ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1938C>G (p.Ser646Arg)

dbSNP: rs28897711
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001996427 SCV002287003 uncertain significance Hereditary breast ovarian cancer syndrome 2023-06-14 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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: 1498140). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 646 of the BRCA2 protein (p.Ser646Arg).
University of Washington Department of Laboratory Medicine, University of Washington RCV003157016 SCV003846393 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).
Ambry Genetics RCV003157016 SCV003855553 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-28 criteria provided, single submitter clinical testing The p.S646R variant (also known as c.1938C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 1938. The serine at codon 646 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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