ClinVar Miner

Submissions for variant NM_007299.4(BRCA1):c.181T>G (p.Cys61Gly) (rs28897672)

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Total submissions: 32
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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) RCV000019229 SCV000244308 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
Invitae RCV000047597 SCV000075610 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 61 of the BRCA1 protein (p.Cys61Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is present in population databases (rs28897672, ExAC 0.01%). This variant is a common cause of breast and ovarian cancer in individuals of Eastern European ancestry (PMID: 20345474, 20507347, 20569256, 19594371). It has been reported in hundreds of individuals affected with these cancers (PMID: 7894493, 10788334, 21324516, 20180014). It is also known as 300T>G in the literature. ClinVar contains an entry for this variant (Variation ID: 17661). 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: 11278247, 9525870, 22172724, 23161852, 23867111). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131902 SCV000186957 pathogenic Hereditary cancer-predisposing syndrome 2018-02-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Other strong data supporting pathogenic classification,Deficient protein function in appropriate functional assay(s)
Michigan Medical Genetics Laboratories,University of Michigan RCV000019229 SCV000195877 pathogenic Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000159935 SCV000210067 pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.181T>G at the cDNA level, p.Cys61Gly (C61G) at the protein level, and results in the change of a Cysteine to a Glycine (TGT>GGT). This variant, also known as BRCA1 300T>G using alternate nomenclature, is a recurrent pathogenic founder variant in the Polish, German, Czech Republic, and Austrian populations, and has been identified in numerous hereditary breast and/or ovarian cancer families (Gorski 2000, Ratajska 2008, Brozek 2011, Karami 2013). This variant has been demonstrated in mouse and in vitro studies to disrupt proper function of the BRCA1 protein (Ruffner 2001, Chang 2009, Ransburgh 2010, Drost 2011). BRCA1 Cys61Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located at a Ubiquitination site in the RING finger domain and in a region known to interact with multiple other proteins (Wu 1996, Harte 2010, Borg 2010, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000159935 SCV000230340 pathogenic not provided 2015-05-13 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000047597 SCV000271313 pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-22 criteria provided, single submitter clinical testing The p.Cys61Gly variant in BRCA1 has been identified in >300 individuals with BRC A1-associated cancers and has segregated with disease in multiple families, incl uding one male with breast cancer (Friedman 1994, Gorski 1999, Cherbal 2010, Bog danova 2010, Breast Cancer Information Core database, www.research.nhgri.nih.gov /bic/). This variant has been identified in 8/65364 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs2889 7672). Please note this frequency is low enough to be consistent with the freque ncy of hereditary breast and ovarian cancer (HBOC) in the general population. In vitro functional studies have shown that the p.Cys61Gly variant disrupts protei n function and produces drug-resistant tumors in mouse models (Brzvoic 1998 and Drost 2011). In summary, this variant meets our criteria to be classified as pat hogenic for HBOC in an autosomal dominant manner based upon segregation studies, presence in affected individuals, low frequency in controls, and functional evi dence. ACMG/AMP criteria applied: PS4, PS3_M, PP1_M, PM2_P.
Color RCV000131902 SCV000292141 pathogenic Hereditary cancer-predisposing syndrome 2014-12-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159935 SCV000296283 pathogenic not provided 2015-02-18 criteria provided, single submitter clinical testing
GeneKor MSA RCV000239114 SCV000296762 pathogenic Familial cancer of breast 2018-08-01 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019229 SCV000325150 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000412714 SCV000492470 pathogenic Neoplasm of the breast criteria provided, single submitter research
Baylor Genetics RCV000239114 SCV000540933 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000019229 SCV000564349 pathogenic Breast-ovarian cancer, familial 1 2015-07-01 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000047597 SCV000588026 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000047597 SCV000591246 pathogenic Hereditary breast and ovarian cancer syndrome 2012-06-15 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000019229 SCV000593687 pathogenic Breast-ovarian cancer, familial 1 2016-12-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506927 SCV000602706 pathogenic not specified 2016-11-29 criteria provided, single submitter clinical testing
Counsyl RCV000019229 SCV000677634 pathogenic Breast-ovarian cancer, familial 1 2015-11-12 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000131902 SCV000679704 pathogenic Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000047597 SCV000698888 pathogenic Hereditary breast and ovarian cancer syndrome 2017-08-24 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.181T>G (p.Cys61Gly) variant involves the alteration of a conserved nucleotide that leads to the alteration of an amino acid residue in the RING domain of BRCA1 protein (InterPro). 4/5 in silico tools predict a damaging outcome for this variant and several functional studies demonstrated the Cys61Gly mutation affects several functional properties of the BRCA1 NH2-terminal domain (e.g. Brzovic 1998, 2003). This variant was found in 8/119006 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000122 (8/65364). This frequency is smaller than the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This is a well established disease variant that was reported in multiple patients with HBOC (e.g. Friedman 1994, Gorski 2000, Thorstenson 2003, Bogdanova 2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics RCV000047597 SCV000839313 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000019229 SCV000839890 pathogenic Breast-ovarian cancer, familial 1 2017-05-25 criteria provided, single submitter clinical testing The c.181T>G (p.Cys61Gly) variant has been detected in a multiple patients with breast and ovarian cancer [PMID 20507347, 21965345, 21503673, 20180014, 20345474, 23695190, 24728189, 21324516, 20569256 among others] and prostate cancer [PMID 27433846]. Functional in vitro assays showed that this variant was deleterious [PMID 23867111]. This variant has been reported in 8 non-Finnish Europeans from the ExAC database (http://exac.broadinstitute.org/variant/17-41258504-A-C). This variant occurs at high frequency in Eastern European countries and is considered a founder mutation in these countries [PMID 20507347, 20345474]. Cysteine at amino acid position 61 of the BRCA1 protein is highly conserved in mammals. While not validated for clinical use, computer-based algorithms predict this p.Cys61Gly change to be deleterious. Other changes affecting the same amino acid have been reported in patients with breast and/or ovarian cancer (p.Cys61Arg, p.Cys61Ser, p.Cys61Tyr). This variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763010 SCV000893455 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; FANCONI ANEMIA, COMPLEMENTATION GROUP S 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000019229 SCV000039517 pathogenic Breast-ovarian cancer, familial 1 2000-06-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000019229 SCV000109295 pathogenic Breast-ovarian cancer, familial 1 2013-09-18 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000019229 SCV000144574 not provided Breast-ovarian cancer, familial 1 no assertion provided clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415051 SCV000492590 pathogenic Breast carcinoma 2016-04-06 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000047597 SCV000587024 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000019229 SCV000733679 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000159935 SCV000778779 pathogenic not provided 2016-12-07 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785199 SCV000923767 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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