Submissions for variant NM_000059.4(BRCA2):c.1022G>A (p.Cys341Tyr)

gnomAD frequency: 0.00001  dbSNP: rs80358403

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000575372	SCV000668715	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-23	criteria provided, single submitter	clinical testing	The p.C341Y variant (also known as c.1022G>A), located in coding exon 9 of the BRCA2 gene, results from a G to A substitution at nucleotide position 1022. The cysteine at codon 341 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in a Greek breast and/or ovarian cancer family (Konstantopoulou I et al. Clin Genet, 2014 Jan;85:36-42). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001230162	SCV001402634	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-10-12	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: 483059). 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 cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 341 of the BRCA2 protein (p.Cys341Tyr).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000575372	SCV003849788	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).
GeneDx	RCV003441951	SCV004169677	uncertain significance	not provided	2023-10-02	criteria provided, single submitter	clinical testing	Observed in an individual with familial breast/ovarian cancer (Konstantopoulou et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 1250G>A; This variant is associated with the following publications: (PMID: 24010542, 29884841, 32377563)
All of Us Research Program, National Institutes of Health	RCV004001012	SCV004846854	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 341 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with a personal or family history of breast and/or ovarian cancer (PMID: 24010542). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003441951	SCV005624313	uncertain significance	not provided	2023-10-27	criteria provided, single submitter	clinical testing	The BRCA2 c.1022G>A (p.Cys341Tyr) variant has been reported in the published literature in a family with breast cancer (PMID: 24010542 (2014)). The variant is described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.0000066 (1/152202 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.