ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.115T>C (p.Cys39Arg) (rs80357164)

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Total submissions: 15
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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) RCV000077483 SCV000244296 pathogenic 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 5 based on posterior probability = 0.99
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077483 SCV000324971 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077483 SCV000488027 pathogenic Breast-ovarian cancer, familial 1 2015-12-28 criteria provided, single submitter clinical testing
Genologica Medica RCV000077483 SCV000577916 pathogenic Breast-ovarian cancer, familial 1 2017-01-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000570028 SCV000665362 pathogenic Hereditary cancer-predisposing syndrome 2017-05-31 criteria provided, single submitter clinical testing The p.C39R pathogenic mutation (also known as c.115T>C), located in coding exon 2 of the BRCA1 gene, results from a T to C substitution at nucleotide position 115. The cysteine at codon 39 is replaced by arginine, an amino acid with highly dissimilar properties. This mutation has been reported in multiple hereditary breast and/or ovarian cancer families (Rostagno P et al. J. Hum. Genet., 2003 Jul;48:362-6; Machackova E et al. BMC Cancer, 2008 May;8:140; Konecny M et al. Breast Cancer Res. Treat., 2011 Feb;126:119-30). Furthermore, this alteration has been classified as definitely pathogenic (>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Sweet K et al. Breast Cancer Res Treat. 2010 Feb;119(3):737-43; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8; Lindor NM et al. Hum. Mutat., 2012 Jan;33:8-21; Whiley PJ et al. PLoS ONE, 2014 Jan;9:e86836). Functional studies using yeast assays have shown that this mutation results in deficient protein compared to wild-type BRCA1 (Thouvenot P et al. PLoS Genet., 2016 06;12:e1006096). The p.C39R alteration is located in a critical region of the BRCA1 protein RING domain, and, along with other alterations at this codon including p. C39Y and p.C39S, has been shown to alter the structure of the RING domain and negatively impact protein function and binding (Ruffner H et al. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5134-9; Brzovic PS et al. Proc Natl Acad Sci USA. 2003 May;100(10):5646-51; Ransburgh DJ et al. Cancer Res. 2010 Feb 1;70(3):988-95; Sweet K et al. Breast Cancer Res Treat. 2010 Feb;119(3):737-43). One other functional study has demonstrated that p.C39R causes abolishment and decreased activity of ubiquitin protein ligase function in the BRCA1 RING finger in vitro (Morris JR et al. Hum. Mol. Genet., 2006 Feb;15:599-606). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Of note, this alteration has also been designated as 234T>C in published literature. Based on the supporting evidence to date, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985365 SCV001133477 pathogenic not provided 2018-12-05 criteria provided, single submitter clinical testing Statistically enriched in patients compared to ethnically matched controls. Not found in the total gnomAD dataset, and the data is high quality (0/282180 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000077483 SCV001435001 pathogenic Breast-ovarian cancer, familial 1 2019-02-01 criteria provided, single submitter clinical testing The c.115T>C (p.Cys39Arg) variant in the BRCA1 gene has been reported in multiple patients with hereditary breast and ovarian cancer (PMID 12827452, 18489799, 28993434). This variant is absent from large databases of genetic variation in the general population. Functional classification using saturation genome editing showed that this variant to be loss-of-function (PMID 30209399). Multiple lines of prediction algorithms support the deleterious effect of the variant. Loss of function variants in the BRCA1 gene have been associated with familial breast-ovarian cancer-1 (BROVCA1, MIM# 604370). Therefore, c.115T>C (p.Cys39Arg) variant in the BRCA1 gene is classified as pathogenic.
Invitae RCV000496824 SCV001586683 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-11 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 39 of the BRCA1 protein (p.Cys39Arg). 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 reported in families and an individual with breast and/or ovarian cancer (PMID: 12827452, 21203900, 18489799, 15024741, 26822949). ClinVar contains an entry for this variant (Variation ID: 54152). Based on multiple multifactorial likelihood algorithms using genetic and in silico data, this variant has been determined to have a high probability of being pathogenic (PMID: 24489791, 27272900, 19543972). This variant affects the highly conserved Cys39 residue within the second Zn2+ binding loop of the N-terminal BRCA1 RING domain (PMID: 12732733, 22843421). Experimental studies have shown that this missense change reduces the ability of BRCA1 to bind to BARD1 and abrogates their ubiquitin ligase activity (PMID: 16403807, 25823446, 24489791). Different missense substitutions at this codon (p.Cys39Ser, p.Cys39Tyr, p.Cys39Gly) have also been determined to be pathogenic (PMID: 17262179, 23683081, 25823446, 11320250, 9808526, 19504351, 18500671). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000985365 SCV001804196 pathogenic not provided 2020-03-26 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: impairs E2 and BARD1 binding and reduces E3 ubiquitin ligase activity (Morris 2006, Starita 2015); Not observed in large population cohorts (Lek 2016); Observed in individuals with Hereditary Breast and Ovarian Cancer syndrome (Rostagno 2003, Machackova 2008, Sweet 2010, Konecny 2011, Lhota 2016, Ng 2016, Wen 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as BRCA1 c.234T>C; This variant is associated with the following publications: (PMID: 12827452, 24489791, 28993434, 27272900, 25823446, 29446198, 33087888, 21990134, 30209399, 15235020, 19543972, 16403807, 21203900, 18493658, 26822949, 26757417, 22753008, 18489799, 15024741)
Research and Development, ARUP Laboratories RCV001660023 SCV001877789 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000077483 SCV000109281 pathogenic Breast-ovarian cancer, familial 1 2008-07-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077483 SCV000144349 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496824 SCV000587013 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Brotman Baty Institute,University of Washington RCV000077483 SCV001241900 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
CZECANCA consortium RCV001270963 SCV001451767 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing

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