristine-dexamethasone-rituximab or a combination of dasatinib and chemotherapy, although some of the patients in this case series appeared to benefit from the introduction of TKIs. The patient died early of sepsis in a context of uncontrolled disease (survival 2 months). 31434701 PubMed Tanasi et al., 2019, Blood 2 accepted 9153 3272 4 The LSM14A-ABL1 fusion is composed of part of the LSM14A (LSM14A mRNA processing body assembly factor) gene at the 5’ end (N-terminus of the fusion protein) and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The fusion is in-frame and it has been documented in two patients with BCR-ABL1-like B-lymphoblastic leukemia (Ph-like ALL). The first patient was a child with high risk Ph-like ALL and the second patient was a 36 years old male who had a poor prednisone response and did not reach complete remission after vincristine-dexamethasone-rituximab or a combination of dasatinib and chemotherapy. The second patient died early of sepsis in a context of uncontrolled disease (survival 2 months). Somatic 2021-08-19 13:31:57 UTC https://civicdb.org/links/evidence_items/9153 https://civicdb.org/links/variants/3272 https://civicdb.org/links/genes/4 false ABL1 25 SFPQ::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Young adult onset Oncogenic N/A C N/A The authors describe two cases of B-lymphoblastic leukemia (B-ALL) with the t(1;9)(p34;q34) rearrangement, resulting in a fusion between the pre-mRNA processing protein gene SFPQ and the ABL1 kinase gene. Patient 1 was a 19-year old female patient with common B-cell ALL expressing 2 myeloid markers. Due to the presence of the 2 myeloid markers, she was treated with a classic acutemyeloid leukemia (AML) induction regimen (cytarabine and idarubicin), along with imatinib due to the involvement of the ABL1 locus. Patient achieved complete remission, followed by a consolidation regimen with cytarabine and mitoxantrone, a non-familial allogeneic hematopoietic stem cell transplantation with a dose-reduced conditioning, and a maintenance treatment with dasatinib. Complete remission was maintained 32 months after the allograft. Patient 2 was a 28 year old female, diagnosed with common B-ALL (EGIL B-II), and was included in the GRAALL 2005 protocol with intensified cyclophosphamide administration, and was corticosensitive but chemoresistant (60% blasts at day 8). She achieved complete remission after the induction regimen, and this was followed by consolidation regimen with cytarabine, high-dose methotrexate and cyclophosphamide. After this, familial allograft with her brother as donor was performed, and she remained in complete remission 18 months after allograft. FISH and sequencing have confirmed the fusion between SFPQ-ex9 and ABL-ex4 in both patients. The authors conclude that the t(1;9)(p34;q34), fusing SFPQ in 1p34 with ABL1 in 9q34, represents a recurrent abnormality in B-ALL. 21388681 PubMed Duhoux et al., 2011, Leuk Res 3 accepted 9158 3287 4 The SFPQ -ABL1 fusion is composed of part of the SFPQ (Splicing factor proline and glutamine rich) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 9 of SFPQ to exon 4 of ABL1 (SFPQ -ABL1). The fusion is the result of a reciprocal translocation t(1;9)(p34;q34) and has been identified by RT-PCR, Sanger sequencing, and RNA sequencing. The role of the partner gene SFPQ in this fusion remains to be investigated. SFPQ encodes for a protein belonging to a new functionally related group of fusion partners for tyrosine kinases involved in pre-mRNA processing. The presence of 2 coiled-coil domains in the 9 remaining exons of SFPQ could theoretically lead to SFPQ–ABL1 oligomerization, thus leading to constitutive activation of the resulting tyrosine kinase, as reported with other partner genes. Though uncommon, this translocation might be targeted by tyrosine kinase inhibitors. Clinical significance: The SFPQ -ABL1 fusion has been documented in six patients (3 male, 3 female) between the ages of 10 and 34 years with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. Two patients had tyrosine kinase inhibitors (dasatinib + imatinib) added to their chemotherapy regimens, who did not have relapse. One additional patient who did not have tyrosine kinase inhibitor also did not suffer from relapse. The clinical details of these cases may predict response to treatment with tyrosine kinase inhibitors. Functional studies are needed to substantiate the efficacy of TKI treatment of this particular ABL-class fusion. Somatic 2021-10-11 07:59:53 UTC https://civicdb.org/links/evidence_items/9158 https://civicdb.org/links/variants/3287 https://civicdb.org/links/genes/4 false ABL1 25 SFPQ::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Young adult onset Imatinib,Dasatinib Sequential Predictive Supports C Sensitivity/Response Using fluorescence in situ hybridization (FISH) analysis with break-apart probes, the authors screened retrospectively 55 pediatric and 50 adult B-lymphoblastic leukemia (B-ALL) cases negative for common drivers (B-other) for rearrangements involving ABL1, ABL2 and PDGFRB tyrosine kinase genes. Three (6%) of the adult but none of the childhood B-other cases were positive for ABL-class aberrations. One of these adult patients was a 29-year old male with a t(1;9)(p34;q34). RT-PCR and sequencing confirmed that the translocation resulted in a rare SFPQ-ABL1 fusion. The patient was treated with allogenic stem-cell transplant with addition of dasatinib and imatinib, and was in remission at the time of publication (28 months after the diagnosis). A review of 6 previously published cases with SFPQ-ABL1 fusion indicated that exon 9 of SFPQ and exon 4 of ABL1 were consistently involved. The fusion was typically found in adolescents/younger adults without hyperleukocytosis, and IKZF1 deletions were recurrently found. In the cases reported, patients who were not treated with tyrosine kinase inhibitors (TKIs) and/or allogeneic stem cell transplantation had relapsed, and the authors therefore suggest that TKIs should be added to the therapy of SFPQ-ABL1-positive B-ALL. 32306475 PubMed Biloglav et al., 2020, Genes Chromosomes Cancer 3 accepted 9159 3287 4 The SFPQ -ABL1 fusion is composed of part of the SFPQ (Splicing factor proline and glutamine rich) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 9 of SFPQ to exon 4 of ABL1 (SFPQ -ABL1). The fusion is the result of a reciprocal translocation t(1;9)(p34;q34) and has been identified by RT-PCR, Sanger sequencing, and RNA sequencing. The role of the partner gene SFPQ in this fusion remains to be investigated. SFPQ encodes for a protein belonging to a new functionally related group of fusion partners for tyrosine kinases involved in pre-mRNA processing. The presence of 2 coiled-coil domains in the 9 remaining exons of SFPQ could theoretically lead to SFPQ–ABL1 oligomerization, thus leading to constitutive activation of the resulting tyrosine kinase, as reported with other partner genes. Though uncommon, this translocation might be targeted by tyrosine kinase inhibitors. Clinical significance: The SFPQ -ABL1 fusion has been documented in six patients (3 male, 3 female) between the ages of 10 and 34 years with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. Two patients had tyrosine kinase inhibitors (dasatinib + imatinib) added to their chemotherapy regimens, who did not have relapse. One additional patient who did not have tyrosine kinase inhibitor also did not suffer from relapse. The clinical details of these cases may predict response to treatment with tyrosine kinase inhibitors. Functional studies are needed to substantiate the efficacy of TKI treatment of this particular ABL-class fusion. Somatic 2021-09-20 14:41:13 UTC https://civicdb.org/links/evidence_items/9159 https://civicdb.org/links/variants/3287 https://civicdb.org/links/genes/4 false ABL1 25 SFPQ::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Young adult onset Diagnostic Supports C Positive A 34-year-old woman was hospitalized because of weakness and mild fever. Physical examination revealed multiple and superficial lymph nodes. Peripheral blood counting showed a 47% blasts. Bone marrow aspirates showed marked hypercellularity and 72.5% blasts, but no Auer body. Karyotype analysis showed a t(1;9)(p34;q34), resulting in a SFPQ-ABL1 fusion. After two courses of VDP induction chemotherapy containing vindesine, daunorubicin, and prednisone, the patient achieved CR with 1.5% blasts in bone marrow. Unfortunately, the patient relapsed with 55% blasts in bone marrow in February 2014. Eventually, the patient died from disease progression. 27894117 PubMed Sheng et al., 2017, Acta Haematol 3 accepted 9160 3287 4 The SFPQ -ABL1 fusion is composed of part of the SFPQ (Splicing factor proline and glutamine rich) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 9 of SFPQ to exon 4 of ABL1 (SFPQ -ABL1). The fusion is the result of a reciprocal translocation t(1;9)(p34;q34) and has been identified by RT-PCR, Sanger sequencing, and RNA sequencing. The role of the partner gene SFPQ in this fusion remains to be investigated. SFPQ encodes for a protein belonging to a new functionally related group of fusion partners for tyrosine kinases involved in pre-mRNA processing. The presence of 2 coiled-coil domains in the 9 remaining exons of SFPQ could theoretically lead to SFPQ–ABL1 oligomerization, thus leading to constitutive activation of the resulting tyrosine kinase, as reported with other partner genes. Though uncommon, this translocation might be targeted by tyrosine kinase inhibitors. Clinical significance: The SFPQ -ABL1 fusion has been documented in six patients (3 male, 3 female) between the ages of 10 and 34 years with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. Two patients had tyrosine kinase inhibitors (dasatinib + imatinib) added to their chemotherapy regimens, who did not have relapse. One additional patient who did not have tyrosine kinase inhibitor also did not suffer from relapse. The clinical details of these cases may predict response to treatment with tyrosine kinase inhibitors. Functional studies are needed to substantiate the efficacy of TKI treatment of this particular ABL-class fusion. Somatic 2021-10-04 18:32:52 UTC https://civicdb.org/links/evidence_items/9160 https://civicdb.org/links/variants/3287 https://civicdb.org/links/genes/4 false ABL1 25 SFPQ::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Young adult onset Oncogenic N/A C N/A A 22-year-old male presenting with B-lymphoblastic leukemia (B-ALL) characterized by a t(1;9)(p34;q34) was found to carry an SFPQ-ABL1 fusion. The fusion was confirmed by amplification of the genomic breakpoints and RT-PCR; it was shown to be in-frame and to encode the N-terminal domain of the SFPQ-encoded protein and the entire tyrosine kinase domain and C-terminal sequences of the ABL1 kinase. The SFPQ (Splicing Factor Proline And Glutamine Rich) gene, encoding a protein that specifically binds to intronic polypyrimidine tracts in pre-mRNA and regulates signal-induced alternative splicing, was thus described as a new 5’ partner of the ABL1 gene in B-ALL. 18205209 PubMed Hidalgo-Curtis et al., 2008, Genes Chromosomes Cancer 2 accepted 9161 3287 4 The SFPQ -ABL1 fusion is composed of part of the SFPQ (Splicing factor proline and glutamine rich) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 9 of SFPQ to exon 4 of ABL1 (SFPQ -ABL1). The fusion is the result of a reciprocal translocation t(1;9)(p34;q34) and has been identified by RT-PCR, Sanger sequencing, and RNA sequencing. The role of the partner gene SFPQ in this fusion remains to be investigated. SFPQ encodes for a protein belonging to a new functionally related group of fusion partners for tyrosine kinases involved in pre-mRNA processing. The presence of 2 coiled-coil domains in the 9 remaining exons of SFPQ could theoretically lead to SFPQ–ABL1 oligomerization, thus leading to constitutive activation of the resulting tyrosine kinase, as reported with other partner genes. Though uncommon, this translocation might be targeted by tyrosine kinase inhibitors. Clinical significance: The SFPQ -ABL1 fusion has been documented in six patients (3 male, 3 female) between the ages of 10 and 34 years with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. Two patients had tyrosine kinase inhibitors (dasatinib + imatinib) added to their chemotherapy regimens, who did not have relapse. One additional patient who did not have tyrosine kinase inhibitor also did not suffer from relapse. The clinical details of these cases may predict response to treatment with tyrosine kinase inhibitors. Functional studies are needed to substantiate the efficacy of TKI treatment of this particular ABL-class fusion. Somatic 2021-09-20 16:52:13 UTC https://civicdb.org/links/evidence_items/9161 https://civicdb.org/links/variants/3287 https://civicdb.org/links/genes/4 false ABL1 25 RCSD1::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Juvenile onset Diagnostic Supports C Positive The study evaluated 15 B-ALL cases which were previously identified as Ph-like using prediction analysis of microarrays (PAM). Paired-end messenger RNA sequencing (RNA-seq) was performed to identify underlying genetic drivers. The RCSD1-ABL1 fusion was identified in a 15 yo boy with confirmed Ph-like B-ALL signature from Children’s Oncology Group (COG) AALL0232 study. WBC was 47.8x109L. Outcome data was not provided. This observation suggests that the presence of the RCSD1-ABL1 fusion in B-ALL is associated with the Ph-like molecular subtype of the disease. 22897847 PubMed Roberts et al., 2012, Cancer Cell 2 accepted 9162 2681 4 The RCSD1-ABL1 fusion is composed of part of the RCSD1 (RCS Domain Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 2 or, more frequently, exon 3 of RCSD1 to exon 4 of ABL1 (RCSD1-ABL1 3-4). The fusion is the result of a reciprocal translocation t(1;9)(q24.2;q34.12) and has been identified by FISH/karyotype, RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the ABL1 SH2, actin binding domain, and tyrosine kinase domain, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The RCSD1-ABL1 fusion has been documented in greater than fifteen pediatric and adult patients with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. The majority that that were exposed to tyrosine kinase inhibitors (TKIs: imatinib, dasatinib, or ponatinib) experienced durable remissions until the TKIs were discontinued. The clinical details of these cases may predict response to treatment with TKIs and are the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-05-17 14:40:23 UTC https://civicdb.org/links/evidence_items/9162 https://civicdb.org/links/variants/2681 https://civicdb.org/links/genes/4 false ABL1 25 RCSD1::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Juvenile onset Diagnostic Supports C Positive De Braekeleer et al. reported a 11-yr-old boy with pre-B ALL associated with a t(1;9)(q24;q34) translocation. FISH analysis using bacterial artificial chromosome (BAC) clones showed colocalization of BACs containing the ABL1 and RCSD1 genes, probably indicating the presence of a RCSD1-ABL1 fusion gene. 17541395 PubMed De Braekeleer et al., 2007, Leukemia 2 accepted 9163 2681 4 The RCSD1-ABL1 fusion is composed of part of the RCSD1 (RCS Domain Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 2 or, more frequently, exon 3 of RCSD1 to exon 4 of ABL1 (RCSD1-ABL1 3-4). The fusion is the result of a reciprocal translocation t(1;9)(q24.2;q34.12) and has been identified by FISH/karyotype, RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the ABL1 SH2, actin binding domain, and tyrosine kinase domain, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The RCSD1-ABL1 fusion has been documented in greater than fifteen pediatric and adult patients with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. The majority that that were exposed to tyrosine kinase inhibitors (TKIs: imatinib, dasatinib, or ponatinib) experienced durable remissions until the TKIs were discontinued. The clinical details of these cases may predict response to treatment with TKIs and are the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-09-19 14:47:46 UTC https://civicdb.org/links/evidence_items/9163 https://civicdb.org/links/variants/2681 https://civicdb.org/links/genes/4 false ABL1 25 RCSD1::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Young adult onset Dasatinib Predictive Supports C Sensitivity/Response Authors reported a 40-yr-old male patient with pre-B ALL and t(1;9)(q24;q34) translocation. Two different RCSD1-ABL1 fusion transcripts, presumably resulting from alternative splicing, were identified, one consisting of the first three exons of RCSD1 fused to ABL1 starting from exon 4, the second of the first two exons of RCSD1 fused to exon 4 of ABL1. The patient received a modified CVAD induction therapy. After 2 induction courses, the BM had residual disease with 50% of leukemic blasts. At day 10 from the start of the 3rd induction regimen, dasatinib was introduced at a dose of 140 mg once daily. Two weeks later morphological remission was confirmed, and only minimal residual disease (1.5% of leukemic cells) was detectable by FISH. The first consolidation therapy consisted of dasatinib 140 mg once daily and high-dose methotrexate. BM at four weeks post consolidation showed complete morphological and cytogenetic remission (CCyR). Dasatinib was continued until an allogeneic hematopoietic stem cell transplantation (HSCT) was performed four months after diagnosis. After transplantation, no TKI therapy was used. At 12 months from HSCT, the patient experienced a cytogenetic relapse and a month later a hematologic relapse. Immunosuppressive drugs were discontinued, and the patient received a re-induction therapy with dasatinib 70 mg twice daily combined with one cycle of high-dose chemotherapy. The patient successfully reentered in CCyR, which has been maintained with dasatinib monotherapy for more than nine months. 19794096 PubMed Mustjoki et al., 2009, Haematologica 3 accepted 9164 2681 4 The RCSD1-ABL1 fusion is composed of part of the RCSD1 (RCS Domain Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 2 or, more frequently, exon 3 of RCSD1 to exon 4 of ABL1 (RCSD1-ABL1 3-4). The fusion is the result of a reciprocal translocation t(1;9)(q24.2;q34.12) and has been identified by FISH/karyotype, RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the ABL1 SH2, actin binding domain, and tyrosine kinase domain, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The RCSD1-ABL1 fusion has been documented in greater than fifteen pediatric and adult patients with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. The majority that that were exposed to tyrosine kinase inhibitors (TKIs: imatinib, dasatinib, or ponatinib) experienced durable remissions until the TKIs were discontinued. The clinical details of these cases may predict response to treatment with TKIs and are the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-09-01 17:58:51 UTC https://civicdb.org/links/evidence_items/9164 https://civicdb.org/links/variants/2681 https://civicdb.org/links/genes/4 false ABL1 25 RCSD1::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Juvenile onset Dasatinib Predictive Supports C Sensitivity/Response Authors reported a 15-year-old female patient with B-ALL diagnosed in June 2014. Conventional cytogenetics and FISH identified t(1;9)(q23;q34) and RCSD1ABL1 fusion. Microarray identified an approximately 70 kb deletion at 7p12.2 disrupting the IKZF1 gene. The patient was enrolled on AALL-1131 and received a 4-drug induction therapy with Vincristine/Daunorubicin/Pegaspargase/Prednisone. Her day 8 peripheral blood minimal residual disease (MRD) testing showed 18–25% blasts and her day 29 bone marrow evaluation revealed induction failure. She continued chemotherapy per the very high-risk control arm of AALL-1131 with the addition of dasatinib due to the RCSD1-ABL1 fusion. Her consolidation course was complicated due to presumed fungal infection and C. difficile colitis, but she was able to complete the consolidation treatment. The last bone marrow done on November 2014 showed no evidence of persistent/recurrent leukemia. The patient had a bone marrow transplant from a sibling in November 2014, but a few weeks after transplant she developed severe sepsis as well as capillary leak syndrome. She remained admitted to the intensive care unit where she unfortunately died on March 12, 2015. 26600955 PubMed Kamran et al., 2015, Case Rep Hematol 2 accepted 9165 2681 4 The RCSD1-ABL1 fusion is composed of part of the RCSD1 (RCS Domain Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 2 or, more frequently, exon 3 of RCSD1 to exon 4 of ABL1 (RCSD1-ABL1 3-4). The fusion is the result of a reciprocal translocation t(1;9)(q24.2;q34.12) and has been identified by FISH/karyotype, RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the ABL1 SH2, actin binding domain, and tyrosine kinase domain, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The RCSD1-ABL1 fusion has been documented in greater than fifteen pediatric and adult patients with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. The majority that that were exposed to tyrosine kinase inhibitors (TKIs: imatinib, dasatinib, or ponatinib) experienced durable remissions until the TKIs were discontinued. The clinical details of these cases may predict response to treatment with TKIs and are the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-08-19 13:55:39 UTC https://civicdb.org/links/evidence_items/9165 https://civicdb.org/links/variants/2681 https://civicdb.org/links/genes/4 false ABL1 25 RCSD1::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Young adult onset Dasatinib Predictive Supports C Reduced Sensitivity Author reported a 31-year-old male patient diagnosed with B-ALL. RT-PCR and sequence analyses detected transcription of a single RCSD1-ABL1 fusion gene variant, which had breakpoints in exon 3 of RCSD1 and exon 4 of ABL1. The patient was treated with hyper-CVAD combination without achieving complete remission (CR). Therefore, the patient was treated with combination chemotherapy comprising 800 mg of imatinib for 7 days and 40 mg of dexamethasone for 4 days followed by 140 mg of dasatinib daily. On day 74, lymphoblasts disappeared from the peripheral blood, but 15% remained in the bone marrow. A second course of hyper-CVAD with 140 mg of dasatinib daily was administered. Twenty days after therapy using 1.5 g of methotrexate and cytarabine (total dose; 18 g), lymphoblasts suddenly increased by 82%. Administration of 40 mg of dexamethasone for 4 days was highly effective in reducing lymphoblast count. Administration of triplicated dexamethasone and dasatinib achieved stable disease with partial remission in the bone marrow. However, during the seventh administration of dexamethasone, the disease recurred and there was no further response to treatment. 