Submissions for variant NM_000059.4(BRCA2):c.6815G>A (p.Arg2272Lys)

gnomAD frequency: 0.00001  dbSNP: rs199522406

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000689614	SCV000817273	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 2272 of the BRCA2 protein (p.Arg2272Lys). This variant is present in population databases (rs199522406, gnomAD 0.007%). 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: 569078). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758936	SCV000887894	uncertain significance	not provided	2017-12-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001025681	SCV001187921	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-09	criteria provided, single submitter	clinical testing	The p.R2272K variant (also known as c.6815G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 6815. The arginine at codon 2272 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is highly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509514	SCV002819367	uncertain significance	not specified	2022-12-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6815G>A (p.Arg2272Lys) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250316 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6815G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence for causality (Azribi_2021). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001025681	SCV003847473	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).