ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.182G>A (p.Cys61Tyr) (rs80357093)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235674 SCV000293061 pathogenic not provided 2019-06-17 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15235020, 20215423, 28664506, 32741062, 26287763, 23867111, 23161852, 18159056, 22752604, 30209399, 25823446, 29446198, 25428789)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077497 SCV000325156 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000775191 SCV000909417 pathogenic Hereditary cancer-predisposing syndrome 2017-08-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000775191 SCV001173919 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-13 criteria provided, single submitter clinical testing <span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms">The p.C61Y<span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms"> variant (also known as c.182G>A), located in coding exon<span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms"> 3 of the BRCA1<span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms"> gene, results from a G to A substitution at nucleotide position 182. The cysteine<span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms"> at codon<span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms"> 61 is replaced by tyrosine, an amino acid with highly dissimilar properties. In one study on an African American breast cancer cohort, this variant was reported in a triple negative breast cancer patient diagnosed at 39 years of age (Churpek<span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms"> JE et al. Breast Cancer Res. Treat.<span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms"> 2015 Jan;149:31-9). This variant was also reported in another African American breast cancer patient in another HBOC<span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms"> study on young black women in Florida diagnosed with breast cancer under 50 years of age (Pal T et al. Cancer. 2015 Dec;121(23):4173-80).<span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms"> This alteration was identified in a Malaysian <span style="font-family:sans-serif,arial,verdana,trebuchet ms">patient diagnosed Her-2 positive breast cancer at age 45 (Yang XR et al. Breast Cancer Res. Treat. 2017 Oct;165:687-697), and in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). <span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms">In one high throughput functional study, this variant was shown to impair both BARD1<span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms"> binding activity and E3 Ubiquitin<span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms"> ligase<span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms"> function of the <span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms">protein (Starita<span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms"> LM et al. Genetics.<span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms"> 2015 Jun;200:413-22). One functional 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;562:217-222). <span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms">This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. <span style="font-family:sans-serif,arial,verdana,trebuchet ms">Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000496241 SCV001554585 pathogenic Hereditary breast and ovarian cancer syndrome 2021-03-21 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.182G>A (p.Cys61Tyr) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain (IPR001841) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250754 control chromosomes. c.182G>A has been reported in the literature in multiple individuals from families 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. Several publications report experimental evidence evaluating an impact on protein function (example, Findlay_2018). The most pronounced variant effect results in loss of homology directed repair (HDR) activity. Three clinical diagnostic laboratories, one research submitter, and one consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=4)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000496241 SCV001589380 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 61 of the BRCA1 protein (p.Cys61Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with breast cancer (PMID: 28664506, 22752604), and may be a recurrent variant in African Americans (PMID: 18159056, 25428789, 26287763). ClinVar contains an entry for this variant (Variation ID: 54364). This variant affects the highly conserved Cys61 residue within the N-terminal RING domain of the BRCA1 protein (PMID: 22843421). Experimental studies have shown that this variant disrupts several aspects of BRCA1 function (PMID: 25823446, 30209399). A different missense substitution at this codon (p.Cys61Gly) is a common variant in individuals of Eastern European ancestry, and has been determined to be pathogenic (PMID: 7894493, 19594371,9525870, 22172724, 11278247, 19770520). 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.
Sharing Clinical Reports Project (SCRP) RCV000077497 SCV000109296 pathogenic Breast-ovarian cancer, familial 1 2011-05-06 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077497 SCV000144576 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 RCV000496241 SCV000587025 pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-17 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000235674 SCV000591247 pathogenic not provided no assertion criteria provided clinical testing The BRCA1 p.Cys61Tyr variant was identified in dbSNP (ID: rs80357093) “With pathogenic allele”, HGMD, and the BIC database (6X with unknown clinical importance). The p.Cys61 residue is conserved across mammals and lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Cys61Tyr variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Abkevich (2004) notes that p.Cys61 is a C3HC4 RING finger canonical residue, and that the p.Cys61Tyr variant is classified as deleterious by Myriad. In addition, another variant at this amino acid position, p.Cys61Gly, has been listed in public databases as a pathogenic variant, including 45X in UMD (as a "causal" variant) and 239X in the BIC database (as a variant with clinical importance). This p.Cys61Gly variant has also been characterized as deleterious by different functional assays, including evaluations of the p.Cys61Gly variant on double strand break repair and protein expression (Li 2010, Towler 2013, Bouwman 2013), suggesting that this residue is functionally important and the p.Cys61Tyr variant may also impact protein function. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Brotman Baty Institute,University of Washington RCV000077497 SCV001242517 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.