21863287 PubMed Inokuchi et al., 2011, Int J Hematol 3 accepted 9166 2681 4 The RCSD1-ABL1 fusion is composed of part of the RCSD1 (RCS Domain Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 2 or, more frequently, exon 3 of RCSD1 to exon 4 of ABL1 (RCSD1-ABL1 3-4). The fusion is the result of a reciprocal translocation t(1;9)(q24.2;q34.12) and has been identified by FISH/karyotype, RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the ABL1 SH2, actin binding domain, and tyrosine kinase domain, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The RCSD1-ABL1 fusion has been documented in greater than fifteen pediatric and adult patients with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. The majority that that were exposed to tyrosine kinase inhibitors (TKIs: imatinib, dasatinib, or ponatinib) experienced durable remissions until the TKIs were discontinued. The clinical details of these cases may predict response to treatment with TKIs and are the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-09-19 14:36:46 UTC https://civicdb.org/links/evidence_items/9166 https://civicdb.org/links/variants/2681 https://civicdb.org/links/genes/4 false ABL1 25 RCSD1::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Young adult onset,Juvenile onset Diagnostic Supports C Positive Authors studied five patients with B-ALL and potential RCSD1-ABL1 fusion. Patients’ age ranged from 11 to 40 years. Patient 1 was previously reported in PMID 17541395. Sequencing showed that the first three exons of RCSD1 were fused to exons 4– 11 of ABL1 in all five patients. Gene expression signature of patient 1 and 3 was distinct from that of ALL patients with BCR–ABL1 gene. Several genes overexpressed in the RCSD1–ABL1 group compared with the BCR–ABL1 group code transcription factors such as AFF1 and PBX4. 23168614 PubMed De Braekeleer et al., 2013, Leukemia 3 accepted 9167 2681 4 The RCSD1-ABL1 fusion is composed of part of the RCSD1 (RCS Domain Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 2 or, more frequently, exon 3 of RCSD1 to exon 4 of ABL1 (RCSD1-ABL1 3-4). The fusion is the result of a reciprocal translocation t(1;9)(q24.2;q34.12) and has been identified by FISH/karyotype, RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the ABL1 SH2, actin binding domain, and tyrosine kinase domain, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The RCSD1-ABL1 fusion has been documented in greater than fifteen pediatric and adult patients with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. The majority that that were exposed to tyrosine kinase inhibitors (TKIs: imatinib, dasatinib, or ponatinib) experienced durable remissions until the TKIs were discontinued. The clinical details of these cases may predict response to treatment with TKIs and are the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-09-19 14:40:53 UTC https://civicdb.org/links/evidence_items/9167 https://civicdb.org/links/variants/2681 https://civicdb.org/links/genes/4 false ABL1 25 RCSD1::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Late onset Dasatinib Predictive Supports C Sensitivity/Response Authors reported a 61-year old female diagnosed with B-ALL in August 2012. The RCSD1-ABL1 t(1;9)(q22;q34) fusion between exon 3 of RCSD1 and exon 4 of ABL1 was identified by RT-PCR. The patient was enrolled on GMALL elderly (01/2003) and treated accordingly with an induction failure. She therefore continued chemotherapy with high-dose methotrexate and asparaginase. Her disease achieved first complete remission in January 2013, and high-dose cytarabine was administered. The patient experienced a BM relapse in April 2013. Re-induction chemotherapy with one cycle of FLAG-Ida comprising fludarabine, cytarabine, GCSF and idarubicin was administered, but BM revealed residual disease with 70% of leukemic blasts in May 2013. The patient was included in the BEZ235 study and treated with an oral PI3K/mTOR inhibitor, but no remission could be achieved. Salvage therapy with single agent dasatinib was initiated at a dose of 100 mg once daily, in July 2013. A stable disease with partial remission in the BM was achieved. Moreover, inhibition of RCSD1-ABL1 activity by dasatinib was shown by Western analysis of phosphorylated ABL1 and its downstream target CRKL. Treatment with dasatinib was complemented with two cycles of chemotherapy, including clofarabine and cyclophosphamide. CR 2 was achieved in October 2013, whereas minimal residual disease (MRD) levels still remained positive. In this regard, treatment with blinatumomab was started within the MT103-203 study in January 2014, and MRD levels became negative. In March 2014, allo-SCT was performed successfully. Since then, there is an ongoing remission that, to date, has lasted 30 months. 28057740 PubMed Frech et al., 2017, Haematologica 3 accepted 9168 2681 4 The RCSD1-ABL1 fusion is composed of part of the RCSD1 (RCS Domain Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 2 or, more frequently, exon 3 of RCSD1 to exon 4 of ABL1 (RCSD1-ABL1 3-4). The fusion is the result of a reciprocal translocation t(1;9)(q24.2;q34.12) and has been identified by FISH/karyotype, RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the ABL1 SH2, actin binding domain, and tyrosine kinase domain, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The RCSD1-ABL1 fusion has been documented in greater than fifteen pediatric and adult patients with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. The majority that that were exposed to tyrosine kinase inhibitors (TKIs: imatinib, dasatinib, or ponatinib) experienced durable remissions until the TKIs were discontinued. The clinical details of these cases may predict response to treatment with TKIs and are the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-09-19 14:35:25 UTC https://civicdb.org/links/evidence_items/9168 https://civicdb.org/links/variants/2681 https://civicdb.org/links/genes/4 false ABL1 25 RCSD1::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Juvenile onset Tyrosine Kinase Inhibitor Predictive Supports C Sensitivity/Response Authors reported a 15-year-old female diagnosed with B-ALL with the t(1;9)(q24;q34.1). RNAseq data were consistent with a fusion between the exon 3 of RCSD1 and exon 4 of ABL1, resulting in the formation of an in-frame RCSD1-ABL1 fusion transcript. The patient achieved complete remission upon addition of TKIs to the post-induction chemotherapy regimen, but developed fatal complications after HSCT. 27855558 PubMed Yap et al., 2017, Leuk Lymphoma 2 accepted 9169 2681 4 The RCSD1-ABL1 fusion is composed of part of the RCSD1 (RCS Domain Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 2 or, more frequently, exon 3 of RCSD1 to exon 4 of ABL1 (RCSD1-ABL1 3-4). The fusion is the result of a reciprocal translocation t(1;9)(q24.2;q34.12) and has been identified by FISH/karyotype, RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the ABL1 SH2, actin binding domain, and tyrosine kinase domain, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The RCSD1-ABL1 fusion has been documented in greater than fifteen pediatric and adult patients with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. The majority that that were exposed to tyrosine kinase inhibitors (TKIs: imatinib, dasatinib, or ponatinib) experienced durable remissions until the TKIs were discontinued. The clinical details of these cases may predict response to treatment with TKIs and are the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-09-19 14:46:20 UTC https://civicdb.org/links/evidence_items/9169 https://civicdb.org/links/variants/2681 https://civicdb.org/links/genes/4 false BRAF 673 V600E Thyroid Gland Papillary Carcinoma 3969 Prognostic Supports B Poor Outcome Clinical study including 219 patients with papillary thyroid cancer (PTC) to determine a correlation between the BRAF V600E mutation and poor oncological outcome. This study found that 107 of the 219 (49%) patients had this mutation signifying that the BRAF V600E mutation is one of the most commonly occurring among PTC patients. This cohort was split into two groups—BRAF+ and BRAF-. Of the 107 patients that were BRAF+, 25% had tumor reoccurrence compared with 9% in the BRAF- group (P=0.004). Multivariate analysis was performed to assess BRAF correlation independent of known contributing factors to cancer such as age, gender, and multifocality. The results showed that the BRAF mutation is indicative/contributes to lymph node metastasis, associated with tumor reoccurrence, stage, and that recurrent disease was more extensive and required more aggressive treatments in BRAF+ patients compared with BRAF- patients. The authors conclude that PTC patients with the BRAF V600E mutation have worse clinicopathological outcomes, and that the BRAF mutation can be used to assess risk stratification in patients with PTC. 16174717 PubMed Xing et al., 2005, J Clin Endocrinol Metab 4 accepted 9170 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2021-03-23 18:31:15 UTC https://civicdb.org/links/evidence_items/9170 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false ABL1 25 ETV6::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Imatinib Predictive Supports C Sensitivity/Response A 4-year-old female presented with relapsed B-cell precursor ALL and no MLL or BCR-ABL1 rearrangement per cytogenetic studies. During multiple periods of short remission and relapse she was treated with high risk induction chemotherapy, craniospinal irradiation and matched unrelated donor bone marrow transplant. Finally, WES and RNA-seq were performed on the tumor and normal samples, which identified a cryptic ETV6-ABL1 fusion as well as a biallelic CDKN2A deletion. She was administered imatinib and achieved a morphologic, cytogenetic, and molecular remission, which were maintained for 18 months. After a fourth relapse, clinical sequencing was repeated and ultimately identified the persisting ETV6-ABL1 fusion (with no mutation identified in the kinase domain of ABL1) as well as a previously undetected MLL2-ADCY9 fusion resulting in truncation of MLL2 (also known as KMT2D). Treatments of Dasatinib, Ponatinib, and Panobinostat were unsuccessful and the patient ultimately succumbed to her disease 7 year after her initial diagnosis. 30028819 PubMed Mankuzhy et al., 2019, J Pediatr Hematol Oncol 3 accepted 9171 2575 4 Somatic 2021-05-09 18:01:16 UTC https://civicdb.org/links/evidence_items/9171 https://civicdb.org/links/variants/2575 https://civicdb.org/links/genes/4 false ABL1 25 SNX2::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Juvenile onset Diagnostic Supports C Positive This retrospective study intended to clarify clinical characteristics of patients with B-lymphoblastic leukemia/lymphoma (B-ALL) and kinase fusions that are not well described (excluding ETV6-RUNX1, E2A-PBX1, MLL rearrangements and BCR-ABL). The SNX2-ABL1 fusion is rare; in this study investigating 373 high risk pediatric B-ALL patients of which 29 demonstrated uncommon kinase gene fusions, only one case with SNX2-ABL1 (exon 3-exon 4) was observed. Gene expression profiles were compared to Ph-positive B-ALL and reportedly all fusion-containing samples (except P2RY8-CRLF2) were similar to BCR-ABL1-positive patients. This patient did not respond to tyrosine kinase inhibitors administered in combination with chemotherapy at the first or second relapses. 27176795 PubMed Imamura et al., 2016, Blood Cancer J 3 accepted 9177 2678 4 5 122110691 122135550 ENST00000379516.2 9 133738150 133763062 ENST00000372348.2 75 GRCh37 The SNX2-ABL1 fusion is composed of part of the SNX2 (Sorting Nexin 2) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 3 of SNX2 to exon 4 of ABL1 (SNX2-ABL1 3-4). The fusion is the result of a reciprocal translocation t(5;9)(p23.2;q34.12) and has been identified by RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the sorting nexin, N-terminal domain of SNX2 and the SH2, tyrosine kinase, and F actin binding domains of ABL1, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The SNX2-ABL1 fusion has been documented in six young men between the ages of 7 and 29 years with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. Two patients had tyrosine kinase inhibitors (imatinib and dasatinib + imatinib) added to their chemotherapy regimens that, while producing initially encouraging results, ultimately did not prevent these individuals from succumbing to their disease. The clinical details of these cases may predict response to treatment with tyrosine kinase inhibitors and is the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-04-20 17:26:47 UTC https://civicdb.org/links/evidence_items/9177 https://civicdb.org/links/variants/2678 https://civicdb.org/links/genes/4 false ABL1 25 SNX2::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Juvenile onset Diagnostic Supports C Positive In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In one adolescent male, an in-frame SNX2-ABL1 fusion (exon 3 and exon 4) with the ABL1 tyrosine kinase domain intact was identified and confirmed by RT-PCR and Sanger. This patient, evaluated by WES and RNA-seq, also harbored IKZF1, EBF1, and VPREB deletions, and was designated Ph-like non CRLF2. 25207766 PubMed Roberts et al., 2014, N. Engl. J. Med. 3 accepted 9178 2678 4 5 122110691 122135550 ENST00000379516.2 9 133738150 133763062 ENST00000372348.2 75 GRCh37 The SNX2-ABL1 fusion is composed of part of the SNX2 (Sorting Nexin 2) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 3 of SNX2 to exon 4 of ABL1 (SNX2-ABL1 3-4). The fusion is the result of a reciprocal translocation t(5;9)(p23.2;q34.12) and has been identified by RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the sorting nexin, N-terminal domain of SNX2 and the SH2, tyrosine kinase, and F actin binding domains of ABL1, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The SNX2-ABL1 fusion has been documented in six young men between the ages of 7 and 29 years with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. Two patients had tyrosine kinase inhibitors (imatinib and dasatinib + imatinib) added to their chemotherapy regimens that, while producing initially encouraging results, ultimately did not prevent these individuals from succumbing to their disease. The clinical details of these cases may predict response to treatment with tyrosine kinase inhibitors and is the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-04-20 16:57:15 UTC https://civicdb.org/links/evidence_items/9178 https://civicdb.org/links/variants/2678 https://civicdb.org/links/genes/4 false ABL1 25 RANBP2::ABL1 B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Young adult onset Dasatinib Predictive Supports C Sensitivity/Response This retrospective study reported the outcome of 24 patients with Ph-like acute lymphoblastic leukemia (Ph-like ALL) harboring ABL-class fusions, who were treated with a combination of tyrosine kinase inhibitors (TKIs) and chemotherapy. Of the 24 patients reported, 12 had fusions involving ABL1; in 7/12 patients the ABL1 fusion was detected at diagnosis, and in 5/12 it was identified at relapse. One relapse patient was found to have a RANBP2-ABL1 fusion. This patient was a 20 year old female. An IKZF1 intragenic deletion was detected in her leukemia in addition to the RANBP2-ABL1 fusion. She had good initial prednisone response and reached complete remission (CR) after treatment on the GRAALL2005R trial. However, she relapsed with refractory disease. The RANBP2-ABL1 fusion was detected at relapse, and dasatinib (140 mg daily) was added to chemotherapy; this resulted in a brief response even though her leukemia was previously refractory to several lines of salvage treatment (best MRD level 8x10-3). However, the patient experienced another relapse and died of progressive disease. The case illustrates partial response to TKIs in combination with chemotherapy in a relapsed Ph-like B-ALL with RANBP2-ABL1 fusion. 31434701 PubMed Tanasi et al., 2019, Blood 2 accepted 9211 3268 4 2 109336063 109375004 ENST00000283195 9 133729451 133763062 ENST00000372348.2 75 GRCh37 The RANBP2-ABL1 fusion is composed of part of the RANBP2 (RAN Binding Protein 2) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 18 of RANBP2 to exon 2 of ABL1 (RANBP2-ABL1 18-2). The fusion is the result of a reciprocal translocation t(2;9)(p12.3;q34.12) and has been identified by FISH/karyotype and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, includes the leucine zipper of RANBP2 and the tyrosine kinase of ABL1, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The RANBP2-ABL1 fusion has been documented in several juvenile and young adult patients with B-lymphoblastic leukemia, some of which were further classified as BCR-ABL1 (Ph)-like subtype. Most of the documented patients were treated with a tyrosine kinase inhibitor (specifically dasatinib) added to their chemotherapy regimens, but they eventually experienced relapse and succumbed to their disease. The use of tyrosine kinase inhibitors is the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-04-26 17:12:05 UTC https://civicdb.org/links/evidence_items/9211 https://civicdb.org/links/variants/3268 https://civicdb.org/links/genes/4 false PPP2R1A 5518 P179R Functional Supports D Loss of Function Immunoprecipitation experiments in a serous endometrial carcinoma cell line that expressed V5 tagged PPP2R1A P179R protein revealed that binding of PPP2R1A to the PP2A holoenzyme complex members was significantly reduced for PPP2R1A P179R compared to wildtype protein. In vitro reconstitution of the PPP2A holoenzyme was also inhibited by PPP2R1A P179R. Crystal structures of the mutant and wildtype proteins revealed changes in PPP2R1A protein structural conformation that impacts the interaction with the PPP2CA C-subunit, and increases the binding energy between the PPP2R1A and PPP2CA subunits from 236 to 347 kJ/mol for wildtype and mutant protein, respectively. Cell lines that expressed PPP2R1A P179R had increased proteosome-mediated degradation of the PPP2CA (C-subunit), PPP2R2A (B55α) and PPP2R5A (B56α) subunits. Together, this evidence points to PPP2R1A P179R mediated disruption of the PPP2A complex. 31142515 PubMed Taylor et al., 2019, Cancer Res 4 accepted 9212 3299 4463 Somatic 2021-03-29 20:51:24 UTC https://civicdb.org/links/evidence_items/9212 https://civicdb.org/links/variants/3299 https://civicdb.org/links/genes/4463 false ABL1 25 RCSD1::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Young adult onset Ponatinib Predictive Supports C Sensitivity/Response Authors reported a 26 year-old female patient with B-ALL and RCSD1-ABL1 fusion identified by FISH and PCR. Sequencing showed that RCSD1 exon 3 was fused to ABL1 exon 4. This patient was treated with chemotherapy and HSC transplant and relapsed. Ex vivo drug response profiling (DRP) of the patient leukemic blasts was performed at first relapse. Resistance and/or low response were observed for dasatinib and nilotinib, and measurable responses were noted to ponatinib. This differential response to ponatinib as compared with dasatinib was confirmed in a secondary dose-response study and in mice inoculated with leukemia cells. Then the patient was started on ponatinib monotherapy (45 mg/day) based on her RCSD1-ABL1 fusion and achieved a remission. She received a second HSC transplant but relapsed at day 77 post transplantation. Ponatinib was restarted at this time that resulted in response but didn’t reach remission. The patient died of a septic shock 2 weeks later. 25768406 PubMed Collette et al., 2015, Blood Cancer J 3 accepted 9213 2681 4 The RCSD1-ABL1 fusion is composed of part of the RCSD1 (RCS Domain Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 2 or, more frequently, exon 3 of RCSD1 to exon 4 of ABL1 (RCSD1-ABL1 3-4). The fusion is the result of a reciprocal translocation t(1;9)(q24.2;q34.12) and has been identified by FISH/karyotype, RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the ABL1 SH2, actin binding domain, and tyrosine kinase domain, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The RCSD1-ABL1 fusion has been documented in greater than fifteen pediatric and adult patients with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. The majority that that were exposed to tyrosine kinase inhibitors (TKIs: imatinib, dasatinib, or ponatinib) experienced durable remissions until the TKIs were discontinued. The clinical details of these cases may predict response to treatment with TKIs and are the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-05-17 16:07:23 UTC https://civicdb.org/links/evidence_items/9213 https://civicdb.org/links/variants/2681 https://civicdb.org/links/genes/4 false ABL1 25 RCSD1::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Young adult onset Ponatinib Predictive Supports D Sensitivity/Response The authors performed an ex vivo functional evaluation of the drug response profiling (DRP) of the leukemic blasts from a B-ALL patient with RCSD1-ABL1 fusion with a specific focus on TKIs. Resistance and/or low response to some TKIs were observed such as dasatinib or nilotinib (EC50> or ~20 μM), whereas measurable responses to ponatinib were noted (E50 = 0.8 μM). In parallel, the samples of the patient collected at diagnosis, and at relapse were grafted into NSG mice. Blast counts showed reduced progression of the disease in dasatinib-treated animals as compared with control animals at day 28 (P<0.0001), and a significant regression in ponatinib-treated animals, both at day 14 (P<0.0001) and day 28 (P<0.0001). 