ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.536A>G (p.Tyr179Cys) (rs56187033)

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Total submissions: 24
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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) RCV000031242 SCV000244401 benign 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 1 based on posterior probability = 0.00000000000173
Invitae RCV000167816 SCV000076978 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Counsyl RCV000031242 SCV000154033 likely benign Breast-ovarian cancer, familial 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: 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000168482 SCV000219190 likely benign not specified 2016-06-17 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000031242 SCV000267684 benign Breast-ovarian cancer, familial 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 and ovarian cancer syndrome 2015-09-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000168482 SCV000333419 likely benign not specified 2015-08-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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 1 2015-09-01 criteria provided, single submitter clinical testing
Color Health, Inc 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 1 2020-05-03 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656646 SCV000806971 likely benign not provided 2017-05-16 criteria provided, single submitter clinical testing
Mendelics RCV000031242 SCV001140631 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656646 SCV001151339 uncertain significance not provided 2019-12-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000031242 SCV001285178 benign Breast-ovarian cancer, familial 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.
Sharing Clinical Reports Project (SCRP) RCV000031242 SCV000053846 benign Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031242 SCV000145609 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 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 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

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