Submissions for variant NM_000059.4(BRCA2):c.8825C>A (p.Ala2942Asp)

dbSNP: rs373227180

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160159	SCV000210486	uncertain significance	not provided	2018-02-20	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8825C>A at the cDNA level, p.Ala2942Asp (A2942D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCT>GAT). Using alternate nomenclature, this variant would be defined as BRCA2 9053C>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala2942Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant 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 currently available evidence, it is unclear whether BRCA2 Ala2942Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000166381	SCV000217173	likely benign	Hereditary cancer-predisposing syndrome	2021-04-30	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	RCV000693651	SCV000821528	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2942 of the BRCA2 protein (p.Ala2942Asp). This variant is present in population databases (rs373227180, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 182256). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781101	SCV000918932	uncertain significance	not specified	2024-03-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160159	SCV001470458	uncertain significance	not provided	2024-07-10	criteria provided, single submitter	clinical testing	The BRCA2 c.8825C>A (p.Ala2942Asp) variant has not been reported in individuals with BRCA2-related conditions in the published literature. The frequency of this variant in the general population, 0.000004 (1/250828 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV003462081	SCV004213713	uncertain significance	Familial cancer of breast	2024-02-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998452	SCV004846075	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with aspartic acid at codon 2942 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 1/250828 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.