25768406 PubMed Collette et al., 2015, Blood Cancer J 3 accepted 9214 2681 4 The RCSD1-ABL1 fusion is composed of part of the RCSD1 (RCS Domain Containing 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 2 or, more frequently, exon 3 of RCSD1 to exon 4 of ABL1 (RCSD1-ABL1 3-4). The fusion is the result of a reciprocal translocation t(1;9)(q24.2;q34.12) and has been identified by FISH/karyotype, RT-PCR, Sanger sequencing, and RNA sequencing. The fusion is in-frame and results in production of an abnormal hybrid protein, containing the ABL1 SH2, actin binding domain, and tyrosine kinase domain, which is thought to upregulate the mitogen-activate protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Specifically, the inclusion of the tyrosine kinase domain may affect functionality and offer a target for therapeutic inhibition. Clinical significance: The RCSD1-ABL1 fusion has been documented in greater than fifteen pediatric and adult patients with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. The majority that that were exposed to tyrosine kinase inhibitors (TKIs: imatinib, dasatinib, or ponatinib) experienced durable remissions until the TKIs were discontinued. The clinical details of these cases may predict response to treatment with TKIs and are the focus of an ongoing prospective clinical trial evaluating the efficacy of these drugs when treating young patients with high-risk and BCR-ABL1-like B-lymphoblastic leukemia (Clinicaltrials.gov Identifier: NCT02883049). Somatic 2021-08-19 14:00:35 UTC https://civicdb.org/links/evidence_items/9214 https://civicdb.org/links/variants/2681 https://civicdb.org/links/genes/4 false ATRX 546 Deletion Cancer 162 Fluorouracil,Cisplatin Substitutes Predictive Supports D Sensitivity/Response Transgenic mice were generated with conditional knockouts affecting exon 18 of the mouse ATRX gene, previously shown to be an equivalent of a loss of function. Macrophages derived from the knockout mice were significantly more sensitive to 5-FU (P<0.05) compared to macrophages derived from wild-type mice, as demonstrated by reduced survival by TUNEL assays. Re-introduction of ATRX rescued cells from 5-FU treatment. Similar significant (P<0.05) increases in TUNEL-positive cells were seen for ATRX-deficient neurons treated with 5-FU, as well as myoblasts and embryonic fibroblasts treated with 5-FU or cisplatin. The authors conclude that ATRX loss leads to sensitivity to DNA damaging agents. 23284920 PubMed Conte et al., 2012, PLoS One 3 accepted 9239 3309 525 X 76760356 77041702 ENST00000373344.5 75 GRCh37 N/A 2022-01-27 17:44:36 UTC https://civicdb.org/links/evidence_items/9239 https://civicdb.org/links/variants/3309 https://civicdb.org/links/genes/525 false CDKN1A 1026 rs1059234 Retinoblastoma 768 Predisposing N/A B N/A This study examined two CDKN1A polymorphisms (rs1801270 and rs1059234) in 141 carriers of RB1 variants and 120 unrelated healthy individuals. Authors found that RB1 carriers were more likely to have the non-wildtype CT genotype for rs1059234 than healthy controls (p=0.0065), and the chance of developing retinoblastoma increased 2.15 fold with the CT genotype compared to the wildtype CC genotype (OR: 2.15, 95% CI: 1.23-3.76). 24045412 PubMed Carvalho et al., 2013, Carcinogenesis 3 accepted 9244 3313 913 Common Germline 2021-04-14 20:09:17 UTC https://civicdb.org/links/evidence_items/9244 https://civicdb.org/links/variants/3313 https://civicdb.org/links/genes/913 false TP53 7157 P250L Functional Supports D Gain of Function In a pre-clinical study, wild-type and P250L TP53 were transiently overexpressed in the human osteosarcoma SaOS-2 cell line, which lacks endogenous p53. Immunofluorescence revealed that the P250L mutant cell line had reduced nuclear and increased cytoplasmic staining as compared to the wildtype. The punctate staining suggested that the P250L mutant forms large aggregates within the perinucleus. Chemical disruption of the microtubule assembly resulted in a shift from punctate to diffuse cytoplasmic staining in the P250L cell line. The oligomerization state of the wild type and P250L p53 was analyzed using Blue-Native PAGE (BN-PAGE) and western blot analysis: It was found that the wild type p53 appeared as monomers, tetramers and octamers while the P250L p53 formed large masses. More importantly, it was found that the formation of these aggregates by the P250L mutant could lead to co-aggregation of the wild-type p53, causing dominant negative activity. Additionally, the P250L mutant was found to inactivate the p53 paralogs, p63 and p73, while upregulating HSP70 and HSP90. 21445056 PubMed Xu et al., 2011, Nat Chem Biol 5 accepted 9285 3318 45 Unknown 2021-05-03 20:00:07 UTC https://civicdb.org/links/evidence_items/9285 https://civicdb.org/links/variants/3318 https://civicdb.org/links/genes/45 false TP53 7157 A161T Functional Supports D Loss of Function The TP53 A161T variant was identified in a chronic lymphocytic leukemia (CLL) cohort. In vitro work identified the A161T mutation as temperature sensitive, displaying the mutant loss-of-function phenotype (red yeast colonies) at 35 °C and the wild type phenotype (white yeast colonies) at 25 °. Protein activity was assessed via FASAY (functional analysis of separated alleles in yeast). 21232794 PubMed Pekova et al., 2011, Leuk Res 3 accepted 9286 1114 45 17 7578449 7578449 C T GRCh37 Somatic 2021-06-21 16:48:24 UTC https://civicdb.org/links/evidence_items/9286 https://civicdb.org/links/variants/1114 https://civicdb.org/links/genes/45 false KRAS 3845 G10_A11insG Colorectal Cancer 9256 Oncogenic N/A D N/A FFPE tumor tissue from 1506 colorectal cancer patients was analyzed at codons 12, 13, 61 and 146 by PCR. 672 KRAS mutations were found in 670 patients, and from these, two were inframe insertions located near codon 12. G10_A11insG was validated by direct sequencing. G10_A11insG, G12V and wildtype KRAS were transfected into 293FT and NIH3T3 cells. Increased p-ERK and GTP-bound RAS was seen with G10_A11insG and G12V, but not wildtype. Significantly increased colony formation, and larger tumor size of NIH3T3 cells injected into nude mice was seen with G10_A11insG and G12V over wildtype cells. Enhanced signaling, clonogenicity, and growth suggest G10_A11insG promotes oncogenic transformation in these cell types. 24642870 PubMed Tong et al., 2014, Cancer Biol Ther 4 accepted 9330 3341 30 Somatic 2021-06-21 18:26:14 UTC https://civicdb.org/links/evidence_items/9330 https://civicdb.org/links/variants/3341 https://civicdb.org/links/genes/30 false KRAS 3845 A11_G12insGA Colorectal Cancer 9256 Oncogenic N/A D N/A FFPE tumor tissue from 1506 colorectal cancer patients was analyzed at codons 12, 13, 61 and 146 by PCR. 672 KRAS mutations were found in 670 patients, and from these, two were inframe insertions, which were located near codon 12. A11_G12insGA was validated by direct sequencing. A11_G12insGA, G12V and wildtype KRAS were transfected into 293FT and NIH3T3 cells. Increased p-ERK and GTP-bound RAS was seen with A11_G12insGA and G12V, but not wildtype. Significantly increased colony formation, and larger tumor size of NIH3T3 cells injected into nude mice was seen with A11_G12insGA and G12V over wildtype cells. 24642870 PubMed Tong et al., 2014, Cancer Biol Ther 4 accepted 9331 3342 30 Somatic 2021-06-04 18:32:12 UTC https://civicdb.org/links/evidence_items/9331 https://civicdb.org/links/variants/3342 https://civicdb.org/links/genes/30 false EGFR 1956 R222C Functional Supports D Gain of Function A moderate throughput platform was used to functionally characterize 1000 somatic cancer variants. The platform found EGFR R222C to be an activating mutation based on in vitro screening in two growth-factor–dependent cell models using reverse-phase protein arrays for assessment. This was also the consensus from 5 other tools as well: HotSpot3D, HotMAPS, VEST, CanDrA, and Mutation Assessor (supplemental figure S5). 29533785 PubMed Ng et al., 2018, Cancer Cell 2 accepted 9333 3344 19 7 55220274 55220274 C T ENST00000275493.2 75 GRCh37 Somatic 2021-06-03 18:12:58 UTC https://civicdb.org/links/evidence_items/9333 https://civicdb.org/links/variants/3344 https://civicdb.org/links/genes/19 false KDR 3791 R1032Q Colorectal Cancer 9256 Dovitinib,Lenvatinib,Cabozantinib,Axitinib Substitutes Predictive Supports D Sensitivity/Response R1032Q affects the gene's universal kinase catalytic motif. The authors found that injection of mice with COLO-320 cells that harbor this mutation resulted in tumor generation, indicating that this mutation could have oncogenic potential. In vitro kinase assays showed R1032Q reduced VEGFR2 kinase activity. Using proliferation studies with the COLO-320 cell-line, the authors observed sensitivity to 4 tyrosine kinase inhibitors. Treatment of the MDST8 colorectal cancer cell line carrying the R1032Q mutation with cabozantinib resulted in significant reduction in cell growth and increased ERK phosphorylation levels. 29588308 PubMed Toledo et al., 2018, Clin Cancer Res 2 accepted 9339 3350 3153 Unknown 2021-06-03 22:29:08 UTC https://civicdb.org/links/evidence_items/9339 https://civicdb.org/links/variants/3350 https://civicdb.org/links/genes/3153 false CSF1R 1436 MEF2D::CSF1R B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Young adult onset Imatinib Predictive Supports C Sensitivity/Response This study describes a cohort of 24 patients with BCR-ABL1-like B-ALL and ABL-class kinase rearrangement exposed to TKI frontline or at relapse, who showed favorable MRD response and outcome. Specifically, one 34-year-old man with MEF2D-CSF1R identified by RNAseq was prescribed an unspecified dose of imatinib as adjuvant to his frontline chemotherapy (protocol GRAALL-2014). His initial MRD analysis at 94 days remained positive for blasts (1 x 10^-4), but was consistent with continuous complete remission at day 147. 31434701 PubMed Tanasi et al., 2019, Blood 3 accepted 9360 30 33 1 156446804 156470620 ENST00000348159.4 5 149433787 149441412 ENST00000286301.3 75 GRCh37 MEF2D-CSF1R is a fusion that has been observed in acute lymphocytic leukemia. In cell lines harboring this event, treatment with imatinib has shown notable sensitivity. Somatic 2021-11-01 01:17:45 UTC https://civicdb.org/links/evidence_items/9360 https://civicdb.org/links/variants/30 https://civicdb.org/links/genes/33 false CSF1R 1436 TBL1XR1::CSF1R B-lymphoblastic Leukemia/lymphoma, BCR-ABL1–like 0080650 Young adult onset,Juvenile onset Diagnostic Supports C Positive This study included 1389 cases of high-risk pediatric B-ALL, of which 284 were identified by TaqMan Low Density Array to have a BCR-ABL1-like (Ph-like) gene expression signature. RT-PCR or RNAseq performed on Ph-like, CRLF2 negative patients revealed one case of the novel TBL1XR1-CSF1R fusion. No clinical information pertaining to this individual was disclosed. Considering the previously confirmed Ph-like expression signature in the tested cases, the results suggest that the presence of the TBL1XR1-CSF1R fusion in B-ALL may indicate the BCR-ABL1-like (Ph-like) subtype of the disease. 28408464 PubMed Reshmi et al., 2017, Blood 3 accepted 9361 3359 33 The TBL1XR1-CSF1R fusion is composed of part of the TBL1XR1 (Transducin Beta Like 1 X-Linked Receptor 1) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (Colony Stimulating Factor 1 Receptor) gene at the 3’ end (C-terminus of the fusion protein). CSF1R is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The breakpoint is not published, but is predicted to be the result of a reciprocal translocation t(3;5)(q26.32;q32) and has been identified by RNA sequencing in a single pediatric patient. The consequence of this fusion with respect to treatment response and disease outcome is unknown. Somatic 2021-11-01 00:57:39 UTC https://civicdb.org/links/evidence_items/9361 https://civicdb.org/links/variants/3359 https://civicdb.org/links/genes/33 false ABL1 25 SFPQ::ABL1 B-lymphoblastic Leukemia/lymphoma 0080630 Young adult onset,Juvenile onset Oncogenic N/A C N/A 219 newly diagnosed NCI high-risk, Ph-negative, B-ALL patients between ages 1 to 18 were enrolled on DFCI ALL Consortium protocol 05-001 (NCT00400946) between 2005 and 2011. This study sought to determine the frequency of kinase-activating fusions in this patient cohort. Testing of 105 patients by validated multiplex reverse transcriptase polymerase chain reaction (RT-PCR) assays identified one male patient (age>10) with the SFPQ-ABL1 fusion. This patient was also positive for the IKZF1 gene deletion. Although no other information is available for the patient with the SFPQ-ABL1 fusion, in univariate analysis, fusion-positivity and IKZF1 deletion were each associated with inferior event-free survival and IKZF1 deletion also retained statistical significance in multivariable analysis. 29507076 PubMed Tran et al., 2018, Blood Adv 2 accepted 9362 3287 4 The SFPQ -ABL1 fusion is composed of part of the SFPQ (Splicing factor proline and glutamine rich) gene at the 5’ end (N-terminus of the fusion protein), and part of the ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene at the 3’ end (C-terminus of the fusion protein). ABL1 is considered as the key partner that defines the functional/oncogenic effects of the fusion protein. The published breakpoint joins exon 9 of SFPQ to exon 4 of ABL1 (SFPQ -ABL1). The fusion is the result of a reciprocal translocation t(1;9)(p34;q34) and has been identified by RT-PCR, Sanger sequencing, and RNA sequencing. The role of the partner gene SFPQ in this fusion remains to be investigated. SFPQ encodes for a protein belonging to a new functionally related group of fusion partners for tyrosine kinases involved in pre-mRNA processing. The presence of 2 coiled-coil domains in the 9 remaining exons of SFPQ could theoretically lead to SFPQ–ABL1 oligomerization, thus leading to constitutive activation of the resulting tyrosine kinase, as reported with other partner genes. Though uncommon, this translocation might be targeted by tyrosine kinase inhibitors. Clinical significance: The SFPQ -ABL1 fusion has been documented in six patients (3 male, 3 female) between the ages of 10 and 34 years with B-lymphoblastic leukemia, some of which were further diagnosed with BCR-ABL1 (Ph)-like subtype. Two patients had tyrosine kinase inhibitors (dasatinib + imatinib) added to their chemotherapy regimens, who did not have relapse. One additional patient who did not have tyrosine kinase inhibitor also did not suffer from relapse. The clinical details of these cases may predict response to treatment with tyrosine kinase inhibitors. Functional studies are needed to substantiate the efficacy of TKI treatment of this particular ABL-class fusion. Somatic 2021-10-04 17:54:24 UTC https://civicdb.org/links/evidence_items/9362 https://civicdb.org/links/variants/3287 https://civicdb.org/links/genes/4 false EZH2 2146 Y646H Diffuse Large B-cell Lymphoma 0050745 Tazemetostat Predictive Supports C Sensitivity/Response A phase I safety and dose-escalation study (NCT01897571) was completed for tazemetostat in relapsed or refractory B-cell non-Hodgkin lymphoma or advanced solid tumors. Durable objective responses, including complete responses, were observed in eight (38%) of 21 patients with B-cell non-Hodgkin lymphoma and two (5%) of 43 patients with solid tumours. EZH2 mutation status was assessed retrospectively. Two DLBCL patients had mutations. One of these (with a Y646H mutation) had a durable partial response before disease progression after 16 months on study. The variant in the second patient was not reported and the duration of therapy for this patient that did not respond was among the shortest in the trial. 29650362 PubMed Italiano et al., 2018, Lancet Oncol. NCT01897571 2 accepted 9377 3364 63 7 148508728 148508728 A G GRCh37 Somatic 2022-06-09 21:26:03 UTC https://civicdb.org/links/evidence_items/9377 https://civicdb.org/links/variants/3364 https://civicdb.org/links/genes/63 false ALK 238 I1171T Neuroblastoma 769 Childhood onset Ceritinib Predictive Supports C Sensitivity/Response This case reports a 16-mo-old boy with metastatic neuroblastoma (stage M). Genomic analysis of a diagnostic biopsy of the tumor and matched normal identified two germline mutations in FANCA and somatic ALK-I1171T mutation. Functional investigation of this mutation including PC12 cell neurite outgrowth, NIH3T3 transformation and phosophoproteomics showing increased ALK signaling all suggested that it was a gain function. The patient was treated with Ceritinib as a monotherapy for 7.5 months. The residual primary decreased in size (44% volume reduction at 6 months of treatment) and was surgically removed. At 21 months of followup a complete remission was observed (including all metastatic sites). 29907598 PubMed Guan et al., 2018, Cold Spring Harb Mol Case Stud 4 accepted 9404 3371 1 Somatic 2021-06-16 12:14:09 UTC https://civicdb.org/links/evidence_items/9404 https://civicdb.org/links/variants/3371 https://civicdb.org/links/genes/1 false EZH2 2146 Y646 Functional Supports D Gain of Function Using a baculovirus expression system, wild-type EZH2 or Y641 (Y641F, Y641H, Y641N, Y641S) mutants were coexpressed with the PRC2 complex in Spodoptera frugiperda cells. Methyltransferase activity assays showed that the Y641 mutants were more effective than the wildtype in catalyzing dimethyl to trimethyl reactions. In comparison to the wildtype, the enzyme turnover and catalytic efficiency for the mutants was lower for the non methylated and monomethylated substrates, and higher for dimethylated substrates. Western blots of patient derived lymphoma cell lines (one homozygous wildtype and four heterozygous Y641 mutant lines) supported steady state enzyme kinetic predictions where the homozygous wildtype line demonstrated increased me1 and me2, but decreased 3me at H3K27. Alternatively, the heterozygous lines displayed increased 3me but decreased me1 and me2 at H3K27. These results suggest both the wildtype and Y641 mutants contribute to trimethylation and therefore the altered expression signature. 21078963 PubMed Sneeringer et al., 2010, Proc Natl Acad Sci U S A 3 accepted 9412 165 63 7 148508726 148508728 ENST00000320356.2 75 GRCh37 Mutations of Y646 are associated with a diagnosis of Germinal Center B type DLBCL and Follicular non-Hodgkin Lymphoma. In vitro experimental findings suggest that this may be due to reduced methyltransferase activity of EZH2 on protein H3K27 (Morin et al., 2010). Somatic 2021-08-26 17:31:51 UTC https://civicdb.org/links/evidence_items/9412 https://civicdb.org/links/variants/165 https://civicdb.org/links/genes/63 false PIK3R2 5296 G373R Functional Supports D Gain of Function Lymphoblastoid cell lines were derived from patients with megalencephaly syndromes, who had the PIK3R2 p.G373R mutation. PIP3 immunostaining was used to compared PI3K activity among mutant and control cell lines. The mutant cell line had increased PIP3 levels compared to the control, pointing to increased PI3K activity, since PI3K converts PIP2 to PIP3. Use of PI3K inhibitor, PI-103, led to reduction of PIP3 levels in the mutant cell line, suggesting that the impact of the PIK3R2 mutation on PIP3 levels depends on PI3K. 22729224 PubMed Rivière et al., 2012, Nat Genet 1 accepted 9420 3381 4290 Rare Germline 2021-06-17 18:20:56 UTC https://civicdb.org/links/evidence_items/9420 https://civicdb.org/links/variants/3381 https://civicdb.org/links/genes/4290 false PTEN 5728 C136R Functional Supports D Loss of Function In PHTS-derived lymphoblasts, PTEN protein expression, PTEN mRNA levels, and proteasome activity was measured in the PTEN C136R and control cells. In PTEN-C136R cells, PTEN protein expression was significantly reduced, PTEN mRNA levels was comparable to wildtype(wt), and proteasome activity was 30% greater than wt. This increased proteasomal activity was also found in MCF-7 and HEK-293 cell lines transfected with C136R-PTEN, and in mice expressing C136R-PTEN. Further experiments found the mutant localizes to the cytosol, where its increased proteasomal activity is observed. Cycloheximide (CHX) treatment of MCF-7 cells expressing wt or C136R-PTEN revealed this mutant to be highly unstable. Using P-AKT and P-ERK as markers of PI3K and MAPK pathway activity, respectively, it was found that C136R-PTEN resulted in increased fold change of both, inferring increased pathway activation. The authors further inferred that the mutant results in impaired PTEN lipid phosphatase and protein phosphatase. 