Submissions for variant NM_000059.4(BRCA2):c.9350A>G (p.His3117Arg)

dbSNP: rs80359206

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219723	SCV000277152	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-29	criteria provided, single submitter	clinical testing	The p.H3117R variant (also known as c.9350A>G), located in coding exon 24 of the BRCA2 gene, results from an A to G substitution at nucleotide position 9350. The histidine at codon 3117 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is poorly 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	RCV000698559	SCV000827229	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 3117 of the BRCA2 protein (p.His3117Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 232894). 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	RCV003128600	SCV002046638	uncertain significance	not provided	2023-11-13	criteria provided, single submitter	clinical testing	The BRCA2 c.9350A>G (p.His3117Arg) variant has not been reported in individuals with BRCA2-related conditions in the published literature. The frequency of this variant in the general population, 0.000004 (1/251332 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV003128600	SCV003805527	uncertain significance	not provided	2023-02-24	criteria provided, single submitter	clinical testing	Observed in individuals with unspecified personal and family history who underwent hereditary cancer multigene panel (Li et al., 2020); 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 9578A>G; This variant is associated with the following publications: (PMID: 12228710, 32377563, 29884841, 31853058)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001800567	SCV004038730	uncertain significance	not specified	2023-08-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998008	SCV004835449	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 3117 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported to have a likelihood ratio for pathogenicity based on personal and family history of 0.3385 (PMID: 31853058). This variant has been identified in 1/251332 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.
Fulgent Genetics, Fulgent Genetics	RCV005008168	SCV005633995	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-01-19	criteria provided, single submitter	clinical testing