ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.3251G>A (p.Ser1084Asn)

gnomAD frequency: 0.00001  dbSNP: rs543748012
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000477381 SCV000560449 likely benign Hereditary breast ovarian cancer syndrome 2025-01-30 criteria provided, single submitter clinical testing
GeneDx RCV001712318 SCV000569858 likely benign not provided 2019-09-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23096355, 25925381)
Color Diagnostics, LLC DBA Color Health RCV000773251 SCV000906869 likely benign Hereditary cancer-predisposing syndrome 2018-05-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000773251 SCV002612429 likely benign Hereditary cancer-predisposing syndrome 2024-04-30 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000773251 SCV003851804 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).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001712318 SCV004219579 uncertain significance not provided 2023-09-01 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in an individual with breast cancer (PMID: 23096355 (2012)). The frequency of this variant in the general population, 0.0000085 (2/236564 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003488624 SCV004242104 uncertain significance not specified 2023-12-01 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3251G>A (p.Ser1084Asn) results in a conservative amino acid change in 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 8.5e-06 in 236564 control chromosomes in gnomAD. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3251G>A has been reported in the literature along with another VUS missense variant in at-lease one individual affected with Breast Cancer, without strong evidence for causality (Lara_2012). In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was only reported in 1/53461 controls, but not found in cases (Dorling_2021 through LOVD). These report(s) do 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. The following publications have been ascertained in the context of this evaluation (PMID: 23096355, 33471991). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Likely benign, n=4, VUS, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health RCV004802038 SCV005424371 likely benign BRCA2-related cancer predisposition 2024-06-11 criteria provided, single submitter clinical testing

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