Submissions for variant NM_007294.4(BRCA1):c.536A>G (p.Tyr179Cys)

gnomAD frequency: 0.00029  dbSNP: rs56187033

Total submissions: 38

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031242	SCV000244401	benign	Breast-ovarian cancer, familial, susceptibility to, 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 1 based on posterior probability = 0.00000000000173
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167816	SCV000076978	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000031242	SCV000154033	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-04-07	criteria provided, single submitter	literature only
GeneDx	RCV000168482	SCV000167228	benign	not specified	2014-01-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000162619	SCV000213051	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031242	SCV000267684	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000167816	SCV000297228	uncertain significance	Hereditary breast ovarian cancer syndrome	2015-09-02	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000168482	SCV000333419	likely benign	not specified	2015-08-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168482	SCV000538441	likely benign	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 6 B/LB, including expert panel
Fulgent Genetics, Fulgent Genetics	RCV000031242	SCV000575709	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162619	SCV000683307	likely benign	Hereditary cancer-predisposing syndrome	2014-12-15	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000031242	SCV000746298	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-05-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000656646	SCV000806971	likely benign	not provided	2017-05-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000031242	SCV001140631	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656646	SCV001151339	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	BRCA1: BP1, BS3:Moderate, BS1
Illumina Laboratory Services, Illumina	RCV000031242	SCV001285178	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-11-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798034	SCV002043456	likely benign	Breast and/or ovarian cancer	2023-02-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000168482	SCV002070511	likely benign	not specified	2022-01-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162619	SCV002537848	benign	Hereditary cancer-predisposing syndrome	2020-06-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168482	SCV002551054	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656646	SCV002774168	benign	not provided	2022-09-03	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031242	SCV004016760	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656646	SCV004563116	benign	not provided	2023-09-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031242	SCV004818439	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000656646	SCV005251087	benign	not provided		criteria provided, single submitter	not provided
Sharing Clinical Reports Project (SCRP)	RCV000031242	SCV000053846	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031242	SCV000145609	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000168482	SCV000587062	benign	not specified	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353554	SCV000591279	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Tyr179Cys variant has been identified in 11 of 5342 proband chromosomes (frequency 0.002) in individuals with breast or ovarian cancers (Akbari 2011, Augello 2006, Caligo 2008, Diez 2003, Jalkh 2012, Russo 2007, Solano 2012) and was absent in 400 control chromosomes from these studies. Myriad reports this variant as a polymorphism, and Exome Server Project reports a frequency of 0.0003 in European American alleles, and 0.0002 in African American alleles. This variant has been also been reported in dbSNP (ID: rs56187033) “with non-pathogenic allele”, in the BIC database 54X as a variant of unknown clinical importance, and in UMD 27X as a neutral variant which co-occurred with pathogenic mutations in BRCA1 or BRCA2 four times (BRCA1 c.2043dup (p.Asn682X), BRCA1 c.191G>A (p.Cys64Tyr), BRCA2 c.6082_6086delGAAGA (p.Glu2028LysfsX19), BRCA2 c.5909C>A (p.Ser1970X)). The p.Tyr179 residue is conserved in mammals; however, computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein, and this information is not very predictive of pathogenicity. Functional studies on the p.Tyr179Cys variant have suggested that it may have a deleterious effect on BRCA1 function, in assays evaluating its effect in homologous repair (Caligo 2008, Di Cecco 2009), non-homologous end-joining (Guidugli 2011), interaction of BRCA1 with Filamin A (Velkova 2010), and accumulation of BRCA1 at double-strand breaks (Wei 2008). Many studies have identified the p.Tyr179Cys variant co-occurring with two other BRCA1 variants, p.Phe486Lys and p.Asn550His, in individuals with breast or ovarian cancers (Augello 2006, Caligo 2008, Diez 2003, Jalkh 2012), suggesting that together they constitute a rare haplotype (Tavtigian 2006). Furthermore, Augello (2006) identified these three mutations in three members of one family indicating that they exist in cis, and suggests that the presence of the three variants might produce an effect on the conformation of the protein and, consequently, on its function. In summary, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031242	SCV000733670	benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656646	SCV000778777	benign	not provided	2017-08-01	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162619	SCV000805235	likely benign	Hereditary cancer-predisposing syndrome	2018-04-05	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000168482	SCV001906072	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000168482	SCV001955365	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000168482	SCV001972723	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000168482	SCV002035365	benign	not specified		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000167816	SCV002506600	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-07	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031242	SCV004244164	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing