ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3739G>A (p.Val1247Ile) (rs80357191)

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Total submissions: 9
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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 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 and ovarian cancer syndrome 2017-12-28 criteria provided, single submitter clinical testing
GeneDx RCV000048308 SCV000209958 likely benign not specified 2017-12-19 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000162980 SCV000213468 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing
Color RCV000162980 SCV000537455 likely benign Hereditary cancer-predisposing syndrome 2015-05-08 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048308 SCV000591468 likely benign not specified 2017-02-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Sharing Clinical Reports Project (SCRP) RCV000077555 SCV000109356 benign Breast-ovarian cancer, familial 1 2010-02-03 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077555 SCV000144854 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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