ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3739G>A (p.Val1247Ile)

gnomAD frequency: 0.00006  dbSNP: rs80357191
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Total submissions: 17
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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) RCV000077555 SCV000244347 benign Breast-ovarian cancer, familial, susceptibility to, 1 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 = 0.00000251
Invitae RCV000195343 SCV000076321 benign Hereditary breast ovarian cancer syndrome 2024-01-24 criteria provided, single submitter clinical testing
GeneDx RCV001353892 SCV000209958 likely benign not provided 2020-12-23 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 27153395, 24916970, 25682074, 17924331, 15385441, 18824701, 15235020, 25337278, 26689913, 16826315, 27157322, 22753008, 18779604, 21990134, 27907908, 16267036, 10923033, 23704879, 33087888)
Ambry Genetics RCV000162980 SCV000213468 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as 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.
Color Diagnostics, LLC DBA Color Health RCV000162980 SCV000537455 likely benign Hereditary cancer-predisposing syndrome 2022-01-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048308 SCV000699066 benign not specified 2019-03-26 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3739G>A (p.Val1247Ile) 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 9.5e-05 in 282924 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.001 in the gnomAD database. This frequency is about the same that is expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.001), suggesting that the variant might be a benign polymorphism found primarily in populations of East Asian origin. c.3739G>A has been reported in the literature in individuals, mostly of East Asian origin, affected with breast or ovarian cancer, however these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.5213_5216delCTTA (p.Thr1738fsX2) in the UMD BRCA1 database), providing supporting evidence for a benign role. In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, predicted this variant to be likely neutral (Easton 2007 and Lindor 2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other 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 laboratories classified the variant as benign (1x) / likely benign (3x) while the expert panel ruled on its classification as benign (1x). Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000077555 SCV001140545 benign Breast-ovarian cancer, familial, susceptibility to, 1 2019-05-28 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000162980 SCV002538239 likely benign Hereditary cancer-predisposing syndrome 2021-02-03 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000048308 SCV004026772 benign not specified 2023-08-15 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004554667 SCV004752661 benign BRCA1-related disorder 2019-03-26 criteria provided, single submitter clinical testing This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Sharing Clinical Reports Project (SCRP) RCV000077555 SCV000109356 benign Breast-ovarian cancer, familial, susceptibility to, 1 2010-02-03 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077555 SCV000144854 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001353892 SCV000591468 uncertain significance not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000048308 SCV001958310 benign not specified no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000048308 SCV001970522 benign not specified no assertion criteria provided clinical testing
Center for Precision Medicine, Meizhou People's Hospital RCV002250539 SCV002520870 likely benign Familial cancer of breast no assertion criteria provided literature only
Genetic Services Laboratory, University of Chicago RCV000048308 SCV003839265 likely benign not specified 2022-08-29 no assertion criteria provided clinical testing

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