Submissions for variant NM_000059.4(BRCA2):c.6295A>G (p.Arg2099Gly)

gnomAD frequency: 0.00004  dbSNP: rs398122551

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222158	SCV000273912	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-20	criteria provided, single submitter	clinical testing	The p.R2099G variant (also known as c.6295A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 6295. The arginine at codon 2099 is replaced by glycine, an amino acid with 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800378	SCV000296497	uncertain significance	not provided	2021-04-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695728	SCV000824243	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2099 of the BRCA2 protein (p.Arg2099Gly). This variant is present in population databases (rs398122551, gnomAD 0.01%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 21120943). ClinVar contains an entry for this variant (Variation ID: 91442). 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.
Color Diagnostics, LLC DBA Color Health	RCV000222158	SCV001350285	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 2099 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: 21120943). This variant has been identified in 3/275762 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199915	SCV001370684	uncertain significance	not specified	2020-05-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6295A>G (p.Arg2099Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 244356 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6295A>G has been reported in the literature in at least one individual affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Caux-Moncoutier_2011). 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 other 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.
GeneDx	RCV001800378	SCV002097417	uncertain significance	not provided	2022-02-03	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; Observed in individuals with a personal or family history including breast and/or ovarian cancer (Caux-Moncoutier 2011); Also known as 6523A>G; This variant is associated with the following publications: (PMID: 21120943)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000222158	SCV003852401	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).
PreventionGenetics, part of Exact Sciences	RCV004528279	SCV004112229	uncertain significance	BRCA2-related disorder	2023-08-24	criteria provided, single submitter	clinical testing	The BRCA2 c.6295A>G variant is predicted to result in the amino acid substitution p.Arg2099Gly. This variant has been reported in at least one individual with a personal and/or family history of breast and/or ovarian cancer (Table S2B, Caux-Moncoutier et al. 2010. PubMed ID: 21120943). This variant is reported in 3 of ~276,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/13-32914787-A-G). It is interpreted as uncertain significance by the vast majority of clinical submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/91442/). This variant occurs within a region of the BRCA2 gene that is predicted to be tolerant to variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000076959	SCV004846733	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 2099 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: 21120943). This variant has been identified in 3/275762 chromosomes 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.
Sharing Clinical Reports Project (SCRP)	RCV000076959	SCV000108756	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-06-28	no assertion criteria provided	clinical testing