ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.181T>C (p.Cys61Arg) (rs28897672)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000111959 SCV000325149 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759499 SCV000888850 likely pathogenic not provided 2018-02-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001328445 SCV001519582 likely pathogenic Hereditary breast and ovarian cancer syndrome 2021-02-28 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.181T>C (p.Cys61Arg) results in a non-conservative amino acid change located in the RING domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250754 control chromosomes. c.181T>C has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. At least two publications report somewhat conflicting experimental evidence evaluating an impact on homology directed repair (HDR) capacity (example, Starita_2015, Findlay_2018). The most pronounced variant effect in one study reports a loss of E3 ligase activity, BARD1 binding activity and a predicted loss of homology directed repair (HDR) capacity (Starita_2015). However, a subsequent study by the same authors reports an intermediate HDR activity (Findlay_2018). One clinical diagnostic laboratory and one consortium (CIMBA, captured in Rebbeck_2018) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001328445 SCV001574881 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-08-23 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 61 of the BRCA1 protein (p.Cys61Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with a personal and/or family history of breast and/or ovarian cancer (PMID: 19329713, 26757417, 25948282, 30078507). This variant is also known as 300T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 54360). This variant affects the highly conserved Cys61 residue within the N-terminal RING domain of the BRCA1 protein (PMID: 22843421). While this variant has been reported to have insufficient data to determine the effect on BRCA1 protein function (PMID: 30209399), other experimental studies have shown that this variant disrupts several aspects of BRCA1 function (PMID: 25823446). This variant disrupts the p.Cys61 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7894493, 19594371,9525870, 22172724, 11278247, 19770520). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111959 SCV000144573 uncertain significance Breast-ovarian cancer, familial 1 2001-11-29 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000111959 SCV001242515 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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