23475934 PubMed He et al., 2013, Cancer Res 3 accepted 9421 3382 41 Unknown 2021-06-17 23:55:27 UTC https://civicdb.org/links/evidence_items/9421 https://civicdb.org/links/variants/3382 https://civicdb.org/links/genes/41 false CD44 960 CD44v6 Ovarian Cancer 2394 Prognostic Supports B Poor Outcome In a clinical study including 59 stage III-IV ovarian cancer patients with peritoneal disseminated tumors, Kaplan-Meier analysis showed a significant association between CD44v6 high expression and worse OS (P=0.0059), but not PFS (P=0.4290). Similarly, high CD44v6 expression was found to be a predictive factor by univariate (P = 0.007; HR, 2.930; 95% CI, 1.334–6.436) and multivariate (P = 0.022; HR, 2.568; 95% CI, 1.149–5.738) analyses. In vivo experiments showed that CD44v6-positive ES-2 cells produced larger tumors and more frequent metastases than CD44v6-negative cells, when implanted in nude mice. 26250934 PubMed Tjhay et al., 2015, Cancer Sci 4 accepted 9427 3373 855 Somatic 2021-06-19 07:33:30 UTC https://civicdb.org/links/evidence_items/9427 https://civicdb.org/links/variants/3373 https://civicdb.org/links/genes/855 false EZH2 2146 Y646F Functional Supports D Gain of Function H3K27me3 (histone H3 Lys-27–specific trimethylation) level was higher in EZH2 (Y641F) bearing germinal center B-cell type DLBCL derived lymphoma cell lines and tumors than in wild-type cells. There was no difference of H3K27Me2 and H3K9Me3 levels between Y641F/N and WT, indicating specificity in a gain of function of Y641F/N. Expression of Y641F mutation in HEK293T cells with wild-type EZH2 led to an increase in H3K27me3. Primary murine B-cell lines with Y641F mutation also showed an increase of H3K27me3. Structural modeling indicated that Y641F/N helped push the equilibrium to favor trimethylated products. A 3H methyl incorporation assay was used to study the activity of the PRC2 complex containing Y641F mutation in vitro. PRC2 complexes containing Y641F showed nearly two times higher activity with H3K27me2 substrates than PRC complexes with wild-type EZH2. This study indicates that EZH2 (Y641F) increases H3K27 trimethylation. 21190999 PubMed Yap et al., 2011, Blood 3 accepted 9517 2989 63 7 148508727 148508727 T A ENST00000320356.7 GRCh37 Y646F has been reported as one of the most recurrent alterations of EZH2 in DLBCL, FL and other malignancies. This mutation is thought to alter methyltransferase activity of EZH2 and confer sensitivity to EZH2 inhibitors such as tazemetostat. Somatic 2022-04-12 22:08:46 UTC https://civicdb.org/links/evidence_items/9517 https://civicdb.org/links/variants/2989 https://civicdb.org/links/genes/63 false EZH2 2146 Y646N Functional Supports D Gain of Function H3K27me3 (histone H3 Lys-27–specific trimethylation) level was higher in EZH2 (Y641N) bearing germinal center B-cell type DLBCL derived lymphoma cell lines and tumors than in wild-type cells. There was no difference of H3K27Me2 and H3K9Me3 levels between Y641F/N and WT, indicating specificity in a gain of function of Y641F/N. Expression of Y641N mutation in HEK293T cells with wild-type EZH2 led to an increase in H3K27me3. Structural modeling indicated that Y641F/N helped push the equilibrium to favor trimethylated products. A 3H methyl incorporation assay was used to study the activity of the PRC2 complex containing Y641N mutation in vitro. PRC2 complexes containing Y641N showed nearly two times higher activity with H3K27me2 substrates than PRC complexes with wild-type EZH2. This study indicates that EZH2 (Y641N) increases H3K27 trimethylation. 21190999 PubMed Yap et al., 2011, Blood 3 accepted 9518 4090 63 Somatic 2022-06-30 16:49:56 UTC https://civicdb.org/links/evidence_items/9518 https://civicdb.org/links/variants/4090 https://civicdb.org/links/genes/63 false EZH2 2146 Y646F Functional Supports D Loss of Function A 3H methyl incorporation assay tested the function of EZH2 Y641F containing PRC2 complexes in vitro. It showed that Y641F/N PRC2 complexes had significantly decreased enzyme activity on unmethylated and monomethylated H3 mimicking peptide substrates compared with wild-type. 21190999 PubMed Yap et al., 2011, Blood 3 accepted 9519 2989 63 7 148508727 148508727 T A ENST00000320356.7 GRCh37 Y646F has been reported as one of the most recurrent alterations of EZH2 in DLBCL, FL and other malignancies. This mutation is thought to alter methyltransferase activity of EZH2 and confer sensitivity to EZH2 inhibitors such as tazemetostat. Somatic 2022-04-12 22:10:33 UTC https://civicdb.org/links/evidence_items/9519 https://civicdb.org/links/variants/2989 https://civicdb.org/links/genes/63 false EZH2 2146 Y646N Functional Supports D Loss of Function A 3H methyl incorporation assay tested the function of EZH2 Y641N containing PRC2 complexes in vitro. It showed that Y641F/N PRC2 complexes had significantly decreased enzyme activity on unmethylated and monomethylated H3 mimicking peptide substrates compared with wild-type. 21190999 PubMed Yap et al., 2011, Blood 3 accepted 9520 4090 63 Somatic 2022-06-30 16:49:33 UTC https://civicdb.org/links/evidence_items/9520 https://civicdb.org/links/variants/4090 https://civicdb.org/links/genes/63 false EZH2 2146 Y646H Functional Supports D Gain of Function Whole-cell lysates from frozen GCB-derived lymphoma sections with EZH2 Y641H showed a higher level of H3K27me3 (histone H3 Lys-27–specific trimethylation) compared with those from tumor with wild-type EZH2 in western blots using an antibody specific for H3K27me3 (sample number 178). 21190999 PubMed Yap et al., 2011, Blood 3 accepted 9521 3364 63 7 148508728 148508728 A G GRCh37 Somatic 2022-07-01 18:49:29 UTC https://civicdb.org/links/evidence_items/9521 https://civicdb.org/links/variants/3364 https://civicdb.org/links/genes/63 false EZH2 2146 Y646S Functional Supports D Gain of Function Whole-cell lysates from frozen GCB-derived lymphoma sections with EZH2 Y641H showed a higher level of H3K27me3 (histone H3 Lys-27–specific trimethylation) compared with those from tumor with wild-type EZH2 in western blots using an antibody specific for H3K27me3 (sample number 353). 21190999 PubMed Yap et al., 2011, Blood 3 accepted 9522 2666 63 Somatic 2021-07-09 15:57:55 UTC https://civicdb.org/links/evidence_items/9522 https://civicdb.org/links/variants/2666 https://civicdb.org/links/genes/63 false BRAF 673 G463E Cancer 162 Oncogenic N/A D N/A The BRAF mutation G463E resulted in elevated kinase activity relative to wild-type BRAF in vitro. B-RAF activity was determined using kinase dead MEK as a substrate. G463E activity was 28 times higher than basal WT BRAF. The authors classified G463E activity as intermediate since its kinase activity was between basal WT BRAF and G12V RAS-activated WT B-RAF cells. In comparison, some BRAF variants displayed high kinase activity above the G12V RAS-activated WT BRAF cells. NIH3T3 transformation assay yielded 24 +/- 14 foci/ng of transfected BRAF DNA, in comparison to WT, which yielded zero foci, indicating an oncogenic effect of BRAF G463E. 15035987 PubMed Wan et al., 2004, Cell 3 accepted 9527 3432 5 Unknown 2021-07-12 18:18:28 UTC https://civicdb.org/links/evidence_items/9527 https://civicdb.org/links/variants/3432 https://civicdb.org/links/genes/5 false MYOD1 4654 L122R Rhabdomyosarcoma 3247 Pediatric onset,Young adult onset Prognostic Supports B Poor Outcome This study evaluated 641 cases of rhabdomyosarcoma (RMS), enrolled on Children’s Oncology Group trials (1998-2017) and UK malignant mesenchymal tumor and RMS2005 trials (1995-2016), for mutations in 39 genes previously implicated in RMS. The analysis was done using a custom-capture sequencing assay. MYOD1 L122R variant was identified in 17 cases (3%) and was not restricted to spindle-cell histology, but was also observed in association with other histologic patterns (including cases with densely packed cells that mimicked embryonal rhabdomyosarcoma (ERMS) or RMS not otherwise specified ). MYOD1 mutation showed association with older age, head and neck primary site, and a dismal survival. In both COG and UK patient cohorts, patients with the MYOD1 L122R mutation had rapid disease progression and significantly worse event free survival as compared to the patients with wild-type MYOD1. 34166060 PubMed Shern et al., 2021, J Clin Oncol 4 accepted 9532 3032 3777 11 17741694 17741694 T G ENST00000250003.3 75 GRCh37 Somatic 2021-07-18 03:31:22 UTC https://civicdb.org/links/evidence_items/9532 https://civicdb.org/links/variants/3032 https://civicdb.org/links/genes/3777 false NFE2L2 4780 G31A Functional Supports D Gain of Function The NFE2L2:p.G31A allele was expressed in HA1E-M cells and its tumorigenic potential was tested in a pooled and individual in vivo (mice) assay. The G31A mutation did not lead to tumor formation in the pooled assay but did cause tumor formation in 6/6 mice in the individual experiment. The NFE2L2:p.G31A allele was also found to be expressed at significantly higher levels as compared to wild type. Short term gene expression correlation analysis was also completed using HA1E cells and the L1000 Luminex bead-based gene expression assay. Transcript level of 978 landmark genes were measured to formulate a gene expression signature for the allele. Overexpression of the mutant allele led to a similar signature as overexpression of the wild type, suggesting that the gain-of-function changes induced by the mutant can also be seen in NFE2L2-overexpressed cells. 27147599 PubMed Kim et al., 2016, Cancer Discov 3 accepted 9574 3457 3878 Unknown 2022-01-22 00:12:56 UTC https://civicdb.org/links/evidence_items/9574 https://civicdb.org/links/variants/3457 https://civicdb.org/links/genes/3878 false TP53 7157 ALTERATION Rhabdomyosarcoma 3247 Pediatric onset,Young adult onset Prognostic Supports B Poor Outcome This study evaluated 641 cases of rhabdomyosarcoma (RMS) that were enrolled in the Children’s Oncology Group (COG) trials from 1998 to 2017 and the UK malignant mesenchymal tumor and RMS2005 trails from 1995 to 2016. Molecular testing included 39 genes which had been implicated in the past with regards to RMS. The analysis was performed with a custom-capture sequencing assay. Altered TP53 was noted in 69 out of 515 FOXO1 fusion-negative RMS cases (13%), with the most frequent mutations at codons G245S (6 cases), R248Q or W (6 cases), R175H (4 cases), and P72A (4 cases). These cases displayed a worse event free survival. In FOXO1 fusion-positive RMS subtype, there was a small number of cases with altered TP53 (3 and 2 cases in the COG and UK patient cohorts, respectively), but they were universally fatal. Due to lack of a matched germline sample, it could not be determined whether the TP53 abnormalities were of somatic or germline origin. Nevertheless, both cohorts show that mutations in TP53 are associated with a poor prognosis in both fusion-negative and fusion-positive RMS, with a particularly bleak outcome in fusion-positive RMS. 34166060 PubMed Shern et al., 2021, J Clin Oncol 4 accepted 9594 1307 45 17 7571720 7590856 ENST00000269305.4 75 GRCh37 P53 ALTERATION is a bucket type variant used in studies which is constructed by combining all cases of p53 mutation together with p53 overexpression. This includes cases which have p53 mutation or overexpression alone or as well as cases where both occur in combination. Somatic 2021-08-10 16:36:53 UTC https://civicdb.org/links/evidence_items/9594 https://civicdb.org/links/variants/1307 https://civicdb.org/links/genes/45 false HRAS 3265 Mutation Bladder Urothelial Carcinoma 4006 Tipifarnib Predictive Supports B Sensitivity/Response 4 of 16 patients with urothelial carcinoma harboring HRAS hotspot point mutations and 1 patient with an HRAS frameshift insertion had a partial response to the farnesyltransferase inhibitor tipifarnib while none of the 6 patients with wild-type HRAS responded. 32636318 PubMed Lee et al., 2020, Clin Cancer Res 2 accepted 9632 275 2747 11 533873 534289 ENST00000451590.1 75 GRCh37 Somatic 2022-06-01 07:48:05 UTC https://civicdb.org/links/evidence_items/9632 https://civicdb.org/links/variants/275 https://civicdb.org/links/genes/2747 false HRAS 3265 Mutation Head And Neck Squamous Cell Carcinoma 5520 Tipifarnib Predictive Supports B Sensitivity/Response In a phase II HNSCC trial, an objective response rate of 55% was seen in HRAS-mutant patients (11 of 20) treated with the farnesyltransferase inhibitor tipifarnib with a PFS of 5.6 months and an OS of 15.6 months (providing the allele fraction was at least 20%). 33750196 PubMed Ho et al., 2021, J Clin Oncol NCT02383927 2 accepted 9633 275 2747 11 533873 534289 ENST00000451590.1 75 GRCh37 Somatic 2022-06-01 07:16:35 UTC https://civicdb.org/links/evidence_items/9633 https://civicdb.org/links/variants/275 https://civicdb.org/links/genes/2747 false EZH2 2146 Activating Mutation Follicular Lymphoma 0050873 Tazemetostat Predictive Supports B Sensitivity/Response Tazemetostat was found to have significantly increased anti-tumor activity in patients with relapsed/refractory follicular lymphoma with gain-of-function EZH2 mutations (cobas EZH2 Mutation Test; objective response rate of 69%) versus patients with wild-type EZH2 (objective response rate of 35%). Treatment shows good tolerability and durability of response in both groups of patients. 33035457 PubMed Morschhauser et al., 2020, Lancet Oncol NCT01897571 3 accepted 9709 3737 63 Somatic 2022-02-18 16:25:09 UTC https://civicdb.org/links/evidence_items/9709 https://civicdb.org/links/variants/3737 https://civicdb.org/links/genes/63 false NUP98 4928 NUP98::NSD1 Acute Myeloid Leukemia 9119 Young adult onset,Pediatric onset Prognostic Supports B Poor Outcome In this study >1000 well-characterized pediatric and adult AML cases were screened using a NUP98/NSD1-specific RT-PCR. In the pediatric cohort (n = 293; age, 0-18 years), NUP98/NSD1 was present in 16.1% of the cases. The authors identified the cytogenetically cryptic NUP98/NSD1 translocation as an independent factor for dismal clinical outcome for both pediatric and adult patients. The remission rate (CR) of NUP98/NSD1-positive cases in the pediatric cohort was 100%, but 10 of the 12 cases relapsed early. The cumulative incidence of nonresponse/relapse (pCIR) at 4 years was 83 ± 13% for NUP98/NSD1-positive versus 45 ± 3% for negative cases (P < .001). NUP98/NSD1 cases had a poor event-free survival (pEFS) and overall survival (pOS) (4-years pEFS, 8 ± 8% vs 46 ± 3%, P < .001; and 4-years pOS, 31 ± 16% vs 64 ± 3%, P = .011 for NUP98/NSD1-positive vs negative cases, respectively). 21813447 PubMed Hollink et al., 2011, Blood 4 accepted 9720 2593 3995 Somatic 2021-09-24 05:23:16 UTC https://civicdb.org/links/evidence_items/9720 https://civicdb.org/links/variants/2593 https://civicdb.org/links/genes/3995 false PDGFB 5155 COL1A1::PDGFB Dermatofibrosarcoma Protuberans 3507 Diagnostic Supports B Positive This study analyzed 27 formalin-fixed-paraffin-embedded samples of patients with known dermatofibrosarcoma protuberans (DFSP) using a newly designed multiplex RT-PCR assay. The assay identified COL1A1-PDGFB fusion transcripts in all but one DFSP case, which was consistent with concurrent FISH testing on the same samples. The study concluded that COL1A1-PDGFB rearrangements appear more prevalent in DFSP (96%) than previously reported. The use of sensitive molecular assays for detection of COL1A1-PDGFB fusion may improve diagnosis in cases of atypical, variant, or metastatic DFSP. 17950782 PubMed Patel et al., 2008, Hum Pathol 4 accepted 9787 2972 4173 Somatic 2021-10-21 18:38:03 UTC https://civicdb.org/links/evidence_items/9787 https://civicdb.org/links/variants/2972 https://civicdb.org/links/genes/4173 false CTNNB1 1499 S45F Desmoid Tumor 0080366 Prognostic Supports B Poor Outcome This was a multi-institutional retrospective cohort study which looked at the prognostic value of CTNNB1 gene mutations in aggressive fibromatosis (also known as desmoid tumor). The study analyzed 101 patients who had undergone surgical resection of confirmed primary extra-abdominal or abdominal wall aggressive fibromatosis. Specimens were reviewed for the presence of T41A, S45F, and 45P mutations on the CTNNB1 gene. Mutations were found in 76 patients, with T41A being most common (n = 49), followed by S45F (n = 18), and 45P (n = 3). The 5-year cumulative risk of recurrence was 22.8%. Further analysis revealed that patients with an S45F mutation had a 5-year recurrence risk of 63.8% and an 8.5-fold higher risk of recurrence compared to patients with wild type tumors (P=0.006). 25341748 PubMed van Broekhoven et al., 2015, Ann Surg Oncol 4 accepted 9788 1286 1290 3 41266137 41266137 C T ENST00000349496.5 75 GRCh37 Somatic 2021-10-21 18:42:07 UTC https://civicdb.org/links/evidence_items/9788 https://civicdb.org/links/variants/1286 https://civicdb.org/links/genes/1290 false TP53 7157 R342P Functional Supports D Loss of Function Cancer-associated TP53 mutations were assessed for effects on the stability and oligomeric structure of p53. TP53 R324P protein eluted as a single peak contemporaneously with the known monomer mutant L330A, and separate from tetrameric TP53, during gel-filtration chromatography. The introduction of Proline at the solvent-exposed residue R342 inhibited tetramer formation resulting in p53 remaining in an unfolded monomeric state. Since formation of a tetramer is important for p53 function, destabilization of the tetrameric structure is likely to result in loss of p53 tumor suppressor activity. 20978130 PubMed Kamada et al., 2011, J Biol Chem 3 accepted 9805 3579 45 Unknown 2021-11-04 16:43:31 UTC https://civicdb.org/links/evidence_items/9805 https://civicdb.org/links/variants/3579 https://civicdb.org/links/genes/45 false TP53 7157 L330P Functional Supports D Loss of Function Cancer-associated TP53 mutations were assessed for effects on the stability and oligomeric structure of p53. TP53 L330P protein eluted as a single peak contemporaneously with the known monomer mutant L330A, and separate from tetrameric TP53, during gel-filtration chromatography. The introduction of Proline at residue L330 in the hydrophobic core caused the protein to elute as a single peak contemporaneously with the monomer mutant L330A, indicating inhibited tetramer formation, resulting in p53 remaining in an unfolded monomeric state. Since formation of a tetramer is important for p53 function, destabilization of the tetrameric structure is likely to result in loss of p53 tumor suppressor activity. 20978130 PubMed Kamada et al., 2011, J Biol Chem 3 accepted 9806 3580 45 Unknown 2021-11-04 16:43:00 UTC https://civicdb.org/links/evidence_items/9806 https://civicdb.org/links/variants/3580 https://civicdb.org/links/genes/45 false TP53 7157 L330R Functional Supports D Loss of Function Cancer-associated TP53 mutations were assessed for effects on the stability and oligomeric structure of p53. TP53 L330R protein eluted as a single peak contemporaneously with the known monomer mutant L330A, and separate from tetrameric TP53, during gel-filtration chromatography. The L330R mutation in the hydrophobic core inhibited tetramer formation resulting in p53 remaining in an unfolded monomeric state. Since formation of a tetramer is important for p53 function, destabilization of the tetrameric structure is likely to result in loss of p53 tumor suppressor activity. 20978130 PubMed Kamada et al., 2011, J Biol Chem 3 accepted 9807 3581 45 Unknown 2021-11-04 16:42:04 UTC https://civicdb.org/links/evidence_items/9807 https://civicdb.org/links/variants/3581 https://civicdb.org/links/genes/45 false TP53 7157 R337P Functional Supports D Loss of Function Cancer-associated TP53 mutations were assessed for effects on the stability and oligomeric structure of p53. TP53 R337P protein eluted as a single peak contemporaneously with the known monomer mutant L330A, and separate from tetrameric TP53, during gel-filtration chromatography. The introduction of Proline at residue R337 in the hydrophobic core inhibited tetramer formation resulting in p53 remaining in an unfolded monomeric state. Since formation of a tetramer is important for p53 function, destabilization of the tetrameric structure is likely to result in loss of p53 tumor suppressor activity. 20978130 PubMed Kamada et al., 2011, J Biol Chem 3 accepted 9808 3582 45 Unknown 2021-11-04 16:41:45 UTC https://civicdb.org/links/evidence_items/9808 https://civicdb.org/links/variants/3582 https://civicdb.org/links/genes/45 false TP53 7157 L344P Functional Supports D Loss of Function Cancer-associated TP53 mutations were assessed for effects on the stability and oligomeric structure of p53. TP53 L344P protein eluted as a single peak contemporaneously with the known monomer mutant L330A, and separate from tetrameric TP53, during gel-filtration chromatography. The introduction of Proline at the tetramer interface residue L344 inhibited tetramer formation resulting in p53 remaining in an unfolded monomeric state. Since formation of a tetramer is important for p53 function, destabilization of the tetrameric structure is likely to result in loss of p53 tumor suppressor activity. 20978130 PubMed Kamada et al., 2011, J Biol Chem 3 accepted 9809 3583 45 Unknown 2021-11-04 16:41:20 UTC https://civicdb.org/links/evidence_items/9809 https://civicdb.org/links/variants/3583 https://civicdb.org/links/genes/45 false BRAF 673 V600E Colorectal Cancer 9256 Encorafenib,Cetuximab Combination Predictive Supports A Sensitivity/Response The open-label phase 3 BEACON CRC trial included 665 patients with BRAF V600E-mutated metastatic CRC. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI. The median overall survival was 8.4 months (95% CI, 7.5 to 11.0) in the doublet-therapy group and 5.4 months (95% CI, 4.8 to 6.6) in the control group, with a significantly lower risk of death compared to the control group (hazard ratio for death doublet-group vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group, 20% in the doublet-therapy group (95% CI 13 to 29) and 2% (95% CI, 0 to 7) in the control group (doublet group vs. control P<0.001). Median PFS was 4.2 months (95% CI, 3.7 to 5.4) in the doublet-therapy group, and 1.5 months (95% CI, 1.5 to 1.7) in the control group (hazard ratio for disease progression doublet-group vs control, 0.40; 95% CI, 0.31 to 0.52, P<0.001). 