Submissions for variant NM_000059.4(BRCA2):c.8314G>A (p.Glu2772Lys)

dbSNP: rs397507975

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130828	SCV000185725	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-04	criteria provided, single submitter	clinical testing	The p.E2772K variant (also known as c.8314G>A), located in coding exon 17 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8314. The glutamic acid at codon 2772 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001849937	SCV002306122	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2772 of the BRCA2 protein (p.Glu2772Lys). 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: 142033). 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.
All of Us Research Program, National Institutes of Health	RCV003998082	SCV004845636	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2772 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 affected with breast cancer (PMID: 31871109) and in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002120). 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	RCV004721271	SCV005326576	uncertain significance	not provided	2023-12-22	criteria provided, single submitter	clinical testing	Identified in individual(s) with breast cancer (PMID: 31871109); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8542G>A; This variant is associated with the following publications: (PMID: 29884841, 32377563, 32160537, 31853058, 31871109, 12228710)
PreventionGenetics, part of Exact Sciences	RCV004532566	SCV004720383	uncertain significance	BRCA2-related disorder	2023-12-07	no assertion criteria provided	clinical testing	The BRCA2 c.8314G>A variant is predicted to result in the amino acid substitution p.Glu2772Lys. This variant was reported as a variant of uncertain significance in an individual with breast cancer (Adedokun et al. 2020. PubMed ID: 31871109). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as a variant of uncertain clinical significance in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142033/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.