ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3797G>C (p.Ser1266Thr) (rs80357160)

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Total submissions: 8
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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) RCV000112189 SCV000244349 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 = 0.00000113
Invitae RCV001083483 SCV000076349 benign Hereditary breast and ovarian cancer syndrome 2020-11-25 criteria provided, single submitter clinical testing
GeneDx RCV000048336 SCV000209960 likely benign not specified 2018-01-03 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.
Counsyl RCV000112189 SCV000221022 benign Breast-ovarian cancer, familial 1 2015-01-14 criteria provided, single submitter literature only
Ambry Genetics RCV000215145 SCV000274191 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: 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048336 SCV000699073 benign not specified 2019-11-08 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3797G>C (p.Ser1266Thr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251170 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. However, this variant has been reported in 2/7325 European American women who were older than age 70 and cancer free (in the FLOSSIES database). c.3797G>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, Borg_2010, Capanu_2011). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.9976A>T (p.Lys3326X) and BRCA2 c.5410_5411delGT (p.Val1804Lysfs) in the BIC 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, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton 2007 and Lindor 2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as likely benign (2x) and benign (3x), including one expert panel (ENIGMA, benign). Based on the evidence outlined above, the variant was classified as benign.
Color Health, Inc RCV000215145 SCV000903072 benign Hereditary cancer-predisposing syndrome 2016-04-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112189 SCV000144884 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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