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

Total submissions: 32

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