31566309 PubMed Kopetz et al., 2019, N. Engl. J. Med. NCT02928224 5 accepted 9851 12 5 7 140453136 140453136 A T ENST00000288602.6 75 GRCh37 BRAF V600E has been shown to be recurrent in many cancer types. It is one of the most widely studied variants in cancer. This variant is correlated with poor prognosis in certain cancer types, including colorectal cancer and papillary thyroid cancer. The targeted therapeutic dabrafenib has been shown to be effective in clinical trials with an array of BRAF mutations and cancer types. Dabrafenib has also shown to be effective when combined with the MEK inhibitor trametinib in colorectal cancer and melanoma. However, in patients with TP53, CDKN2A and KRAS mutations, dabrafenib resistance has been reported. Ipilimumab, regorafenib, vemurafenib, and a number of combination therapies have been successful in treating V600E mutations. However, cetuximab and panitumumab have been largely shown to be ineffective without supplementary treatment. Somatic 2022-02-11 23:51:32 UTC https://civicdb.org/links/evidence_items/9851 https://civicdb.org/links/variants/12 https://civicdb.org/links/genes/5 false EZH2 2146 Y646C Functional Supports D Loss of Function EZH2 mutations were identified in a screen of 614 patients with myeloid malignancies. Several mutations in the highly conserved CXC-SET domains were expressed in Sf9 insect cells along with polycomb repressive complex 2 components EED and SUZ12. Complexes were immunoprecipitated and assayed in vitro for H3K27M methyltransferase activity. EZH2 Y646C resulted in reduced methyltransferase activity, similar to the negative control (SET domain deletion). In addition, the SKM-1 cell line expressing EZH2 Y646C showed reduced H3K27M methyltransferase activity compared to EZH2-unmutated SKK-1 and MOLM-13 cell lines. 20601953 PubMed Ernst et al., 2010, Nat Genet 2 accepted 9868 3607 63 Unknown 2022-02-18 03:39:07 UTC https://civicdb.org/links/evidence_items/9868 https://civicdb.org/links/variants/3607 https://civicdb.org/links/genes/63 false PIM1 5292 L2V Diffuse Large B-cell Lymphoma Activated B-cell Type 0080996 Ibrutinib Predictive Supports D Resistance Foundation panel results of baseline tumour samples from 48 patients with diffuse large B cell lymphoma identified PIM1 mutations in 6 patient samples, 5 of which were the DLBCL-ABC subtype. Four out of the 5 DLBCL-ABC patients with PIM1 mutations had stable disease or progressive disease when treated with ibrutinib, suggesting innate resistance to ibrutinib therapy. Three PIM1 mutations L2V, P81S, and S97N were investigated in cell lines studies. Cells transduced with L2V, P81S, and S97N were resistant to ibrutinib compared to cells transduced with wild type PIM1. Combined treatment of PIM1 mutant lines with ibrutinib and a pan-PIM inhibitor, AZD-1208, partially rescued sensitivity to ibrutinib. 27904766 PubMed Kuo et al., 2016, Am J Cancer Res 3 accepted 9945 3643 4286 Somatic 2021-12-10 23:58:08 UTC https://civicdb.org/links/evidence_items/9945 https://civicdb.org/links/variants/3643 https://civicdb.org/links/genes/4286 false PIM1 5292 P81S Diffuse Large B-cell Lymphoma Activated B-cell Type 0080996 Ibrutinib Predictive Supports D Resistance Foundation panel results of baseline tumour samples from 48 patients with diffuse large B cell lymphoma identified PIM1 mutations in 6 patient samples, 5 of which were the DLBCL-ABC subtype. Four out of the 5 DLBCL-ABC patients with PIM1 mutations had stable disease or progressive disease when treated with ibrutinib, suggesting innate resistance to ibrutinib therapy. Three PIM1 mutations L2V, P81S, and S97N were investigated in cell lines studies. Cells transduced with L2V, P81S, and S97N were resistant to ibrutinib compared to cells transduced with wild type PIM1. Combined treatment of PIM1 mutant lines with ibrutinib and a pan-PIM inhibitor, AZD-1208, partially rescued sensitivity to ibrutinib. 27904766 PubMed Kuo et al., 2016, Am J Cancer Res 3 accepted 9946 3644 4286 Somatic 2021-12-10 23:57:06 UTC https://civicdb.org/links/evidence_items/9946 https://civicdb.org/links/variants/3644 https://civicdb.org/links/genes/4286 false PIM1 5292 S97N Diffuse Large B-cell Lymphoma Activated B-cell Type 0080996 Ibrutinib Predictive Supports D Resistance Foundation panel results of baseline tumour samples from 48 patients with diffuse large B cell lymphoma identified PIM1 mutations in 6 patient samples, 5 of which were the DLBCL-ABC subtype. Four out of the 5 DLBCL-ABC patients with PIM1 mutations had stable disease or progressive disease when treated with ibrutinib, suggesting innate resistance to ibrutinib therapy. Three PIM1 mutations L2V, P81S, and S97N were investigated in cell lines (TMD8) studies. Cells transduced with L2V, P81S, and S97N were resistant to ibrutinib compared to cells transduced with wild type PIM1. Combined treatment of PIM1 mutant lines with ibrutinib and a pan-PIM inhibitor, AZD-1208, partially rescued sensitivity to ibrutinib. 27904766 PubMed Kuo et al., 2016, Am J Cancer Res 3 accepted 9947 3645 4286 Somatic 2021-12-10 23:56:51 UTC https://civicdb.org/links/evidence_items/9947 https://civicdb.org/links/variants/3645 https://civicdb.org/links/genes/4286 false ACVR1 90 G328V Diffuse Midline Glioma, H3 K27M-mutant 0080684 Diagnostic Supports C Positive It has been reported that recurrent activating somatic mutations (R206H, R258G, G328E/V/W, G356D) in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, are in 21% (11/52) of DIPG samples. The mutations were highly specific to DIPG, with an overall frequency of 0.3% in other tumors present in the Catalogue of Somatic Mutations in Cancer database. Data was collected from whole genome sequencing on 20 pre-treated biopsy samples of DIPG as well as whole exome sequencing from 1 biopsy sample and five samples obtained at autopsy. An additional 26 DIPG biopsy samples were screened via Sanger sequencing and identified the variant (G328W). DIPG cases with somatic mutations of ACVR1 (R206H, R258G, G328E/V/W, G356D) had longer overall survival (n=11 versus 41; median of 14.9 versus 10.9 months; p=0.05, log-rank test). 24705252 PubMed Taylor et al., 2014, Nat. Genet. 2 accepted 10011 1686 154 2 158622516 158622516 C A ENST00000434821.1 75 GRCh37 Somatic 2021-12-31 20:54:02 UTC https://civicdb.org/links/evidence_items/10011 https://civicdb.org/links/variants/1686 https://civicdb.org/links/genes/154 false ACVR1 90 R206H Diffuse Midline Glioma, H3 K27M-mutant 0080684 Diagnostic Supports C Positive It has been reported that recurrent activating somatic mutations (R206H, R258G, G328E/V/W, G356D) in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, are in 21% (11/52) of DIPG samples. The mutations were highly specific to DIPG, with an overall frequency of 0.3% in other tumors present in the Catalogue of Somatic Mutations in Cancer database. Data was collected from whole genome sequencing on 20 pre-treated biopsy samples of DIPG as well as whole exome sequencing from 1 biopsy sample and five samples obtained at autopsy. An additional 26 DIPG biopsy samples were screened via Sanger sequencing and identified the variant (G328W). DIPG cases with somatic mutations of ACVR1 (R206H, R258G, G328E/V/W, G356D) had longer overall survival (n=11 versus 41; median of 14.9 versus 10.9 months; p=0.05, log-rank test). 24705252 PubMed Taylor et al., 2014, Nat. Genet. 2 accepted 10012 3661 154 Somatic 2021-12-31 20:55:27 UTC https://civicdb.org/links/evidence_items/10012 https://civicdb.org/links/variants/3661 https://civicdb.org/links/genes/154 false ACVR1 90 G328W Diffuse Midline Glioma, H3 K27M-mutant 0080684 Diagnostic Supports C Positive It has been reported that recurrent activating somatic mutations (R206H, R258G, G328E/V/W, G356D) in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, are in 21% (11/52) of DIPG samples. The mutations were highly specific to DIPG, with an overall frequency of 0.3% in other tumors present in the Catalogue of Somatic Mutations in Cancer database. Data was collected from whole genome sequencing on 20 pre-treated biopsy samples of DIPG as well as whole exome sequencing from 1 biopsy sample and five samples obtained at autopsy. An additional 26 DIPG biopsy samples were screened via Sanger sequencing and identified the variant (G328W). DIPG cases with somatic mutations of ACVR1 (R206H, R258G, G328E/V/W, G356D) had longer overall survival (n=11 versus 41; median of 14.9 versus 10.9 months; p=0.05, log-rank test). 24705252 PubMed Taylor et al., 2014, Nat. Genet. 2 accepted 10013 2280 154 2 158622517 158622517 C A ENST00000263640.3 75 GRCh37 Somatic 2021-12-31 20:56:22 UTC https://civicdb.org/links/evidence_items/10013 https://civicdb.org/links/variants/2280 https://civicdb.org/links/genes/154 false ACVR1 90 Mutation Diffuse Midline Glioma, H3 K27M-mutant 0080684 Diagnostic Supports B Positive It has been reported that recurrent activating somatic mutations (R206H, R258G, G328E/V/W, G356D) in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, are in 21% (11/52) of DIPG samples. The mutations were highly specific to DIPG, with an overall frequency of 0.3% in other tumors present in the Catalogue of Somatic Mutations in Cancer database. Data was collected from whole genome sequencing on 20 pre-treated biopsy samples of DIPG as well as whole exome sequencing from 1 biopsy sample and five samples obtained at autopsy. An additional 26 DIPG biopsy samples were screened via Sanger sequencing and identified the variant (G328W). DIPG cases with somatic mutations of ACVR1 (R206H, R258G, G328E/V/W, G356D) had longer overall survival (n=11 versus 41; median of 14.9 versus 10.9 months; p=0.05, log-rank test). 24705252 PubMed Taylor et al., 2014, Nat. Genet. 3 accepted 10014 2983 154 Somatic 2021-12-31 21:03:29 UTC https://civicdb.org/links/evidence_items/10014 https://civicdb.org/links/variants/2983 https://civicdb.org/links/genes/154 false ACVR1 90 G356D Diffuse Midline Glioma, H3 K27M-mutant 0080684 Diagnostic Supports C Positive It has been reported that recurrent activating somatic mutations (R206H, R258G, G328E/V/W, G356D) in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, are in 21% (11/52) of DIPG samples. The mutations were highly specific to DIPG, with an overall frequency of 0.3% in other tumors present in the Catalogue of Somatic Mutations in Cancer database. Data was collected from whole genome sequencing on 20 pre-treated biopsy samples of DIPG as well as whole exome sequencing from 1 biopsy sample and five samples obtained at autopsy. An additional 26 DIPG biopsy samples were screened via Sanger sequencing and identified the variant (G328W). DIPG cases with somatic mutations of ACVR1 (R206H, R258G, G328E/V/W, G356D) had longer overall survival (n=11 versus 41; median of 14.9 versus 10.9 months; p=0.05, log-rank test). 24705252 PubMed Taylor et al., 2014, Nat. Genet. 2 accepted 10015 3662 154 Somatic 2021-12-31 21:02:24 UTC https://civicdb.org/links/evidence_items/10015 https://civicdb.org/links/variants/3662 https://civicdb.org/links/genes/154 false ABCB1 5243 Overexpression Lung Non-small Cell Carcinoma 3908 Lorlatinib,Alectinib Substitutes Predictive Does Not Support D Resistance ALK fusion positive NSCLC cell lines with high expression of P-gp (ABCB1 gene) were found to be resistant to crizotinib and ceritinib. P-gp knockdown via shRNA increased the sensitivity of cells to crizotinib and ceritinib. A cell line developed to overexpress P-gp had increased resistance to crizotinib and ceritinib. These cells did not show increased resistance to alectinib and PF-06463922 (lorlatinib). 26870817 PubMed Katayama et al., 2016, EBioMedicine 3 accepted 10016 2915 4244 Somatic 2022-03-24 20:51:53 UTC https://civicdb.org/links/evidence_items/10016 https://civicdb.org/links/variants/2915 https://civicdb.org/links/genes/4244 false PIK3CA 5290 K944N Colorectal Cancer 9256 Cetuximab Predictive Supports C Resistance A cohort of 32 colorectal cancer patients with acquired resistance to cetuximab (PFS > 12 weeks) was analyzed for resistance mutations using targeted deep sequencing of ctDNA. Three patients had the PIK3CA p.K944N mutation. Cell viability studies of DiFi cells transfected with this PIK3CA variant confirmed resistance. 28424201 PubMed Xu et al., 2017, Clin. Cancer Res. 4 accepted 10031 3666 37 Somatic 2022-05-06 05:00:24 UTC https://civicdb.org/links/evidence_items/10031 https://civicdb.org/links/variants/3666 https://civicdb.org/links/genes/37 false PIK3CA 5290 F930S Colorectal Cancer 9256 Cetuximab Predictive Supports C Resistance A cohort of 32 colorectal cancer patients with acquired resistance to cetuximab (PFS > 12 weeks) was analyzed for resistance mutations using targeted deep sequencing of ctDNA. One patient had the PIK3CA F930S mutation. Cell viability studies of DiFi cells transfected with this PIK3CA variant confirmed resistance. 28424201 PubMed Xu et al., 2017, Clin. Cancer Res. 4 accepted 10032 3667 37 Somatic 2022-05-06 05:00:40 UTC https://civicdb.org/links/evidence_items/10032 https://civicdb.org/links/variants/3667 https://civicdb.org/links/genes/37 false PIK3CA 5290 V955G Colorectal Cancer 9256 Cetuximab Predictive Supports C Resistance A cohort of 32 colorectal cancer patients with acquired resistance to cetuximab (PFS > 12 weeks) was analyzed for resistance mutations using targeted deep sequencing of ctDNA. One patient had the PIK3CA p.V955G mutation. Cell viability studies of DiFi cells transfected with this PIK3CA variant confirmed resistance. 28424201 PubMed Xu et al., 2017, Clin. Cancer Res. 4 accepted 10033 3668 37 Somatic 2022-05-06 05:00:33 UTC https://civicdb.org/links/evidence_items/10033 https://civicdb.org/links/variants/3668 https://civicdb.org/links/genes/37 false PIK3CA 5290 K966E Colorectal Cancer 9256 Cetuximab Predictive Supports C Resistance A cohort of 32 colorectal cancer patients with acquired resistance to cetuximab (PFS > 12 weeks) was analyzed for resistance mutations using targeted deep sequencing of ctDNA. One patient had the PIK3CA p.K966E mutation. Cell viability studies of DiFi cells transfected with this PIK3CA variant confirmed resistance. 28424201 PubMed Xu et al., 2017, Clin. Cancer Res. 4 accepted 10034 3669 37 Somatic 2022-05-06 05:00:15 UTC https://civicdb.org/links/evidence_items/10034 https://civicdb.org/links/variants/3669 https://civicdb.org/links/genes/37 false PIK3CA 5290 L938* Colorectal Cancer 9256 Cetuximab Predictive Does Not Support C Resistance A cohort of 32 colorectal cancer patients with acquired resistance to cetuximab (PFS > 12 weeks) was analyzed. 1 patient had the PIK3CA p.L938* mutation. Cell viability studies of DiFi cells transfected with this PIK3CA variant did not exhibit resistance. 28424201 PubMed Xu et al., 2017, Clin. Cancer Res. 3 accepted 10035 3670 37 Somatic 2022-05-03 23:16:25 UTC https://civicdb.org/links/evidence_items/10035 https://civicdb.org/links/variants/3670 https://civicdb.org/links/genes/37 false TP53 7157 T125T Functional Supports D Loss of Function TP53 mutant cell lines were treated with an MDM2 inhibitor (AMG 232) and expression of TP53, MDM2 and p21 were measured by immunoblot. Lack of upregulation was seen in all TP53 mutant (G>A transversion; T125T; splice variant) cell lines indicating TP53 is non-functional. 25730903 PubMed Saiki et al., 2015, Oncotarget 4 accepted 10059 3684 45 N/A 2022-03-15 00:16:20 UTC https://civicdb.org/links/evidence_items/10059 https://civicdb.org/links/variants/3684 https://civicdb.org/links/genes/45 false EGFR 1956 G598V Cancer 162 Erlotinib Predictive Supports D Sensitivity/Response In an in vitro study, a Ba/F3 cell line expressing EGFR G598V demonstrated increased sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing EGFR wild-type. Variant function was assessed by EGFR auto-phosphorylation. Sensitivity was assessed by cell viability assay using stable transfection of each variant and increasing concentrations of erlotinib (0–10 uM). 17177598 PubMed Lee et al., 2006, PLoS Med. 3 accepted 10066 997 19 7 55233043 55233043 G T ENST00000275493.2 75 GRCh37 Somatic 2022-03-24 23:48:39 UTC https://civicdb.org/links/evidence_items/10066 https://civicdb.org/links/variants/997 https://civicdb.org/links/genes/19 false PTPRB 5787 Loss-of-function Angiosarcoma 0001816 Diagnostic Supports B Positive A cohort of angiosarcomas (n=36) was sequenced and revealed to contain recurrent mutations in PTPRB (10/36) which were predominantly truncating or splice variants which impact the tyrosine phosphotase domain. Loss of function variants in PTPRB are rare in other cancer types suggesting this is specfic to angiosarcomas. 24633157 PubMed Behjati et al., 2014, Nat. Genet. 3 accepted 10079 819 4690 12 70910630 71031220 ENST00000334414.6 75 GRCh37 Somatic 2022-02-08 00:39:49 UTC https://civicdb.org/links/evidence_items/10079 https://civicdb.org/links/variants/819 https://civicdb.org/links/genes/4690 false NTRK1 4914 TPM3::NTRK1 Cancer 162 Entrectinib Predictive Supports D Sensitivity/Response BaF3 cells were transduced with a number of NTRK fusions. IC50 values were measured following treatment with entrectinib: TPM3-NTRK1 (2.5nM), LMNA-NTRK1 (1.4nM), ETV6-NTRK1 (2.5nM), VCL-NTRK2 (4.3nM), AFAP1-NTRK2 (2.7nM), ETV6-NTRK2 (4.5nM), ETV6-NTRK3 (3.8nM), and control (>1000nM). 26884591 PubMed Drilon et al., 2016, Ann. Oncol. NCT02097810 3 accepted 10094 2992 3983 N/A 2022-02-18 00:25:42 UTC https://civicdb.org/links/evidence_items/10094 https://civicdb.org/links/variants/2992 https://civicdb.org/links/genes/3983 false NTRK2 4915 ETV6::NTRK2 Cancer 162 Entrectinib Predictive Supports D Sensitivity/Response BaF3 cells were transduced with a number of NTRK fusions. IC50 values were measured following treatment with entrectinib: TPM3-NTRK1 (2.5nM), LMNA-NTRK1 (1.4nM), ETV6-NTRK1 (2.5nM), VCL-NTRK2 (4.3nM), AFAP1-NTRK2 (2.7nM), ETV6-NTRK2 (4.5nM), ETV6-NTRK3 (3.8nM), and control (>1000nM). 26884591 PubMed Drilon et al., 2016, Ann. Oncol. NCT02097810 3 accepted 10099 2396 3984 N/A 2022-02-05 01:24:54 UTC https://civicdb.org/links/evidence_items/10099 https://civicdb.org/links/variants/2396 https://civicdb.org/links/genes/3984 false FLCN 201163 c.1285dupC Renal Cell Carcinoma 4450 Fibrofolliculoma,Pulmonary cyst,Spontaneous pneumothorax Everolimus Predictive Supports C Sensitivity/Response A case study showed that the mTOR inhibitor everolimus exhibited a relatively long-term effect in a patient with renal cell carcinoma and a FLCN germline mutation (c. 1285dupC, likely loss of function). 23995526 PubMed Nakamura et al., 2013, Hinyokika Kiyo 1 accepted 10137 3727 19959 17 17119708 17119709 G ENST00000285071.9 75 GRCh37 Rare Germline 2022-01-28 01:57:30 UTC https://civicdb.org/links/evidence_items/10137 https://civicdb.org/links/variants/3727 https://civicdb.org/links/genes/19959 false IGF1R 3480 Overexpression Breast Cancer 1612 Exemestane,Metformin Combination Predictive Supports B Sensitivity/Response A randomized phase III trial of hormone sensitive (ER or PR positive) early stage breast cancer (Dutch TEAM cohort, n=2,446) examined the addition of metformin to exemestane for 155 patients. IGF1R IHC was performed and patients classified as IGF1R high (n=105) or low (n=50). In IGF1R-high patients, combining metformin with exemestane was associated with significant RFS (HR 1.12, 95% CI 0.57–2.23 for sequential treatment with metformin, HR 0.73 95% CI 0.56–0.94 for exemestane only, and HR 0.32, 95% CI 0.10–1.00 for exemestane with metformin, p = 0.02, compared to the sequential treatment arm). There was also significant association with OS (HR for OS 1.72, 95% CI 0.96–3.08 for sequential treatment with metformin, HR 0.80, 95% CI 0.62–1.03 for exemestane only, and HR 0.67, 95% CI 0.31–1.45 for exemestane with metformin, p = 0.03, compared to the sequential treatment arm). The authors conclude that adding metformin to exemestane for patients with IGF1R-high expression may have clinical benefit. 26706833 PubMed Engels et al., 2016, Mol Oncol 4 accepted 10138 3259 2899 N/A 2022-01-27 00:15:22 UTC https://civicdb.org/links/evidence_items/10138 https://civicdb.org/links/variants/3259 https://civicdb.org/links/genes/2899 false SF3B1 23451 K700E Leukemia 1240 Olaparib,Etoposide Substitutes Predictive Supports D Sensitivity/Response The cancer-associated SF3B1-K700E mutation compromises homologous recombination repair and increases the sensitivity to ionising radiation and DNA damaging agents, such as etoposide or small molecule inhibitors including olaparib in isogenic K562 cell line. The SF3B1-WT and SF3B1-K700E cell lines were also engrafted subcutaneously into immunocompromised mice, and the mice were treated with etoposide, olaparib or a vehicle control and monitored tumour growth for 28 days. Treatment with either etoposide or olaparib significantly reduced the volume of the SF3B1-K700E mutant tumours, but had little effect on the volume of SF3B1-WT tumours. 35027467 PubMed Lappin et al., 2022, Cancer Res 3 accepted 10139 565 44 2 198266834 198266834 T C ENST00000335508.6 75 GRCh37 Somatic 2022-01-27 18:20:35 UTC https://civicdb.org/links/evidence_items/10139 https://civicdb.org/links/variants/565 https://civicdb.org/links/genes/44 false ERBB2 2064 Exon 20 Insertion Lung Non-small Cell Carcinoma 3908 Trastuzumab Deruxtecan Predictive Supports B Sensitivity/Response In a phase 2 trial, 91 patients with ERBB2-mutant metastatic non-small-cell lung cancer, refractory to standard treatment, were treated with trastuzumab deruxtecan. The objective response was 55% (95% CI, 44 to 65), the median duration of response was 9.3 months (95% CI 5.7 to 14.7), the median PFS was 8.2 months (95% CI 6.0 to 11.9), and the median OS was 17.8 months (95% CI 13.8 to 22.1). 81 of 91 patients had an Exon 20 Insertion mutation and 46 of 78 evaluable patients with this mutation type had a partial response (PR). 