Submissions for variant NM_000059.4(BRCA2):c.6319C>A (p.Pro2107Thr)

dbSNP: rs1593908231

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000817607	SCV000958176	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-07-19	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. 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: 660417). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2107 of the BRCA2 protein (p.Pro2107Thr).
Color Diagnostics, LLC DBA Color Health	RCV001177191	SCV001341363	uncertain significance	Hereditary cancer-predisposing syndrome	2019-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001759593	SCV002005391	uncertain significance	not provided	2019-05-09	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV001177191	SCV002655216	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-08	criteria provided, single submitter	clinical testing	The p.P2107T variant (also known as c.6319C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 6319. The proline at codon 2107 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is conserved. 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	RCV001177191	SCV003852424	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001759593	SCV004220497	uncertain significance	not provided	2023-05-04	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In a breast cancer case-control study, this variant has only been detected in an unaffected control individual (PMID: 33471991 (2021)). The variant has also been reported as a somatic variant in an individual with ovarian cancer (PMID: 34302857 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.