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

gnomAD frequency: 0.00006  dbSNP: rs80357191

Total submissions: 17

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
Labcorp Genetics (formerly Invitae), Labcorp	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
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
PreventionGenetics, part of Exact Sciences	RCV004554667	SCV004752661	benign	BRCA1-related disorder	2019-03-26	no assertion criteria provided	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).