Submissions for variant NM_000059.4(BRCA2):c.5028T>A (p.Ser1676Arg)

dbSNP: rs762458631

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001896432	SCV002165348	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-04-10	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 1392867). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs762458631, gnomAD 0.0009%). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1676 of the BRCA2 protein (p.Ser1676Arg).
University of Washington Department of Laboratory Medicine, University of Washington	RCV003156812	SCV003846932	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).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492695	SCV004240319	uncertain significance	Breast and/or ovarian cancer	2023-06-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003156812	SCV005551933	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-28	criteria provided, single submitter	clinical testing	The p.S1676R variant (also known as c.5028T>A), located in coding exon 10 of the BRCA2 gene, results from a T to A substitution at nucleotide position 5028. The serine at codon 1676 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.