Submissions for variant NM_000059.4(BRCA2):c.2874T>G (p.Ser958Arg)

dbSNP: rs1566227393

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001220005	SCV001391975	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-11	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 958 of the BRCA2 protein (p.Ser958Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 33067490). ClinVar contains an entry for this variant (Variation ID: 948697). 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	RCV001806056	SCV002053331	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-29	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 958 of the BRCA2 protein. Computational protein 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 impact RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer in the literature (PMID: 33067490). 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.
Ambry Genetics	RCV001806056	SCV002749540	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-20	criteria provided, single submitter	clinical testing	The p.S958R variant (also known as c.2874T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 2874. The serine at codon 958 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in a cohort of 200 breast or ovarian cancer patients from Jordan (Abu-Helalah M et al. Sci Rep, 2020 10;10:17573). This amino acid position is not 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001806056	SCV003850197	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).