Submissions for variant NM_000059.4(BRCA2):c.338G>A (p.Arg113Lys)

dbSNP: rs876659161

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215283	SCV000275287	likely benign	Hereditary cancer-predisposing syndrome	2017-05-16	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.
GeneDx	RCV000478500	SCV000571999	uncertain significance	not provided	2022-06-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 566G>A; This variant is associated with the following publications: (PMID: 25929848, 25925381)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637720	SCV000759193	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-05	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 113 of the BRCA2 protein (p.Arg113Lys). This variant is not present in population databases (gnomAD no frequency). 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: 231439). 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.
Color Diagnostics, LLC DBA Color Health	RCV000215283	SCV001357692	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 113 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Sema4, Sema4	RCV000215283	SCV002533788	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-31	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478500	SCV004219588	uncertain significance	not provided	2023-08-29	criteria provided, single submitter	clinical testing	This variant has not been reported in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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.