Submissions for variant NM_000059.4(BRCA2):c.8183T>C (p.Val2728Ala)

gnomAD frequency: 0.00001  dbSNP: rs587781719

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129903	SCV000184721	likely benign	Hereditary cancer-predisposing syndrome	2020-02-25	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463515	SCV000549863	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2728 of the BRCA2 protein (p.Val2728Ala). This variant is present in population databases (rs587781719, gnomAD 0.01%). This missense change has been observed in individual(s) with an unspecified cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 141399). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 33609447, 35736817). 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.
GeneDx	RCV000523831	SCV000617876	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	Observed in an individual with breast or ovarian cancer undergoing multi-gene hereditary cancer panel testing (Bishop et al., 2019); Published functional studies demonstrate no damaging effect: homology-directed repair activity similar to wild-type (Hart et al., 2020; Richardson et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8411T>C; This variant is associated with the following publications: (PMID: 12228710, 33609447, 31415627, 32377563)
Counsyl	RCV000663059	SCV000786115	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-02-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000523831	SCV001133923	uncertain significance	not provided	2024-11-19	criteria provided, single submitter	clinical testing	The BRCA2 c.8183T>C (p.Val2728Ala) variant has been reported in the published literature in a study to evaluate for breast, ovarian, and prostate cancer genetic risk (PMID: 31415627 (2019)). This variant has also been identified an individual with an unspecified hereditary cancer (PMID: 34326862 (2021)). Additionally, a functional study suggests that the variant is not damaging to BRCA2 protein function (PMID: 33609447 (2021), 35736817 (2022)). The frequency of this variant in the general population, 0.000032 (1/31400 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251367	SCV001426940	uncertain significance	not specified	2020-07-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8183T>C (p.Val2728Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250884 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8183T>C has been reported in the literature in at-least one individual in a study of cancer affected individuals from the Alabama hereditary cancer cohort (Bishop_2019). This report does 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000129903	SCV002531920	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-04	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000663059	SCV004845620	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 2728 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant does not impact homology-directed DNA repair activity (PMID: 33609447, 35736817). To our knowledge, this variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 1/31400 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.