Submissions for variant NM_000059.4(BRCA2):c.2813C>A (p.Ala938Glu)

gnomAD frequency: 0.00015  dbSNP: rs55773834

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044067	SCV000072080	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130944	SCV000185857	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000083094	SCV000267755	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000587088	SCV000278842	uncertain significance	not provided	2023-07-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with glioblastoma and breast cancer (Lu et al., 2015; Renata Mendes de Freitas et al., 2022); Also known as 3041C>A; This variant is associated with the following publications: (PMID: 28873162, 23929434, 26689913, 28122867, de Freitas_2022, 32377563, 31911673, 26295337, 29884841, 31853058)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797611	SCV000694633	uncertain significance	not specified	2023-07-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2813C>A (p.Ala938Glu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250824 control chromosomes. Although the observed frequency does not exceed the estimated maximal expected allele frequency of a pathogenic variant in this gene (0.00075), the variant may represent a rare ethnic-specific functional polymorphism as evidenced by it being found in 3 African American women over 70 years old who have never had cancer (FLOSSIES database). c.2813C>A has been reported in the literature in individuals affected with cancer, including glioblastoma (example, Lu_2015, Mandelker_2017). 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. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments; five of them classified the variant as uncertain significance and four of them classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl	RCV000083094	SCV000785779	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-11-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587088	SCV000889011	uncertain significance	not provided	2023-03-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0004 (10/24886 chromosomes in the African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals affected with breast cancer (Freitas et al. 2022. Mastology 32:e20220003), glioblastoma (PMID: 26689913 (2015)), and an advanced cancer (PMID: 28873162 (2017)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000130944	SCV000903800	likely benign	Hereditary cancer-predisposing syndrome	2015-12-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130944	SCV002535530	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130944	SCV003850156	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).
PreventionGenetics, part of Exact Sciences	RCV003415789	SCV004108723	uncertain significance	BRCA2-related condition	2023-04-25	criteria provided, single submitter	clinical testing	The BRCA2 c.2813C>A variant is predicted to result in the amino acid substitution p.Ala938Glu. This variant has been reported in individuals with breast cancer, an individual with glioblastoma multiforme, and an individual with advanced cancer (Infante et al. 2013. PubMed ID: 23929434; Table S13, Lu et al. 2015. PubMed ID: 26689913; eTable, Mandelker et al. 2017. PubMed ID: 28873162). This variant occurs within a region of the BRCA2 gene that is predicted to be tolerant to variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). This variant is reported in 0.040% of alleles in individuals of African descent in gnomAD (https://gnomad.broadinstitute.org/variant/chr13-32911305-C-A). It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51353/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Sharing Clinical Reports Project (SCRP)	RCV000083094	SCV000115168	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2008-01-04	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083094	SCV000146120	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-10-29	no assertion criteria provided	clinical testing