Submissions for variant NM_000059.4(BRCA2):c.2213G>A (p.Cys738Tyr)

gnomAD frequency: 0.00005  dbSNP: rs1219265131

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587463	SCV000694596	uncertain significance	not provided	2016-09-15	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.2213G>A (p.Cys738Tyr) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant is absent in 121132 control chromosomes from ExAC. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available.
Ambry Genetics	RCV001014811	SCV001175569	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-09	criteria provided, single submitter	clinical testing	The p.C738Y variant (also known as c.2213G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 2213. The cysteine at codon 738 is replaced by tyrosine, an amino acid with highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002530888	SCV003454021	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 738 of the BRCA2 protein (p.Cys738Tyr). 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: 495439). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001014811	SCV003846577	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	RCV004002392	SCV004825964	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 738 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 not been reported in individuals affected with BRCA2-related disorders in the literature. 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.
GeneDx	RCV000587463	SCV005370733	uncertain significance	not provided	2023-07-24	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 2441G>A; This variant is associated with the following publications: (PMID: 31911673, 29884841, 32377563)