Submissions for variant NM_000059.4(BRCA2):c.9344A>G (p.Lys3115Arg)

dbSNP: rs276174923

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045795	SCV000073808	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 3115 of the BRCA2 protein (p.Lys3115Arg). This variant is present in population databases (rs276174923, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 33314489). ClinVar contains an entry for this variant (Variation ID: 52817). 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%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 33314489). 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.
Ambry Genetics	RCV000223579	SCV000272968	likely benign	Hereditary cancer-predisposing syndrome	2023-05-10	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.
Counsyl	RCV000114092	SCV000487764	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000223579	SCV000689190	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 3115 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 has shown this variant was able to rescue Brca2-deficient mouse embryonic stem cells in sensitivity assays to DNA damaging agents (PMID: 33314489). This variant has been reported in one individual affected with breast cancer and two unaffected individuals (PMID: 33314489, 33471991; Leiden Open Variation Database DB-ID BRCA2_007522). This variant has been identified in 10/251298 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985625	SCV001133977	uncertain significance	not provided	2023-02-07	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00029 (9/30608 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported have no effect on BRCA2 mRNA splicing (PMID: 31843900 (2019)). In a large-scale breast cancer association study, the variant was observed in an unaffected individual (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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV000985625	SCV002064184	uncertain significance	not provided	2022-09-24	criteria provided, single submitter	clinical testing	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 9572A>G; This variant is associated with the following publications: (PMID: 10923033, 31843900, 12228710)
Genetics and Molecular Pathology, SA Pathology	RCV000114092	SCV002556535	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-05-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001171420	SCV003934768	uncertain significance	not specified	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9344A>G (p.Lys3115Arg) results in a conservative amino acid change located in the BRCA2, OB3 domain (IPR015188) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251298 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 0.00075), allowing no conclusion about variant significance. c.9344A>G has been reported in the literature in individuals affected with breast cancer (example, Lai_2017, Sharma-Oates_2018, Casadei_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Sullivan_2021). The most pronounced variant effect results in approximately >50%-90% of normal activity and the authors concluding a neutral outcome based on 1. functionally indistinguishable from WT-BRCA2 in the mESC functional assay; 2. fully rescued the lethality of BRCA2-null-mESCs and 3. exhibited no sensitivity to 6 different DNA damaging agents. The following publications have been ascertained in the context of this evaluation (PMID: 31843900, 28222693, 35693198, 33314489). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=7; Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000045795	SCV004014970	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-04-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000114092	SCV004846157	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 3115 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 has shown this variant was able to rescue Brca2-deficient mouse embryonic stem cells in sensitivity assays to DNA damaging agents (PMID: 33314489). This variant has been reported in one individual affected with breast cancer and two unaffected individuals (PMID: 33314489, 33471991; Leiden Open Variation Database DB-ID BRCA2_007522). This variant has been identified in 10/251298 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.
Myriad Genetics, Inc.	RCV000114092	SCV004931043	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-13	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114092	SCV000147612	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-09-18	no assertion criteria provided	clinical testing
King Laboratory, University of Washington	RCV001171420	SCV001251325	benign	not specified	2019-09-01	no assertion criteria provided	research