ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9227G>A (p.Gly3076Glu) (rs80359187)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216816 SCV000274761 likely pathogenic Hereditary cancer-predisposing syndrome 2017-03-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000114069 SCV000147572 uncertain significance Breast-ovarian cancer, familial 2 1998-07-10 no assertion criteria provided clinical testing
Counsyl RCV000114069 SCV000489258 uncertain significance Breast-ovarian cancer, familial 2 2016-09-11 criteria provided, single submitter clinical testing
GeneDx RCV000221088 SCV000279359 likely pathogenic not provided 2018-07-27 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9227G>A at the cDNA level, p.Gly3076Glu (G3076E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). This variant, also published as BRCA2 9455G>A using alternate nomenclature, has been reported in at least one individual with breast cancer (Ikeda 2001). Han et al. (2003) also identified BRCA2 Gly3076Glu in three family members, two of whom were diagnosed with both breast and pancreatic cancer and one diagnosed with breast cancer only. Additionally, BRCA2 Gly3076Glu displayed reduced homologous recombination repair activity in a homology-directed DNA break repair assay, which has been shown to have high sensitivity and specificity for determining pathogenicity of BRCA2 missense variants in the DNA-binding domain (Guidugli 2013). Additionally, a multifactorial analysis taking into account these functional results predicts this variant to be pathogenic (Guidugli 2018). BRCA2 Gly3076Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Gly3076Glu is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on the currently available information, we consider BRCA2 Gly3076Glu to be a likely pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000114069 SCV000296594 uncertain significance Breast-ovarian cancer, familial 2 2016-03-19 criteria provided, single submitter clinical testing

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