34534430 PubMed Li et al., 2022, N Engl J Med NCT03505710 5 accepted 10140 2854 20 Somatic 2022-03-01 20:06:06 UTC https://civicdb.org/links/evidence_items/10140 https://civicdb.org/links/variants/2854 https://civicdb.org/links/genes/20 false ERCC1 2067 Underexpression Lung Non-small Cell Carcinoma 3908 Gemcitabine,Carboplatin Combination Predictive Supports B Sensitivity/Response As part of a randomized phase III trial (USO-03012) in advanced NSCLC of gemcitabine vs. combination gemcitabine and carboplatin, protein expression levels for RRM1 (n=69) and ERCC1 (n=65) were evaluated using fluorescence-based IHC. RRM1 levels were significantly inversely correlated with response (r = −0.41; P = .001, n=58), as were ERCC1 levels (r = −0.39; P = .003, n=55). RRM1 and ERCC1 levels were correlated with each other (r = 0.36; P = .003, n=65). There was no significant interaction with treatment arm (P = .64 for RRM1; P = .79 for ERCC1). The authors conclude that RRM1 and ERCC1 expression levels are predictive of response to gemcitabine, and gemcitabine and carboplatin. 19884554 PubMed Reynolds et al., 2009, J Clin Oncol 3 accepted 10142 2409 1735 19 45916692 45926824 ENST00000013807.5 75 GRCh37 N/A 2022-01-27 22:43:10 UTC https://civicdb.org/links/evidence_items/10142 https://civicdb.org/links/variants/2409 https://civicdb.org/links/genes/1735 false RRM1 6240 Underexpression Lung Non-small Cell Carcinoma 3908 Carboplatin,Gemcitabine Combination Predictive Supports B Sensitivity/Response As part of a randomized phase III trial (USO-03012) in advanced NSCLC of gemcitabine vs. combination gemcitabine and carboplatin, protein expression levels for RRM1 (n=69) and ERCC1 (n=65) were evaluated using fluorescence-based IHC. RRM1 levels were significantly inversely correlated with response (r = −0.41; P = .001, n=58), as were ERCC1 levels (r = −0.39; P = .003, n=55). RRM1 and ERCC1 levels were correlated with each other (r = 0.36; P = .003, n=65). There was no significant interaction with treatment arm (P = .64 for RRM1; P = .79 for ERCC1). The authors conclude that RRM1 and ERCC1 expression levels are predictive of response to gemcitabine, and gemcitabine and carboplatin. 19884554 PubMed Reynolds et al., 2009, J Clin Oncol 3 accepted 10143 1257 5051 11 4116039 4160106 ENST00000300738.5 75 GRCh37 N/A 2022-01-27 22:41:51 UTC https://civicdb.org/links/evidence_items/10143 https://civicdb.org/links/variants/1257 https://civicdb.org/links/genes/5051 false IDH1 3417 R132C Cancer 162 Olaparib Predictive Supports D Sensitivity/Response IDH1 R132C mutation confers a switch of function mutation where the mutated protein produces 2-hydroxyglutarate (2HG), rather than α-ketoglutarate (αKG). The novel metabolite induces a homologous recombination (HR) defect that sensitizes the tumor cells to poly (ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitor sensititivity was tested in vivo in HeLa cells where the R132C mutation was create with CRISPR, the HCT116 colon cancer cell line where R132C mutation was created with recombinant adeno-associated virus (rAAV), and the HT1080 human sarcoma cell line which already has R132C. The results were then duplicated in non-commercial glioma cell lines: 6 IDH1 R132 mutant; 4 IDH1 wt. 28148839 PubMed Sulkowski et al., 2017, Sci Transl Med 3 accepted 10144 59 26 2 209113113 209113113 G A ENST00000415913.1 75 GRCh37 IDH1 R132 mutations have been observed in a number of cancer types, and appear to behave quite differently in different environments. In myelodysplastic syndromes and acute myeloid leukemia (AML), IDH1 R132 mutations have been shown to be associated with worse outcome and shorter overall survival. They have also been linked to cytogenetically normal AML, an intermediate risk subtype of the disease. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Also in contrast to AML, in glioblastoma, IDH1 mutations have been associated with the specific cytogenetic abnormalities, 1p and 19q deletions. Somatic 2022-01-28 02:03:17 UTC https://civicdb.org/links/evidence_items/10144 https://civicdb.org/links/variants/59 https://civicdb.org/links/genes/26 false SLC29A1 2030 Overexpression Pancreatic Adenocarcinoma 4074 Gemcitabine Predictive Supports B Sensitivity/Response Surgically resected PDACs were used to create tissue microarrays, which were scored for antibody staining of hENT1 (SLC29A1). For patients treated with gemcitabine (n=243), high levels of hENT1 were associated with longer survival time in Kaplan-Meier survival analysis (HR 0.43, 95% CI 0.29-0.63, P < .0001) and by multivariate proportional hazards model (HR 0.34, 95% CI 0.22-0.53, P < .0001). For patients treated with surgery alone (n=142), there was no association with survival. 22705007 PubMed Maréchal et al., 2012, Gastroenterology 4 accepted 10145 3728 1701 N/A 2022-02-04 03:58:15 UTC https://civicdb.org/links/evidence_items/10145 https://civicdb.org/links/variants/3728 https://civicdb.org/links/genes/1701 false ERCC1 2067 Underexpression Ovary Epithelial Cancer 2152 Platinum Compound Predictive Supports B Sensitivity/Response Ovarian epithelial tumours (n=235) were used to create TMAs and IHC results were scored for ERCC1 (n=114 low, n=121 high). For platinum sensitive patients (n=250 in supplementary table, but not all have ERCC1 levels available), low ERCC1 was associated with better PFS (p = 0.034, HR 1.9, 95% CI 1.1-3.6). For platinum resistant patients (n=26 in supplementary table, but not all have ERCC1 levels available), there was no significant association (p = 0.550, HR 0.5, 95% CI 0.1-4.3). 30797591 PubMed Mesquita et al., 2019, Gynecol Oncol 3 accepted 10146 2409 1735 19 45916692 45926824 ENST00000013807.5 75 GRCh37 N/A 2022-03-01 18:44:57 UTC https://civicdb.org/links/evidence_items/10146 https://civicdb.org/links/variants/2409 https://civicdb.org/links/genes/1735 false NTRK1 4914 Amplification Solid Tumor Larotrectinib Predictive Supports C Sensitivity/Response In a phase I study of larotrectinib in 67 patients with solid tumours, 8 patients were recorded as having objective response. 7 of these harboured NTRK fusions, and one had a NTRK1 amplification. This patient's tumour had a size reduction measured as 45% and a response duration of 3.7 months. It is not stated in the publication whether a survey of amplification status in other patients in the study was done. 30624546 PubMed Hong et al., 2019, Ann. Oncol. NCT02122913 2 accepted 10170 1280 3983 1 156830686 156851434 ENST00000524377.1 75 GRCh37 Somatic 2022-02-24 18:44:37 UTC https://civicdb.org/links/evidence_items/10170 https://civicdb.org/links/variants/1280 https://civicdb.org/links/genes/3983 false CTCF 10664 K365T Functional Supports D Gain of Function Three recurrent CTCF mutations found in endometrial carcinoma were expressed in Ishikawa cells and compared to expression of wild-type CTCF. The K365T mutation did not demonstrate altered localization or anti-proliferative effects but a protective effect against UV-incuded apoptosis was observed. 28319062 PubMed Marshall et al., 2017, Oncogene 3 accepted 10179 3745 8508 N/A 2022-03-08 18:33:47 UTC https://civicdb.org/links/evidence_items/10179 https://civicdb.org/links/variants/3745 https://civicdb.org/links/genes/8508 false KIT 3815 EXPRESSION Glioblastoma 3068 Sunitinib Predictive Supports B Sensitivity/Response Phase II trial of sunitinib in 40 patients with first recurrence of primary glioblastoma. Median PFS 2.2 mo, median OS 9.2 mo, 5 stable disease >=6 months, no objective responses, so primary study endpoint was not met. However, IHC of multiple receptor kinases was performed, and protein expression of KIT in vascular endothelial cells was associated with longer PFS (P = .017; HR, 2.564; 95% CI, 1.180–5.570). All 5 with stable disease were KIT+ in vascular endothelial cells. Note KIT staining was not observed in tumour cells. No association with OS. 24311637 PubMed Hutterer et al., 2014, Neuro Oncol NCT00535379 3 accepted 10180 429 29 4 55524085 55606881 ENST00000288135.5 75 GRCh37 Somatic 2022-03-15 18:35:48 UTC https://civicdb.org/links/evidence_items/10180 https://civicdb.org/links/variants/429 https://civicdb.org/links/genes/29 false SSTR5 6755 expression Neuroendocrine Tumor 169 Pasireotide Predictive Supports B Sensitivity/Response Phase II study of pasireotide in metastatic neuroendocrine tumours enrolled 29 patients. Overall median PFS was 11 months (95% CI, 7.6–16 months). High SSTR5 expression (seen in 17/22 samples measured) was associated with prolonged PFS (P=0.0068). Median PFS for low-SSTR5 tumours was 2.8 months (95% CI, 2.3–12.1 months) vs high tumours 19.9 months (95% CI, 7.7–29.1 months). 25376618 PubMed Cives et al., 2015, Endocr Relat Cancer NCT01253161 3 accepted 10193 3752 5499 Somatic 2022-03-15 18:09:18 UTC https://civicdb.org/links/evidence_items/10193 https://civicdb.org/links/variants/3752 https://civicdb.org/links/genes/5499 false TP53 7157 P98S Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant P98S was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10215 3760 45 Somatic 2022-04-05 06:19:57 UTC https://civicdb.org/links/evidence_items/10215 https://civicdb.org/links/variants/3760 https://civicdb.org/links/genes/45 false TP53 7157 P98L Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant P98L was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10216 3761 45 Somatic 2022-04-05 06:23:26 UTC https://civicdb.org/links/evidence_items/10216 https://civicdb.org/links/variants/3761 https://civicdb.org/links/genes/45 false TP53 7157 Y126D Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant Y126D was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10217 3762 45 Somatic 2022-04-05 06:26:14 UTC https://civicdb.org/links/evidence_items/10217 https://civicdb.org/links/variants/3762 https://civicdb.org/links/genes/45 false TP53 7157 Y126S Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant Y126S was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10218 3763 45 Somatic 2022-04-05 06:29:22 UTC https://civicdb.org/links/evidence_items/10218 https://civicdb.org/links/variants/3763 https://civicdb.org/links/genes/45 false TP53 7157 K139E Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant K139E was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10219 3764 45 Somatic 2022-04-05 06:31:17 UTC https://civicdb.org/links/evidence_items/10219 https://civicdb.org/links/variants/3764 https://civicdb.org/links/genes/45 false TP53 7157 P151S Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant P151S was classified as recessive for RGC and a hotspot for mutation (P < 0.001) by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10220 3765 45 Somatic 2022-04-05 06:34:06 UTC https://civicdb.org/links/evidence_items/10220 https://civicdb.org/links/variants/3765 https://civicdb.org/links/genes/45 false TP53 7157 P151H Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant P151H was classified as recessive for RGC and a hotspot for mutation (P < 0.001) by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10222 1093 45 GRCh37 Somatic 2022-04-05 06:35:45 UTC https://civicdb.org/links/evidence_items/10222 https://civicdb.org/links/variants/1093 https://civicdb.org/links/genes/45 false TP53 7157 P152L Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant P152L was classified as recessive for RGC and a hotspot for mutation (P < 0.01) by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10223 3767 45 Somatic 2022-04-05 06:36:52 UTC https://civicdb.org/links/evidence_items/10223 https://civicdb.org/links/variants/3767 https://civicdb.org/links/genes/45 false TP53 7157 I162F Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant I162F was classified as recessive for RGC and a hotspot for mutation (P < 0.014) by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10224 3768 45 Somatic 2022-04-05 06:38:33 UTC https://civicdb.org/links/evidence_items/10224 https://civicdb.org/links/variants/3768 https://civicdb.org/links/genes/45 false TP53 7157 Y163H Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant Y163H was classified as recessive for RGC and a hotspot for mutation (P < 0.001) by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10225 3769 45 Somatic 2022-04-05 06:39:14 UTC https://civicdb.org/links/evidence_items/10225 https://civicdb.org/links/variants/3769 https://civicdb.org/links/genes/45 false TP53 7157 Y236S Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant Y236S was classified as recessive for RGC and a hotspot for mutation (P < 0.01) by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10226 3770 45 Somatic 2022-04-05 06:40:13 UTC https://civicdb.org/links/evidence_items/10226 https://civicdb.org/links/variants/3770 https://civicdb.org/links/genes/45 false TP53 7157 L252F Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant L252F was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10227 3771 45 Somatic 2022-04-05 06:42:05 UTC https://civicdb.org/links/evidence_items/10227 https://civicdb.org/links/variants/3771 https://civicdb.org/links/genes/45 false TP53 7157 E258K Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant E258K was classified as recessive for RGC and a hotspot for mutation (P < 0.01) by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10228 3772 45 Somatic 2022-04-05 06:43:08 UTC https://civicdb.org/links/evidence_items/10228 https://civicdb.org/links/variants/3772 https://civicdb.org/links/genes/45 false TP53 7157 G262D Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant G262D was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10229 3773 45 Somatic 2022-04-05 06:44:17 UTC https://civicdb.org/links/evidence_items/10229 https://civicdb.org/links/variants/3773 https://civicdb.org/links/genes/45 false TP53 7157 G266R Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant G266R was classified as recessive for RGC and a hotspot for mutation (P < 0.001) by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10230 1055 45 GRCh37 Somatic 2022-04-05 06:45:21 UTC https://civicdb.org/links/evidence_items/10230 https://civicdb.org/links/variants/1055 https://civicdb.org/links/genes/45 false TP53 7157 G266E Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant G266E was classified as recessive for RGC and a hotspot for mutation (P < 0.001) by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10231 3774 45 Somatic 2022-04-05 06:46:42 UTC https://civicdb.org/links/evidence_items/10231 https://civicdb.org/links/variants/3774 https://civicdb.org/links/genes/45 false TP53 7157 A276V Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant A276V was classified as recessive for RGC and a hotspot for mutation (P < 0.01) by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10232 1050 45 17 7577111 7577111 G A ENST00000269305.4 75 GRCh37 Somatic 2022-04-05 06:50:50 UTC https://civicdb.org/links/evidence_items/10232 https://civicdb.org/links/variants/1050 https://civicdb.org/links/genes/45 false TP53 7157 P278S Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant P278S was classified as recessive for RGC and a hotspot for mutation (P < 0.001) by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10233 1049 45 GRCh37 Somatic 2022-04-05 06:51:42 UTC https://civicdb.org/links/evidence_items/10233 https://civicdb.org/links/variants/1049 https://civicdb.org/links/genes/45 false TP53 7157 L308M Functional Does Not Support D Dominant Negative CAUTION: This Evidence Item has not been accepted as accurate or complete! A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant L308M was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10234 3775 45 Somatic 2022-04-05 06:52:43 UTC https://civicdb.org/links/evidence_items/10234 https://civicdb.org/links/variants/3775 https://civicdb.org/links/genes/45 false TP53 7157 L323P Functional Does Not Support D Dominant Negative CAUTION: This Evidence Item has not been accepted as accurate or complete! A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC sequence as a p53 binding site. TP53 variant L323P was classified as recessive for RGC and was not classified as a hotspot for mutation by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10235 3776 45 Somatic 2022-04-05 06:54:12 UTC https://civicdb.org/links/evidence_items/10235 https://civicdb.org/links/variants/3776 https://civicdb.org/links/genes/45 false TP53 7157 Q144P Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant Q144P was classified as recessive for p21, bax, and PIG3. In addition, Q144P was not classified as a hotspot for mutation by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10236 3777 45 Somatic 2022-04-06 09:17:51 UTC https://civicdb.org/links/evidence_items/10236 https://civicdb.org/links/variants/3777 https://civicdb.org/links/genes/45 false TP53 7157 R158H Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant R158H was classified as recessive for p21, bax, and PIG3. In addition, R158H was classified as a hotspot for mutation (P < 0.001) by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10237 1695 45 17 7578457 7578457 C T ENST00000269305.4 75 GRCh37 Somatic 2022-04-06 09:30:17 UTC https://civicdb.org/links/evidence_items/10237 https://civicdb.org/links/variants/1695 https://civicdb.org/links/genes/45 false TP53 7157 P219H Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant P219H was classified as recessive for p21, bax, and PIG3. In addition, P219H was not classified as a hotspot for mutation by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10238 3778 45 Somatic 2022-04-06 09:36:09 UTC https://civicdb.org/links/evidence_items/10238 https://civicdb.org/links/variants/3778 https://civicdb.org/links/genes/45 false TP53 7157 Y220H Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant Y220H was classified as recessive for RGC, p21, bax, and PIG3. In addition, Y220H was classified as a hotspot for mutation (P < 0.001) by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10239 3779 45 Somatic 2022-04-06 09:37:55 UTC https://civicdb.org/links/evidence_items/10239 https://civicdb.org/links/variants/3779 https://civicdb.org/links/genes/45 false TP53 7157 E224K Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant E224K was classified as recessive for RGC, p21, bax, and PIG3. In addition, E224K was not classified as a hotspot for mutation by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10240 3780 45 Somatic 2022-04-06 09:39:28 UTC https://civicdb.org/links/evidence_items/10240 https://civicdb.org/links/variants/3780 https://civicdb.org/links/genes/45 false TP53 7157 Y234H Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant Y234H was classified as recessive for RGC, p21, bax, and PIG3. In addition, Y234H was classified as a hotspot for mutation (P < 0.001) by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10241 3781 45 Somatic 2022-04-06 09:40:28 UTC https://civicdb.org/links/evidence_items/10241 https://civicdb.org/links/variants/3781 https://civicdb.org/links/genes/45 false TP53 7157 T230S Functional Does Not Support D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant T230S was classified as recessive for RGC, p21, bax, and PIG3. In addition, T230S was not classified as a hotspot for mutation by the authors. