Submissions for variant NM_000059.4(BRCA2):c.6556T>A (p.Ser2186Thr)

dbSNP: rs2072559530

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001209383	SCV001380815	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 2186 of the BRCA2 protein (p.Ser2186Thr). 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: 939903). 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.
GeneDx	RCV002265008	SCV002547033	uncertain significance	not provided	2022-01-05	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 6784T>A; This variant is associated with the following publications: (PMID: 25010205)
Ambry Genetics	RCV002365943	SCV002664783	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-20	criteria provided, single submitter	clinical testing	The p.S2186T variant (also known as c.6556T>A), located in coding exon 10 of the BRCA2 gene, results from a T to A substitution at nucleotide position 6556. The serine at codon 2186 is replaced by threonine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with breast cancer (Saied MH et al. Mol Med Rep, 2021 Sep;24:). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002365943	SCV003847268	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).
All of Us Research Program, National Institutes of Health	RCV004010673	SCV004839315	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-01	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV004010673	SCV005402413	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-06-26	criteria provided, single submitter	clinical testing	The BRCA2 c.6556T>A (p.Ser2186Thr) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported as pathogenic in individuals with BRCA2-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.