Submissions for variant NM_000059.4(BRCA2):c.489T>G (p.Ser163Arg)

gnomAD frequency: 0.00001  dbSNP: rs398122787

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205650	SCV000260514	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 163 of the BRCA2 protein (p.Ser163Arg). This variant is present in population databases (rs398122787, gnomAD 0.01%). 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: 91827). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477481	SCV000600615	uncertain significance	not provided	2022-09-16	criteria provided, single submitter	clinical testing	The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000032 (1/31386 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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.
Ambry Genetics	RCV001023225	SCV001185070	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-25	criteria provided, single submitter	clinical testing	The p.S163R variant (also known as c.489T>G), located in coding exon 5 of the BRCA2 gene, results from a T to G substitution at nucleotide position 489. The serine at codon 163 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001023225	SCV001347752	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000506258	SCV001360849	uncertain significance	not specified	2019-05-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.489T>G (p.Ser163Arg) results in a non-conservative amino acid change in 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 3.2e-05 in 31386 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.489T>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000077735	SCV004186071	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV004566943	SCV005059183	uncertain significance	Familial cancer of breast	2023-11-17	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077735	SCV000109538	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-10-14	no assertion criteria provided	clinical testing