ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3691T>C (p.Phe1231Leu)

gnomAD frequency: 0.00013  dbSNP: rs41293451
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195391 SCV000076295 likely benign Hereditary breast ovarian cancer syndrome 2024-01-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131521 SCV000186515 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.
GeneDx RCV001281713 SCV000209955 likely benign not provided 2020-12-20 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25348012, 26295337, 23704879, 15385441, 28873162, 30400234)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001281713 SCV000296415 likely benign not provided 2023-02-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048282 SCV000699058 uncertain significance not specified 2023-02-27 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3691T>C (p.Phe1231Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251286 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3691T>C has been reported in the literature in individuals affected with breast cancer (e.g. Pal_2015, Zabala_2018, Guindalini_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with a pathogenic variant has been observed (BRCA2 c.518delG, p.Gly173ValfsX12), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The variant was classified as either benign (n=1)/likely benign (n=3) or VUS (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics RCV000195391 SCV000839250 uncertain significance Hereditary breast ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131521 SCV000902939 benign Hereditary cancer-predisposing syndrome 2016-02-24 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000131521 SCV002538229 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-01 criteria provided, single submitter curation
University of Washington Department of Laboratory Medicine, University of Washington RCV000131521 SCV003851437 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
PreventionGenetics, part of Exact Sciences RCV004554626 SCV004760470 likely benign BRCA1-related disorder 2019-03-21 criteria provided, single submitter clinical testing This variant is classified as likely 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) RCV000031122 SCV000053720 benign Breast-ovarian cancer, familial, susceptibility to, 1 2010-02-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031122 SCV000144836 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2003-12-23 no assertion criteria provided clinical testing

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