Submissions for variant NM_000059.4(BRCA2):c.7022G>A (p.Arg2341His)

gnomAD frequency: 0.00001  dbSNP: rs786202839

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561472	SCV000661191	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-27	criteria provided, single submitter	clinical testing	The p.R2341H variant (also known as c.7022G>A), located in coding exon 13 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7022. The arginine at codon 2341 is replaced by histidine, an amino acid with highly 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. Based on the available evidence, the clinical significance of this variant remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586832	SCV000695028	uncertain significance	not specified	2019-02-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7022G>A (p.Arg2341His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246036 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.7022G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000561472	SCV000913019	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 2341 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). A functional study in mouse embryonic stem cells has shown that this variant does not impact cell viability or sensitivity to PARP inhibitors (PMID: 37922907). This variant has been reported in an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001548) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.025 and 0.492, respectively (PMID: 31131967). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001069781	SCV001234975	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2341 of the BRCA2 protein (p.Arg2341His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 479281). 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%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 37922907). 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.
Sema4, Sema4	RCV000561472	SCV002536296	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-07	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001724065	SCV004220538	uncertain significance	not provided	2022-02-02	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In a large-scale case-control study, the variant has only been observed in an affected individual with breast cancer (PMID: 33471991 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003999530	SCV004844350	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 2341 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). A functional study in mouse embryonic stem cells has shown that this variant does not impact cell viability or sensitivity to PARP inhibitors (PMID: 37922907). This variant has been reported in an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001548) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.025 and 0.492, respectively (PMID: 31131967). 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.
Baylor Genetics	RCV004569095	SCV005059092	uncertain significance	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001724065	SCV005327360	uncertain significance	not provided	2023-06-12	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 breast cancer (Dorling et al., 2021); Also known as 7250G>A; This variant is associated with the following publications: (PMID: 33471991, 31911673, 31131967, 31853058, 32377563, 29884841)
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001724065	SCV001952332	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001724065	SCV001962829	uncertain significance	not provided		no assertion criteria provided	clinical testing