Submissions for variant NM_000059.4(BRCA2):c.7874G>A (p.Arg2625Lys)

dbSNP: rs864622552

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204378	SCV000261095	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-07-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 2625 of the BRCA2 protein (p.Arg2625Lys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 34196900). ClinVar contains an entry for this variant (Variation ID: 220500). Advanced modeling performed at Invitae incorporating data from internal and/or published 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). 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	RCV000483772	SCV000569381	uncertain significance	not provided	2016-02-10	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.7874G>A at the cDNA level, p.Arg2625Lys (R2625K) at the protein level, and results in the change of an Arginine to a Lysine (AGA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 8102G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Arg2625Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Lysine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Arg2625Lys occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located in DNA binding domain as well as in a region reported to interact with SHFM1 (Marston 1999, Yang 2002) . In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Arg2625Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000509944	SCV000608025	likely benign	Hereditary cancer-predisposing syndrome	2019-12-06	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779999	SCV000916987	uncertain significance	not specified	2018-08-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7874G>A (p.Arg2625Lys) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246032 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7874G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Division of Medical Genetics, University of Washington	RCV001257500	SCV001434322	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-04-01	criteria provided, single submitter	clinical testing	To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an overall allele frequency of 0.000004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. PM2; PP3
Baylor Genetics	RCV003474984	SCV004211873	uncertain significance	Familial cancer of breast	2023-10-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483772	SCV004220575	uncertain significance	not provided	2022-12-13	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251274 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant was found to be of neutral consequence in functional studies utilizing homology-directed repair (HDR) assays (PMIDs: 29884841 (2019), 35736817 (2022)). 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.
All of Us Research Program, National Institutes of Health	RCV001257500	SCV004845565	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 2625 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 (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 1/251274 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.