ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.10045A>G (p.Thr3349Ala) (rs80358387)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031300 SCV000244416 benign Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000000919
Invitae RCV001086443 SCV000071718 benign Hereditary breast and ovarian cancer syndrome 2020-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000759571 SCV000210695 benign not provided 2019-10-24 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25637381, 21120943, 26420498, 10755399, 18403564, 22505045, 24323938, 21520273, 20104584, 12955716, 11979449, 25682074, 25348012, 17924331, 21990134, 29988080, 32123317)
Ambry Genetics RCV000163020 SCV000213508 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
Vantari Genetics RCV000163020 SCV000267028 likely benign Hereditary cancer-predisposing syndrome 2016-02-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000043705 SCV000538477 likely benign not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 5/11516 Latino; ClinVar: 4 B/LB, 1 VUS
Color Health, Inc RCV000163020 SCV000683390 likely benign Hereditary cancer-predisposing syndrome 2015-06-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000043705 SCV000694490 benign not specified 2020-09-28 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.10045A>G (p.Thr3349Ala) results in a non-conservative amino acid change in 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 0.00012 in 251290 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00012 vs 0.00075), allowing no conclusion about variant significance. c.10045A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence of causality. One patient with the variant showed retention of the wild-type allele and loss of the allele harbouring the variant, suggesting the variant is not deleterious (Osorio_2002). Multifactorial models that incorporate family history, co-segregation, co-occurrence, and tumor pathology has predicted the variant to be likely neutral (Easton_2007, Lindor_2012). Multiple publications report experimental evidence evaluating an impact on protein function: splicing is not affected (Houdayer_2012) and HDR and cell survival assays show no difference from WT controls (Mesman_2018), altogether suggesting the variant has no effect on protein function. Seven clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign (n=3)/likely benign (n=5). Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759571 SCV000888967 benign not provided 2019-02-27 criteria provided, single submitter clinical testing
Mendelics RCV000031300 SCV001139283 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642250 SCV001852868 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031300 SCV000053905 benign Breast-ovarian cancer, familial 2 2008-01-08 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031300 SCV000145744 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148421 SCV000190120 likely benign Breast neoplasm 2014-06-01 no assertion criteria provided research
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000043705 SCV001905898 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000043705 SCV001958277 benign not specified no assertion criteria provided clinical testing

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