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10242 3782 45 Somatic 2022-04-06 09:41:44 UTC https://civicdb.org/links/evidence_items/10242 https://civicdb.org/links/variants/3782 https://civicdb.org/links/genes/45 false TP53 7157 H168Y Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant H168Y was classified as dominant negative for p21, bax, and PIG3. In addition, H168Y was classified as a hotspot for mutation (P < 0.014) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10243 3783 45 Somatic 2022-04-21 08:09:37 UTC https://civicdb.org/links/evidence_items/10243 https://civicdb.org/links/variants/3783 https://civicdb.org/links/genes/45 false TP53 7157 P177S Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant P177S was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, P177S was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10244 3784 45 Somatic 2022-04-21 07:55:29 UTC https://civicdb.org/links/evidence_items/10244 https://civicdb.org/links/variants/3784 https://civicdb.org/links/genes/45 false TP53 7157 P177F Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant P177F was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, P177F was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10245 3785 45 Somatic 2022-04-21 07:55:43 UTC https://civicdb.org/links/evidence_items/10245 https://civicdb.org/links/variants/3785 https://civicdb.org/links/genes/45 false TP53 7157 P177H Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant P177H was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, P177H was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10246 3786 45 Somatic 2022-04-21 07:56:01 UTC https://civicdb.org/links/evidence_items/10246 https://civicdb.org/links/variants/3786 https://civicdb.org/links/genes/45 false TP53 7157 H179Y Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant H179Y was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, H179Y was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10247 1083 45 GRCh37 Somatic 2022-04-21 07:56:17 UTC https://civicdb.org/links/evidence_items/10247 https://civicdb.org/links/variants/1083 https://civicdb.org/links/genes/45 false TP53 7157 N239S Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant N239S was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, N239S was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10248 3787 45 Somatic 2022-04-21 07:57:08 UTC https://civicdb.org/links/evidence_items/10248 https://civicdb.org/links/variants/3787 https://civicdb.org/links/genes/45 false TP53 7157 S241T Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant S241T was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, S241T was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10249 3788 45 Somatic 2022-04-21 07:57:20 UTC https://civicdb.org/links/evidence_items/10249 https://civicdb.org/links/variants/3788 https://civicdb.org/links/genes/45 false TP53 7157 S241F Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant S241F was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, S241F was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10250 2777 45 Somatic 2022-04-21 07:57:35 UTC https://civicdb.org/links/evidence_items/10250 https://civicdb.org/links/variants/2777 https://civicdb.org/links/genes/45 false TP53 7157 C242Y Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant C242Y was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, C242Y was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10251 1064 45 17 7577556 7577556 C T ENST00000269305.4 75 GRCh37 Somatic 2022-04-21 07:57:49 UTC https://civicdb.org/links/evidence_items/10251 https://civicdb.org/links/variants/1064 https://civicdb.org/links/genes/45 false TP53 7157 G244S Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant G244S was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, G244S was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10252 1060 45 GRCh37 Somatic 2022-04-21 07:58:02 UTC https://civicdb.org/links/evidence_items/10252 https://civicdb.org/links/variants/1060 https://civicdb.org/links/genes/45 false TP53 7157 G245S Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant G245S was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, G245S was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10253 879 45 17 7577548 7577548 C T ENST00000269305.4 75 GRCh37 Somatic 2022-04-21 07:58:16 UTC https://civicdb.org/links/evidence_items/10253 https://civicdb.org/links/variants/879 https://civicdb.org/links/genes/45 false TP53 7157 G245D Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant G245D was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, G245D was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10254 1036 45 GRCh37 Somatic 2022-04-21 07:58:32 UTC https://civicdb.org/links/evidence_items/10254 https://civicdb.org/links/variants/1036 https://civicdb.org/links/genes/45 false TP53 7157 M246L Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant M246L was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, M246L was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10255 3789 45 Somatic 2022-04-21 07:58:51 UTC https://civicdb.org/links/evidence_items/10255 https://civicdb.org/links/variants/3789 https://civicdb.org/links/genes/45 false TP53 7157 R273C Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant R273C was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, R273C was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10256 121 45 17 7577121 7577121 G A ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R273 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been suggested that the R273 mutants have been correlated with worse overall survival in breast cancer patients when compared to wild-type. Somatic 2022-04-21 08:02:36 UTC https://civicdb.org/links/evidence_items/10256 https://civicdb.org/links/variants/121 https://civicdb.org/links/genes/45 false TP53 7157 V274F Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant V274F was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, V274F was classified as a hotspot for mutation (P < 0.014) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10257 3790 45 Somatic 2022-05-06 03:54:20 UTC https://civicdb.org/links/evidence_items/10257 https://civicdb.org/links/variants/3790 https://civicdb.org/links/genes/45 false TP53 7157 G279E Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant G279E was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, G279E was not classified as a hotspot for mutation by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10258 3791 45 Somatic 2022-04-21 08:06:48 UTC https://civicdb.org/links/evidence_items/10258 https://civicdb.org/links/variants/3791 https://civicdb.org/links/genes/45 false TP53 7157 D281N Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant D281N was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, D281N was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10259 3792 45 Somatic 2022-04-21 08:08:14 UTC https://civicdb.org/links/evidence_items/10259 https://civicdb.org/links/variants/3792 https://civicdb.org/links/genes/45 false TP53 7157 D281E Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant D281E was classified as dominant negative for RGC, p21, bax, and PIG3. In addition, D281E was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10260 1044 45 GRCh37 Somatic 2022-04-21 08:08:54 UTC https://civicdb.org/links/evidence_items/10260 https://civicdb.org/links/variants/1044 https://civicdb.org/links/genes/45 false TP53 7157 R248W Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant R248W was classified as dominant negative for p21, bax, and PIG3. In addition, R248W was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 3 accepted 10261 118 45 17 7577539 7577539 G A ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R248 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, R248 mutations have been shown to confer worse overall survival. Somatic 2022-04-21 08:10:09 UTC https://civicdb.org/links/evidence_items/10261 https://civicdb.org/links/variants/118 https://civicdb.org/links/genes/45 false TP53 7157 P152T Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant P152T was classified as recessive for RGC, p21, and PIG3, but it was classified as dominant negative for bax. In addition, P152T was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 2 accepted 10264 3794 45 Somatic 2022-04-14 13:56:12 UTC https://civicdb.org/links/evidence_items/10264 https://civicdb.org/links/variants/3794 https://civicdb.org/links/genes/45 false TP53 7157 R156P Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant R156P was classified as recessive for RGC, p21, and PIG3, but it was classified as dominant negative for bax. In addition, R156P was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 2 accepted 10265 3795 45 Somatic 2022-04-14 13:59:36 UTC https://civicdb.org/links/evidence_items/10265 https://civicdb.org/links/variants/3795 https://civicdb.org/links/genes/45 false TP53 7157 R181C Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant R181C was classified as recessive for p21 and PIG3, but it was classified as dominant negative for bax. In addition, R181C was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 2 accepted 10266 3796 45 Somatic 2022-04-21 08:09:55 UTC https://civicdb.org/links/evidence_items/10266 https://civicdb.org/links/variants/3796 https://civicdb.org/links/genes/45 false TP53 7157 R181G Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant R181G was classified as recessive for RGC, p21, and PIG3, but it was classified as dominant negative for bax. In addition, R181G was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 2 accepted 10267 3797 45 Somatic 2022-04-21 07:56:32 UTC https://civicdb.org/links/evidence_items/10267 https://civicdb.org/links/variants/3797 https://civicdb.org/links/genes/45 false TP53 7157 R181H Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant R181H was classified as recessive for RGC, p21, and PIG3, but it was classified as dominant negative for bax. In addition, R181H was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 2 accepted 10268 3798 45 Somatic 2022-04-21 07:56:55 UTC https://civicdb.org/links/evidence_items/10268 https://civicdb.org/links/variants/3798 https://civicdb.org/links/genes/45 false TP53 7157 D259V Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant D259V was classified as recessive for RGC, p21, and PIG3, but it was classified as dominant negative for bax. In addition, D259V was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 2 accepted 10269 3401 45 Somatic 2022-04-21 07:59:16 UTC https://civicdb.org/links/evidence_items/10269 https://civicdb.org/links/variants/3401 https://civicdb.org/links/genes/45 false TP53 7157 E286K Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant E286K was classified as recessive for RGC, p21, and PIG3, but it was classified as dominant negative for bax. In addition, E286K was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 2 accepted 10270 915 45 GRCh37 Somatic 2022-04-21 08:09:07 UTC https://civicdb.org/links/evidence_items/10270 https://civicdb.org/links/variants/915 https://civicdb.org/links/genes/45 false TP53 7157 R283H Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant R283H was classified as recessive for p21 and PIG3, but it was classified as dominant negative for bax. In addition, R283H was classified as a hotspot for mutation (P < 0.01) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 2 accepted 10271 3799 45 Somatic 2022-04-21 08:10:22 UTC https://civicdb.org/links/evidence_items/10271 https://civicdb.org/links/variants/3799 https://civicdb.org/links/genes/45 false TP53 7157 Y163N Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant Y163N was classified as recessive for p21, but it was classified as dominant negative for bax and PIG3. In addition, Y163N was classified as a hotspot for mutation (P < 0.001) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 2 accepted 10272 3800 45 Somatic 2022-04-21 08:09:22 UTC https://civicdb.org/links/evidence_items/10272 https://civicdb.org/links/variants/3800 https://civicdb.org/links/genes/45 false TP53 7157 L257P Functional Supports D Dominant Negative A set of previously characterized p53 mutants was tested in the yeast assay to understand their transdominant potential (dominant negative). Each mutant was expressed equally with the wild-type p53. The authors used the RGC, p21, bax, and PIG3 sequences as p53 binding sites. TP53 variant L257P was classified as recessive for p21, but it was classified as dominant negative for RGC, bax and PIG3. In addition, L257P was classified as a hotspot for mutation (P < 0.014) by the authors. The authors proposed a hierarchy of dominance of p53 variants for p21, PIG3, and bax sequences. They observed p53 variants that are dominant negative for p21 are also dominant for PIG3 and bax, and p53 variants that are dominant negative for PIG3 are also dominant for bax. The authors suggested lack of transactivation ability is necessary but not sufficient to predict dominance. 11896595 PubMed Monti et al., 2002, Oncogene 2 accepted 10273 3801 45 Somatic 2022-04-21 07:59:03 UTC https://civicdb.org/links/evidence_items/10273 https://civicdb.org/links/variants/3801 https://civicdb.org/links/genes/45 false PDGFB 5155 COL1A1-PDGFB fusion Dermatofibrosarcoma Protuberans 3507 Oncogenic N/A B N/A In this study, 57 cases of dermatofibrosarcoma protuberans (DFSP) were evaluated. The COL1A1-PDGFB fusion was detected in 42 (74%) out of the 57 sample after performing targeted PCR amplification and direct sequencing. The 42 samples were then evaluated for PDGFB and PDGFRB gene amplification using qPCR. SYBR green assay was also used to evaluate PDGFB gene amplification in comparison with a reference gene and a normal tissue. PDGFB mRNA expression was detected in all analyzed samples and was significantly higher in tumor cells compared to adjacent normal tissue; as amplification levels (copy number of PDGFB/ copy number of reference gene) varied from 0.6. to 8.3 (mean 2.4) in 42 tumor samples, and from 0.4 to 3.0 (mean 1.2) in 20 adjacent normal tissue samples (P = 0.0002). Moreover, the mRNA expression levels of PDGFB and PDGFRB showed a significant correlation (P < 0.0001). The authors of this study conclude that these results demonstrate the generation of the COL1A1-PDGFB fusion transcript that functions as a ligand for PDGFRB which subsequently activates the downstream PDGFB/PDGFRB signaling pathway involved in tumorigenesis of DFSP. 17431412 PubMed Takahira et al., 2007, Mod Pathol 3 accepted 10314 3991 4173 Somatic 2022-05-12 04:40:56 UTC https://civicdb.org/links/evidence_items/10314 https://civicdb.org/links/variants/3991 https://civicdb.org/links/genes/4173 false FGFR1 2260 N546K Pilocytic Astrocytoma 4851 Pemigatinib Predictive Supports C Sensitivity/Response Case report of a 32-year old male patient with pilocytic astrocytoma. Genomic profiling (FoundationOne) revealed a FGFR1 N546K mutation. The patient was enrolled in a phase I/II trial of pemigatinib and achieved a partial response lasting 18 months. 35507888 PubMed Capone et al., 2022, JCO Precis Oncol 3 accepted 10325 515 1885 8 38274849 38274849 G T ENST00000341462.5 75 GRCh37 Somatic 2022-05-11 16:48:16 UTC https://civicdb.org/links/evidence_items/10325 https://civicdb.org/links/variants/515 https://civicdb.org/links/genes/1885 false FGFR3 2261 Overexpression Cancer 162 R3Mab Predictive Supports D Sensitivity/Response Pro-B Ba/F3 cells transfected with wild type FGFR3 resulted in Il-3 independence with FGF1 dependence for growth. Monoclonal antibody R3Mab treatment in addition to FGF1 resulted in suppression of proliferation of Ba/F3 cells with wild type FGFR3. 19381019 PubMed Qing et al., 2009, J. Clin. Invest. 3 accepted 10352 325 23 4 1795039 1810599 ENST00000440486.2 75 GRCh37 Somatic 2022-05-26 21:31:19 UTC https://civicdb.org/links/evidence_items/10352 https://civicdb.org/links/variants/325 https://civicdb.org/links/genes/23 false FGFR3 2261 G370C Cancer 162 R3Mab Predictive Does Not Support D Resistance Ba/F3 cells transfected with wild type FGFR3 or common bladder carcinoma variant FGFR3 G372C both resulted in IL-3 independence with FGF1 dependence for growth. Monoclonal antibody R3Mab treatment with FGF1 suppressed proliferation of Ba/F3 FGFR3 G372C cells. Wildtype FGFR3 overexpression in Ba/F3 cells as well as bladder cancer cell lines RT112 and RT4 (who both have normal levels of endogenously expressed wildtype FGFR3), were similarly sensitive to R3Mab treatment, therefore mutation G372C did not change that responsiveness. 19381019 PubMed Qing et al., 2009, J. Clin. Invest. 3 accepted 10353 2406 23 4 1806089 1806089 G T ENST00000440486.8 75 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. Somatic 2022-06-22 20:43:06 UTC https://civicdb.org/links/evidence_items/10353 https://civicdb.org/links/variants/2406 https://civicdb.org/links/genes/23 false FGFR3 2261 Y373C Cancer 162 R3Mab Predictive Does Not Support D Resistance Pro-B Ba/F3 cells transfected with wild type FGFR3 resulted in IL-3 independence with FGF1 dependence for growth. Cell transfected FGFR3 with mutation Y375C also resulted in IL-3 independence and FGF1 dependence. Monoclonal antibody R3Mab treatment along with FGF1 resulted in suppression of proliferation of Ba/F3 cells with FGFR3 Y375C. Wild type FGFR3 overexpression in Ba/F3 cells with FGF1 was sensitive to monoclonal antibody R3Mab treatment, and mutation Y375C did not change that responsiveness. 19381019 PubMed Qing et al., 2009, J. Clin. Invest. 3 accepted 10354 2404 23 4 1806099 1806099 A G ENST00000440486.2 75 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. Somatic 2022-05-26 22:16:53 UTC https://civicdb.org/links/evidence_items/10354 https://civicdb.org/links/variants/2404 https://civicdb.org/links/genes/23 false FGFR3 2261 K650E Cancer 162 R3Mab Predictive Does Not Support D Resistance Ba/F3 cells transfected with wildtype FGFR3 resulted in IL-3 independence with FGF1 dependence for growth, whereas cells transfected with common bladder carcinoma variant FGFR3 K652E resulted in IL-3 independence, weak ligand-independent proliferation and a strong growth response to FGF1. Monoclonal antibody R3Mab treatment with FGF1 suppressed proliferation of Ba/F3 FGFR3 K652E cells. Wildtype FGFR3 overexpression in Ba/F3 cells as well as bladder cancer cell lines RT112 and RT4 (who both have normal levels of endogenously expressed wildtype FGFR3), were similarly sensitive to R3Mab treatment, therefore mutation K652E did not change that responsiveness. 19381019 PubMed Qing et al., 2009, J. Clin. Invest. 3 accepted 10355 1400 23 4 1807889 1807889 A G ENST00000340107.4 75 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. Somatic 2022-06-22 20:12:48 UTC https://civicdb.org/links/evidence_items/10355 https://civicdb.org/links/variants/1400 https://civicdb.org/links/genes/23 false NTRK2 4915 KANK1::NTRK2 Anaplastic Ependymoma 5889 Juvenile onset Larotrectinib Predictive Supports C Sensitivity/Response An MRI in a previously healthy 6-year-old boy now presenting with neurologic abnormalities and seizers revealed a mass obstructing the foramen of Monro and diffuse leptomeningeal dissemination. The primary tumor was resected and subsequent radiation therapy resulted in moderate cognitive and motor improvements. Seven months later, an MRI detected a recurrence, which led to tumor molecular profiling of patient DNA and RNA. RNA analysis discovered and confirmed an in-frame KANK1::NTRK2 e3::ex16 fusion, which was predicted to preserve NTRK2’s tyrosine kinase domain. The patient was started on larotrectinib and within 2 weeks demonstrated cognitive and motor improvements. After 2 months of therapy, an MRI showed significant tumor response and by 4 months cognition and memory were near-baseline. Overall, larotrectinib resulted in both sustained clinical and radiographic response through 10 months of treatment with no related toxicity. 34651095 PubMed Mangum et al., 2021, JCO Precis Oncol 4 accepted 10360 3158 3984 Somatic 2022-06-01 00:25:50 UTC https://civicdb.org/links/evidence_items/10360 https://civicdb.org/links/variants/3158 https://civicdb.org/links/genes/3984 false NTRK2 4915 KANK1::NTRK2 Glioblastoma 3068 Late young adult onset Larotrectinib Predictive Supports C Sensitivity/Response An MRI of 26-year-old man presenting with motor weakness and language difficultly revealed a lesion in the left frontal lobe that extended across the corpus callosum. Histologic analysis of the biopsy characterized the lesion as a glioblastoma wildtype for IDH and was negative for EGFR and MET amplification based on FISH. The biopsy material was analyzed with a DNA based genotyping panel and RNA-based NGS assay. The latter detected a KANK1::NTRK2 e4::e16 fusion that was confirmed by FISH. Following the partial resection of the tumor and six weeks of concurrent temozolomide and radiation therapy, an MRI revealed enhancement of the remaining tumor with no significant disease progression. Larotrectinib (100mg) was administered and after 49 days an MRI displayed significant treatment response as the lesion shrunk (25mm to <10mm) and the patient demonstrated slight motor improvements. By day 106 of Larotrectinib treatment, disease progression was evident. However, molecular analysis of a rebiopsy revealed KANK1::NTRK2 was no longer detectable, but a minor subclone at diagnosis with PDGFRA amplification was driving disease progression. Therefore, the authors conclude the KANK1::NTRK2 clones were effectively targeted by Larotrectinib treatment over several months resulting in a robust clinical response. 34041811 PubMed Shepherd et al., 2021, Oncologist 3 accepted 10361 3158 3984 Somatic 2022-06-01 00:39:34 UTC https://civicdb.org/links/evidence_items/10361 https://civicdb.org/links/variants/3158 https://civicdb.org/links/genes/3984 false MS4A1 931 Mutation Diffuse Large B-cell Lymphoma 0050745 R-CHOP Regimen Predictive Supports B Resistance A targeted sequencing study of 135 relapsed/refractory DLBCL patients identified an association between missense mutations in MS4A1 and acquired resistance to R-CHOP. 32589730 PubMed Rushton et al., 2020, Blood Adv 3 accepted 10367 4018 827 Somatic 2022-07-14 18:35:03 UTC https://civicdb.org/links/evidence_items/10367 https://civicdb.org/links/variants/4018 https://civicdb.org/links/genes/827 false FGFR3 2261 K650N Functional Supports D Gain of Function Five patients from four families suffering from skeletal dysplasia were found to harbor a novel heterozygous K650N variant in FGFR3. The variant cosegregated in two patients from one family (a father and his daughter), whereas it occurred sporadically in the others. NIH3T3 cells were transfected with the variant construct followed by kinase activity assay that showed increased activity by ~ 4 folds compared to the wild type. The authors suggest that this variant, although showing lower activation levels than other known variants responsible for severe skeletal dysplasia forms, is responsible for the milder skeletal dysplasia form seen in those patients (mild hypochondroplasia phenotype), and they further highlight the significance of Lys650 site in the active domain loop of the receptor. 11055896 PubMed Bellus et al., 2000, Am J Hum Genet 2 accepted 10377 3695 23 4 1807891 1807891 G C ENST00000440486.8 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. N/A 2022-06-21 21:46:32 UTC https://civicdb.org/links/evidence_items/10377 https://civicdb.org/links/variants/3695 https://civicdb.org/links/genes/23 false FGFR3 2261 K650Q Functional Supports D Gain of Function A patient suffering from skeletal dysplasia was found to harbor a novel heterozygous K650Q variant in FGFR3. NIH3T3 cells were transfected with the variant construct followed by kinase activity assay that showed increased activity by 5 folds compared to the wild type. The authors suggest that this variant, although showed lower activation levels than other known variants responsible for severe skeletal dysplasia forms, is responsible for the milder skeletal dysplasia form seen in those patients (mild hypochondroplasia phenotype), and they further highlight the significance of Lys650 site in the active domain loop of the receptor. 11055896 PubMed Bellus et al., 2000, Am J Hum Genet 2 accepted 10378 4019 23 4 1807889 1807889 A C ENST00000440486.8 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. Somatic 2022-06-09 19:35:58 UTC https://civicdb.org/links/evidence_items/10378 https://civicdb.org/links/variants/4019 https://civicdb.org/links/genes/23 false FGFR3 2261 K650M Functional Supports D Gain of Function The K650M variant in FGFR3 is known to be responsible for the severe skeletal dysplasia forms seen in TDI/SADDAN. The mutant receptor was tested for comparison between other variants discussed in this paper. FGFR3 cDNA construct with the K650M variant was synthesized and transfected into NIH3T3 cells. The K650M variant receptor had 18- fold greater kinase activity compared to the wild type receptor. 