Submissions for variant NM_000059.4(BRCA2):c.811G>A (p.Gly271Arg)

gnomAD frequency: 0.00001  dbSNP: rs786204274

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218275	SCV000274810	likely benign	Hereditary cancer-predisposing syndrome	2018-03-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657096	SCV000600787	uncertain significance	not provided	2019-08-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000657096	SCV000617910	uncertain significance	not provided	2019-06-21	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31451522, 32039725, 30212499)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000560451	SCV000635641	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 271 of the BRCA2 protein (p.Gly271Arg). This variant is present in population databases (rs786204274, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 31451522, 32039725). ClinVar contains an entry for this variant (Variation ID: 188426). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000218275	SCV000910942	likely benign	Hereditary cancer-predisposing syndrome	2016-08-18	criteria provided, single submitter	clinical testing
Mendelics	RCV003491925	SCV001138981	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170224	SCV001332784	uncertain significance	Breast and/or ovarian cancer	2018-02-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193280	SCV001362014	uncertain significance	not specified	2021-05-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.811G>A (p.Gly271Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 244314 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.811G>A has been reported in the literature in individuals affected with Breast Cancer (Ebrahimi_2019, Carvalho_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS n=6, likely benign n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000218275	SCV002531912	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-10	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000218275	SCV003848049	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).