Submissions for variant NM_000059.4(BRCA2):c.7472A>G (p.Gln2491Arg)

gnomAD frequency: 0.00001  dbSNP: rs185012573

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567018	SCV000661192	likely benign	Hereditary cancer-predisposing syndrome	2022-01-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781138	SCV000918995	uncertain significance	not specified	2018-08-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7472A>G (p.Gln2491Arg) results in a conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246218 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7472A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000819102	SCV000959745	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-06-24	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 479282). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 2491 of the BRCA2 protein (p.Gln2491Arg). This variant is present in population databases (rs185012573, gnomAD 0.006%). 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. 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.
GeneDx	RCV003328599	SCV004035526	uncertain significance	not provided	2023-03-17	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 7700A>G; This variant is associated with the following publications: (PMID: 31191615, 29884841, 32377563, 31911673, 12228710)