11055896 PubMed Bellus et al., 2000, Am J Hum Genet 1 accepted 10380 4013 23 4 1807890 1807890 A T ENST00000440486.8 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. N/A 2022-06-09 20:56:17 UTC https://civicdb.org/links/evidence_items/10380 https://civicdb.org/links/variants/4013 https://civicdb.org/links/genes/23 false NTRK2 4915 Fusion Solid Tumor Larotrectinib Predictive Supports A Sensitivity/Response A pooled analysis of three phase 1/2 clinical trials investigating the efficacy and safety of larotrectinib in 159 NTRK fusion positive solid tumor patients (1 month - 84 years old) confirmed larotrectinib to be effective and safe in these patients. NTRK2 fusions were found in 4 of the 159 patients. Two cases NTRK2 fusion cases were shown to have reduction in tumor size with another tumor showing only minor growth. 32105622 PubMed Hong et al., 2020, Lancet Oncol NCT02122913,NCT02637687,NCT02576431 2 accepted 10392 2640 3984 Somatic 2022-07-12 18:57:46 UTC https://civicdb.org/links/evidence_items/10392 https://civicdb.org/links/variants/2640 https://civicdb.org/links/genes/3984 false FGFR3 2261 K650E Functional Supports D Gain of Function NIH 3T3 cells were transfected with wild-type and mutant K650E FGFR3. Immunoprecipitation measuring kinase activity showed FGFR3 K650E had 100-fold greater autophosphorylation than wildtype. The authors concluded that the position and charge of K650E lead to its constitutive activation. 8754806 PubMed Webster et al., 1996, Mol Cell Biol 3 accepted 10393 1400 23 4 1807889 1807889 A G ENST00000340107.4 75 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. Common Germline 2022-06-23 07:53:20 UTC https://civicdb.org/links/evidence_items/10393 https://civicdb.org/links/variants/1400 https://civicdb.org/links/genes/23 false EZH2 2146 Y646F B-cell Lymphoma 707 Oncogenic N/A D N/A Ezh2 Y641F (EZH2 Y641F) was conditionally expressed in mouse B-cells and caused high-penetrance lymphoma that was further accelerated by Bcl2 overexpression or p53 loss (but not c-Myc overexpression). Expression of Ezh2 Y641F increased global abundance of H3K27 trimethylation (H3K27me3) and also caused widespread redistribution of H3K27me3 leading to widespread transciptional changes. Overall, these results suggest that Ezh2 Y641F induces B-cell lymphoma through widespread reorganization of chromatin structure. 27135738 PubMed Souroullas et al., 2016, Nat. Med. 4 accepted 10394 2989 63 7 148508727 148508727 T A ENST00000320356.7 GRCh37 Y646F has been reported as one of the most recurrent alterations of EZH2 in DLBCL, FL and other malignancies. This mutation is thought to alter methyltransferase activity of EZH2 and confer sensitivity to EZH2 inhibitors such as tazemetostat. Somatic 2022-06-29 06:43:49 UTC https://civicdb.org/links/evidence_items/10394 https://civicdb.org/links/variants/2989 https://civicdb.org/links/genes/63 false FGFR3 2261 K650D Functional Supports D Gain of Function NIH 3T3 cells were transfected with wild-type and mutant FGFR3 K650D. Immunoprecipitation measuring kinase activity showed FGFR3 K650D had similar autophosphorylation through constitutive action to FGFR3 K650E, which had 100-fold greater autophosphorylation than wildtype. The authors concluded that for constitutive FGFR3 activation, an acidic residue at position 650 is beneficial but not required. 8754806 PubMed Webster et al., 1996, Mol Cell Biol 3 accepted 10400 4024 23 4 1807889 1807891 GAC AAG ENST00000440486.8 GRCh37 Somatic 2022-06-23 08:05:42 UTC https://civicdb.org/links/evidence_items/10400 https://civicdb.org/links/variants/4024 https://civicdb.org/links/genes/23 false FGFR3 2261 K650Q Functional Supports D Gain of Function NIH 3T3 cells were transfected with wild-type and mutant FGFR3 K650Q. Immunoprecipitation measuring kinase activity showed FGFR3 K650Q had much lower autophosphorylation to FGFR3 K650E, which had 100-fold greater autophosphorylation than wildtype, but that FGFR K650Q still had higher autophosphorylation driven by constitutive action than wildtype. The authors concluded that for constitutive FGFR3 activation, an acidic residue at position 650 is beneficial but not required. 8754806 PubMed Webster et al., 1996, Mol Cell Biol 2 accepted 10401 4019 23 4 1807889 1807889 A C ENST00000440486.8 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. Somatic 2022-06-23 08:08:38 UTC https://civicdb.org/links/evidence_items/10401 https://civicdb.org/links/variants/4019 https://civicdb.org/links/genes/23 false FGFR3 2261 K650L Functional Supports D Gain of Function NIH 3T3 cells were transfected with wild-type and mutant FGFR3 K650L. Immunoprecipitation measuring kinase activity showed FGFR3 K650L had much lower autophosphorylation than FGFR3 K650E, which had 100-fold greater autophosphorylation than wildtype but had higher autophosphorylation driven by constitutive action than wildtype. The authors concluded that for constitutive FGFR3 activation, an acidic residue at position 650 is beneficial but not required. 8754806 PubMed Webster et al., 1996, Mol Cell Biol 2 accepted 10402 4025 23 4 1807889 1807890 AA CT ENST00000440486.8 GRCh37 Somatic 2022-06-23 08:09:06 UTC https://civicdb.org/links/evidence_items/10402 https://civicdb.org/links/variants/4025 https://civicdb.org/links/genes/23 false FGFR3 2261 G380R Functional Supports D Gain of Function Achondroplasia associated FGFR3 mutant G380R (ACH), K650E (TDII), and wildtype (WT) FGFR3 constructs were cloned and transfected into NIH3T3 cells, and immunopercipitated with anti-FGFR3. In vitro kinase assays were performed and G380R was found to have activity between WT and K650E, which had approximately 100 fold increase over WT. 8754806 PubMed Webster et al., 1996, Mol Cell Biol 2 accepted 10416 2405 23 4 1806119 1806119 G C ENST00000340107.4 75 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. Unknown 2022-07-30 18:12:31 UTC https://civicdb.org/links/evidence_items/10416 https://civicdb.org/links/variants/2405 https://civicdb.org/links/genes/23 false FGFR3 2261 K650E Functional Supports D Gain of Function A construct of PDGF and FGFR3 was created as a chimeric receptor to study the effect of the K650E variant on downstream signaling pathways. Transfecting PC12 cells showed continuous ligand-independent activity of the chimeric mutant receptor with the presence of an inducer alone (zinc) but not the ligand; PDFG. Upon addition of PDGF, further activation was also observed. Conversely, control cells showed activity only with the addition of both ligand and zinc. Gene expression profiling showed P21 gene was expressed at a higher level (1.7 folds) in mutant receptor cells, providing evidence of ERK1/2 and STAT1/3 activation. The mutant receptor produced a highly sustained ERK1/2 activation even after 1 hour of PDGF treatment, whereas wild-type expressing cells showed a decrease in ERK1/2 activity. Lastly, cells only expressing the variant K650E receptor were able to phosphorylate tyrosine in STAT1, and tyrosine, along with serine, in a ligand-independent manner in STAT3. Authors confirm that mutant FGFR3 activates ERK1/2 and STAT1/3 in a ligand-independent manner and maintains this activation over longer periods of time when treated with ligand than does the wild-type receptor. 15843401 PubMed Nowroozi et al., 2005, Hum Mol Genet 3 accepted 10493 1400 23 4 1807889 1807889 A G ENST00000340107.4 75 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. N/A 2022-07-30 17:57:34 UTC https://civicdb.org/links/evidence_items/10493 https://civicdb.org/links/variants/1400 https://civicdb.org/links/genes/23 false FGFR3 2261 A391E Functional Supports D Gain of Function FRET was used to compare the structural changes in FGFR dimers when FGF1 and FGF2 bind, and found that FGF2 bound dimers were much closer to each other than FGF1. The authors also looked at FGFR3 phosphorylation using western blot analysis and found that FGF2-bound dimers had increased FGFR3 phosphorylation. Therefore it was concluded that the FGF1 bound dimer is the inactive state, while the FGF2 bound dimer is the active state. Common bladder cancer and Crouzon syndrome with acanthosis nigricans variant FGFR3 A391E dimerization and phosphorylation were measured via FRET and western blot assays respectively. The A391E substitution was shown to activate FGFR3 through ligand-independent dimerization similar to the FGF2 bound state. Thus the authors concluded that the A391E mutation traps FGF3R in its most active state. 26725515 PubMed Sarabipour et al., 2016, Nat Commun 4 accepted 10513 4023 23 4 1806153 1806153 C A ENST00000440486.8 GRCh37 This is a pilot variant of the FGFR ClinGen Somatic Cancer Variant Curation Expert Panel (SC-VCEP) used to establish FGFR specific modifications to the ClinGen/CGC/VICC procedure for classification of somatic variant oncogenicity. Somatic 2022-07-21 20:04:32 UTC https://civicdb.org/links/evidence_items/10513 https://civicdb.org/links/variants/4023 https://civicdb.org/links/genes/23 false TP53 7157 R175H Functional Supports D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant R175H originally identified in anaplastic astrocytoma. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing p53 variant and WT p53 produced red/pink colonies, demonstrating that R175H displays transdominance. Authors reported that all of the DN mutants affected the amino acids essential to the upkeep of DNA binding surfaces according to crystallographic structure. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10527 116 45 17 7578406 7578406 C T ENST00000269305.4 75 GRCh37 While loss-of-function events in TP53 are very common in cancer, the R175H variant seems not only to result in loss of tumor-suppression, but also acts as a gain-of-function mutation that promotes tumorigenesis in mouse models. Cell lines harboring this mutant is also more responsive to treatment with doxorubicin than its wild-type counterparts. While the prognostic impact of individual TP53 mutations is influenced by the cohort being studied, it has been shown that the R175H mutation is correlated with worse overall survival than wild-type TP53, but is not as detrimental as the R248W variant. This variant is rare in population databases (ACMG code: PM2; 0.000003980 total exome AF gnomAD v2.1.1). Somatic 2022-07-21 17:35:38 UTC https://civicdb.org/links/evidence_items/10527 https://civicdb.org/links/variants/116 https://civicdb.org/links/genes/45 false TP53 7157 R156H Functional Supports D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant R156H originally identified in an oral lesion. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing p53 variant and WT p53 produced red/pink colonies, demonstrating that R156H displays transdominance. Authors reported that all of the DN mutants affected the amino acids essential to the upkeep of DNA binding surfaces according to crystallographic structure. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10528 4102 45 Somatic 2022-07-21 17:37:01 UTC https://civicdb.org/links/evidence_items/10528 https://civicdb.org/links/variants/4102 https://civicdb.org/links/genes/45 false TP53 7157 H178P Functional Supports D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant H178P originally identified in glioblastoma. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing p53 variant and WT p53 produced red/pink colonies, demonstrating that H178P displays transdominance. Authors reported that all of the DN mutants affected the amino acids essential to the upkeep of DNA binding surfaces according to crystallographic structure. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10529 4103 45 Somatic 2022-07-21 17:38:56 UTC https://civicdb.org/links/evidence_items/10529 https://civicdb.org/links/variants/4103 https://civicdb.org/links/genes/45 false TP53 7157 H179R Functional Supports D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant H179R originally identified in an oral lesion. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing p53 variant and WT p53 produced red/pink colonies, demonstrating that H179R displays transdominance. Authors reported that all of the DN mutants affected the amino acids essential to the upkeep of DNA binding surfaces according to crystallographic structure. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10530 1082 45 GRCh37 Somatic 2022-07-21 17:39:44 UTC https://civicdb.org/links/evidence_items/10530 https://civicdb.org/links/variants/1082 https://civicdb.org/links/genes/45 false TP53 7157 R181P Functional Supports D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant R181P originally identified in breast cancer. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing p53 variant and WT p53 produced red/pink colonies, demonstrating that R181P displays transdominance. Authors reported that all of the DN mutants affected the amino acids essential to the upkeep of DNA binding surfaces according to crystallographic structure. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10531 3390 45 Somatic 2022-07-21 17:40:25 UTC https://civicdb.org/links/evidence_items/10531 https://civicdb.org/links/variants/3390 https://civicdb.org/links/genes/45 false TP53 7157 G245S Functional Supports D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant G245S originally identified in an oral lesion. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing p53 variant and WT p53 produced red/pink colonies, demonstrating that G245S displays transdominance. Authors reported that all of the DN mutants affected the amino acids essential to the upkeep of DNA binding surfaces according to crystallographic structure. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10532 879 45 17 7577548 7577548 C T ENST00000269305.4 75 GRCh37 Somatic 2022-07-21 17:40:57 UTC https://civicdb.org/links/evidence_items/10532 https://civicdb.org/links/variants/879 https://civicdb.org/links/genes/45 false TP53 7157 R249S Functional Supports D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant R249S. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing p53 variant and WT p53 produced red/pink colonies, demonstrating that R249S displays transdominance. Authors reported that all of the DN mutants affected the amino acids essential to the upkeep of DNA binding surfaces according to crystallographic structure. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10540 1696 45 Somatic 2022-07-21 17:23:45 UTC https://civicdb.org/links/evidence_items/10540 https://civicdb.org/links/variants/1696 https://civicdb.org/links/genes/45 false TP53 7157 E68G Functional Does Not Support D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant E68G originally identified in anaplastic astrocytoma. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing E68G and WT p53 produced white colonies, indicating that E68G is not DN. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10541 4106 45 Somatic 2022-07-21 17:07:22 UTC https://civicdb.org/links/evidence_items/10541 https://civicdb.org/links/variants/4106 https://civicdb.org/links/genes/45 false TP53 7157 L111R Functional Does Not Support D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant L111R originally identified in anaplastic astrocytoma. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing L111R and WT p53 produced white colonies, indicating that L111R is not DN. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10554 4111 45 Somatic 2022-07-21 17:09:01 UTC https://civicdb.org/links/evidence_items/10554 https://civicdb.org/links/variants/4111 https://civicdb.org/links/genes/45 false TP53 7157 H115Y Functional Does Not Support D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant H115Y originally identified in anaplastic astrocytoma from a glioma cell line. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing H115Y and WT p53 produced white colonies, indicating that H115Y is not DN. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10555 4112 45 Somatic 2022-07-21 17:04:48 UTC https://civicdb.org/links/evidence_items/10555 https://civicdb.org/links/variants/4112 https://civicdb.org/links/genes/45 false TP53 7157 C124R Functional Does Not Support D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant C124R originally identified in anaplastic astrocytoma. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing C124R and WT p53 produced white colonies, indicating that C124R is not DN. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10556 4113 45 Somatic 2022-07-21 17:01:43 UTC https://civicdb.org/links/evidence_items/10556 https://civicdb.org/links/variants/4113 https://civicdb.org/links/genes/45 false TP53 7157 C135W Functional Does Not Support D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant C135W originally identified in glioblastoma. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing C135W and WT p53 produced white colonies, indicating that C135W is not DN. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10557 924 45 17 7578525 7578525 G C ENST00000269305.4 75 GRCh37 Somatic 2022-07-21 16:57:22 UTC https://civicdb.org/links/evidence_items/10557 https://civicdb.org/links/variants/924 https://civicdb.org/links/genes/45 false TP53 7157 L139N Functional Does Not Support D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant L139N originally identified in breast cancer. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing L139N and WT p53 produced white colonies, indicating that L139N is not DN. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10558 4114 45 Somatic 2022-07-21 16:52:29 UTC https://civicdb.org/links/evidence_items/10558 https://civicdb.org/links/variants/4114 https://civicdb.org/links/genes/45 false TP53 7157 P152L Functional Does Not Support D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant P152L originally identified in an oral lesion. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing P152L and WT p53 produced white colonies, indicating that P152L is not DN. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10559 3767 45 Somatic 2022-07-21 16:58:52 UTC https://civicdb.org/links/evidence_items/10559 https://civicdb.org/links/variants/3767 https://civicdb.org/links/genes/45 false TP53 7157 R158G Functional Does Not Support D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant R158G originally identified in anaplastic astrocytoma. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing R158G and WT p53 produced white colonies, indicating that R158G is not DN. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10560 4115 45 Somatic 2022-07-21 17:00:19 UTC https://civicdb.org/links/evidence_items/10560 https://civicdb.org/links/variants/4115 https://civicdb.org/links/genes/45 false TP53 7157 R158H Functional Does Not Support D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant R158H originally identified in glioblastoma. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing R158H and WT p53 produced white colonies, indicating that R158H is not DN. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10561 1695 45 17 7578457 7578457 C T ENST00000269305.4 75 GRCh37 Somatic 2022-07-21 17:11:17 UTC https://civicdb.org/links/evidence_items/10561 https://civicdb.org/links/variants/1695 https://civicdb.org/links/genes/45 false TP53 7157 G266V Functional Does Not Support D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant G266V originally identified in breast cancer. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing G266V and WT p53 produced white colonies, indicating that G266V is not DN. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10574 4122 45 Somatic 2022-07-21 17:34:32 UTC https://civicdb.org/links/evidence_items/10574 https://civicdb.org/links/variants/4122 https://civicdb.org/links/genes/45 false TP53 7157 G266E Functional Does Not Support D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant G266E originally identified in glioblastoma from a glioma cell line. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing G266E and WT p53 produced white colonies, indicating that G266E is not DN. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10575 3774 45 Somatic 2022-07-21 17:19:50 UTC https://civicdb.org/links/evidence_items/10575 https://civicdb.org/links/variants/3774 https://civicdb.org/links/genes/45 false TP53 7157 F270S Functional Does Not Support D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant F270S originally identified in breast cancer. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing F270S and WT p53 produced white colonies, indicating that F270S is not DN. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10576 1053 45 GRCh37 Somatic 2022-07-21 17:31:52 UTC https://civicdb.org/links/evidence_items/10576 https://civicdb.org/links/variants/1053 https://civicdb.org/links/genes/45 false TP53 7157 V272G Functional Does Not Support D Dominant Negative Yeast strain yIG397 was cultured to express both wild-type (WT) and mutant V272G originally identified in breast cancer. Should the mutant be dominant-negative (DN), TP53 will not bind and transactivate the ADE2 protein, resulting in red/pink colonies. If the mutant is recessive, then WT function is not blocked and ADE2 protein is expressed through TP53 transactivation, resulting in white colonies. Western blot analysis showed that yeast lysates showed expression of both WT and mutant alleles. Yeast expressing V272G and WT p53 produced white colonies, indicating that V272G is not DN. 10519380 PubMed Marutani et al., 1999, Cancer Res 3 accepted 10577 4123 45 Somatic 2022-07-21 17:30:41 UTC https://civicdb.org/links/evidence_items/10577 https://civicdb.org/links/variants/4123 https://civicdb.org/links/genes/45 false