ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.130T>A (p.Cys44Ser) (rs80357327)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000111838 SCV000244298 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 = 1
Ambry Genetics RCV000222092 SCV000277476 pathogenic Hereditary cancer-predisposing syndrome 2020-08-11 criteria provided, single submitter clinical testing The p.C44S pathogenic mutation (also known as c.130T>A), located in coding exon 2 of the BRCA1 gene, results from a T to A substitution at nucleotide position 130. The cysteine at codon 44 is replaced by serine, an amino acid with dissimilar properties. This alteration occurs in the functionally important RING finger domain (Abkevich V et al. J. Med. Genet. 2004 Jul;41:492-507) and has been reported in individuals with early onset breast cancer (Begg CB et al, JAMA 2008 Jan; 299(2):194-201; Capanu M et al, Genet. Epidemiol. 2011 Jul; 35(5):389-97) as well as ovarian cancer (Hansen TV et al, Breast Cancer Res. Treat. 2010 Nov; 124(1):259-64; Sweet K et al, Breast Cancer Res. Treat. 2010 Feb; 119(3):737-43). In addition, a recent study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562(7726):217-222). Further, well described pathogenic mutations (p.C44Y, p.C44F) have been described at the same codon as this alteration. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000111838 SCV000296457 pathogenic Breast-ovarian cancer, familial 1 2016-04-23 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000111838 SCV000325009 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000444956 SCV000516958 pathogenic not provided 2019-10-10 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: classified as non-functional based on a saturation genome editing assay assessing ability to support growth, and demonstrated defective homology-directed repair activity and BARD1 binding (Starita 2015, Findlay 2018, Caleca 2019); Multi-factorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; No data available from control populations to assess the frequency of this variant; Observed in women with a history of breast and/or ovarian cancer and has been suggested to be a recurrent variant in the Greenlandic population (Borg 2010, Hansen 2010, Sweet 2010, Karami 2013); This variant is associated with the following publications: (PMID: 26295337, 21990134, 18182601, 19543972, 24489791, 20104584, 21520273, 20437199, 24312913, 25525159, 25823446, 30209399, 26833046, 21990165, 29339979, 29446198, 18465347, 30678073, 25348012, 30696104, 33087888)
Department of Medical Genetics, Oslo University Hospital RCV000111838 SCV000564369 pathogenic Breast-ovarian cancer, familial 1 2015-07-22 criteria provided, single submitter clinical testing
Counsyl RCV000111838 SCV000677631 pathogenic Breast-ovarian cancer, familial 1 2016-12-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589017 SCV000698845 pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-09 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.130T>A (p.Cys44Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution at a highly conserved cysteine residue in the RING finger domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent from the large control database ExAC and control cohorts reported in the literature (0/112062 control chromosomes). The variant has been identified in numerous HBOC patient. Several overlapping variants are present in HGMD (Cys44Arg, Cys44Gly, Cys44Phe, and Cys44Tyr), suggesting a mutational hotspot that is critical for protein function. In addition, this variant C44S has been functionally tested and shown to disrupt BARD1 binding, and impairs ubiquitin ligase activity and homolgy-directed repair (Starita_2015). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color Health, Inc RCV000222092 SCV001339968 pathogenic Hereditary cancer-predisposing syndrome 2020-08-03 criteria provided, single submitter clinical testing This missense variant replaces cysteine with serine at codon 44 in the RING domain of the BRCA1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). The variant protein has been shown to be functionally defective in a haploid cell proliferation assay (PMID 30209399). This variant has been reported in individuals affected with breast cancer (PMID: 19543972, 20104584) and ovarian cancer (PMID: 20437199). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants affecting the same codon, p.Cys44Tyr and p.Cys44Phe, are known to be pathogenic (Clinvar variation ID: 54199, 54200), indicating that cysteine at this position is important for BRCA1 function. Based on the available evidence, this variant is classified as Pathogenic.
Invitae RCV000589017 SCV001582774 pathogenic Hereditary breast and ovarian cancer syndrome 2020-02-07 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 44 of the BRCA1 protein (p.Cys44Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with breast and ovarian cancer (PMID: 18182601, 19543972, 18500671, 20104584, 20437199). ClinVar contains an entry for this variant (Variation ID: 54191). This variant affects the highly conserved Cys44 Zn-binding residue of the N-terminal BRCA1 RING domain (PMID: 12732733, 25652403, 20029420). Experimental studies have shown that this missense change disrupts several BRCA1 protein functions, including homology directed repair, BARD1 binding and ubiquitin ligase activity (PMID: 12732733). Based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 21990134, 24489791). Different missense substitutions at this codon (p.Cys44Phe, p.Cys44Tyr) have been determined to be pathogenic (PMID: 21990134, 20103620, 16403807, 23161852, 21725363, 27272900, 21922593). This suggests that the cysteine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories RCV001660050 SCV001877791 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
Breast Cancer Information Core (BIC) (BRCA1) RCV000111838 SCV000144397 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000111838 SCV001242867 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.