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|Protein Effect||gain of function|
|Gene Variant Descriptions||ERBB2 (HER2) A775_G776insYVMA results in the insertion of four amino acids in the protein kinase domain of the Erbb2 (Her2) protein between amino acids 775 and 776 (UniProt.org). A775_G776insYVMA results in the same amino acid change as M774_A775insAYVM, which leads to constitutive phosphorylation of Erbb2 (Her2) and is transforming in cell culture (PMID: 17311002, PMID: 29967253).|
|Associated Drug Resistance|
|Transcript||gDNA||cDNA||Protein||Source Database||Genome Build|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|ERBB2 A775_G776insYVMA||lung non-small cell carcinoma||sensitive||Ado-trastuzumab emtansine||Preclinical - Pdx||Actionable||In a preclinical study, treatment with Kadcyla (ado-trastuzumab emtansine) resulted in tumor growth inhibition and tumor regression of patient derived xenograft (PDX) models harboring ERBB2 A775_G776insYVMA, but to a lesser degree than treatment with Pyrotinib (PMID: 30596880; NCT02535507).||30596880|
|ERBB2 A775_G776insYVMA||lung non-small cell carcinoma||sensitive||Ado-trastuzumab emtansine||Case Reports/Case Series||Actionable||In a Phase II trial, Kadcyla (ado-trastuzumab emtansine) treatment demonstrated limited efficacy in patients with relapsed non-small cell lung cancer harboring ERBB2 (Her2) mutations, resulting in a partial response in 20% (1/5) and stable disease in 60% (3/5) of patients harboring ERBB2 (HER2) A775_G776insYVMA (PMID: 29313813).||29313813|
|ERBB2 A775_G776insYVMA||lung non-small cell carcinoma||sensitive||Afatinib||Preclinical - Pdx & cell culture||Actionable||In a preclinical study, treatment with Gilotrif (afatinib) resulted in decreased cell viability of patient-derived non-small cell lung cancer organoids harboring ERBB2 A775_G776insYVMA and tumor growth inhibition and tumor regression in patient derived xenograft (PDX) models, but to a lesser degree than treatment with Pyrotinib (PMID: 30596880; NCT02535507).||30596880|
|ERBB2 A775_G776insYVMA||lung adenocarcinoma||predicted - sensitive||Ado-trastuzumab emtansine||Case Reports/Case Series||Actionable||In a Phase II trial, treatment with Kadcyla (trastuzumab emtansine) resulted in best overall responses of partial response in 44% (8/18) and stable disease in 39% (7/18), and median progression-free survival of 5 months in patients with lung adenocarcinoma harboring ERBB2 (HER2) activating mutations, and a subset of patients specifically harboring ERBB2 (HER2) A775_G776insYVMA mutation had a 60% (3/5) partial response rate (PMID: 29989854; NCT02675829).||29989854|
|ERBB2 A775_G776insYVMA||lung non-small cell carcinoma||sensitive||Pyrotinib||Case Reports/Case Series||Actionable||In a Phase II trial, ten patients with non-small cell lung cancer harboring ERBB2 A775_G776insYVMA demonstrated an objective response rate of 50% (5/10) and a progression-free survival of 4.1 months when treated with Pyrotinib, and preclinical analysis showed Pyrotinib treatment led to reduced cell viability in patient-derived organoids and tumor growth inhibition and regression in patient derived xenograft (PDX) models (PMID: 30596880; NCT02535507).||30596880|
|ERBB2 A775_G776insYVMA||Advanced Solid Tumor||sensitive||JQ1 + Osimertinib||Preclinical||Actionable||In a preclinical study, transgenic mouse models expressing ERBB2 (HER2) A775_G776insYVMA demonstrated greater tumor regression when treated with the combination of JQ1 and Tagrisso (osimertinib) compared to treatment with either agent alone, which resulted in little to no regression (PMID: 29298799).||29298799|
|ERBB2 A775_G776insYVMA PIK3CA R425L||lung non-small cell carcinoma||predicted - resistant||Trastuzumab||Case Reports/Case Series||Actionable||In a clinical study, the PIK3CA R425L mutation was identified as a potential resistance mechanism in a non-small cell lung carcinoma patient harboring ERBB2 (HER2) A775_G776insYVMA, that progressed during Herceptin (trastuzumab) treatment (PMID: 28167203).||28167203|