ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1486C>T (p.Arg496Cys) (rs28897676)

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Total submissions: 18
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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) RCV000111629 SCV000244303 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 = 0.000891
Invitae RCV001084143 SCV000075506 benign Hereditary breast and ovarian cancer syndrome 2020-12-08 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148399 SCV000190098 uncertain significance Breast and/or ovarian cancer 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx RCV000047493 SCV000209927 benign not specified 2015-07-28 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 RCV000162551 SCV000212961 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000047493 SCV000538439 likely benign not specified 2017-02-03 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: Classified in ClinVar with 3 stars as Benign by ENIGMA (expert panel), Invitae, GeneDx, Ambry and as VUS by CSER and BIC. It has a max MAF of 0.026% in ExAC (3 Latino alleles). The AA is not conserved and only mammals have this region, 6 of which have a Cys at this position.
Genetic Services Laboratory, University of Chicago RCV000047493 SCV000593661 likely benign not specified 2016-08-02 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000162551 SCV000679701 likely benign Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162551 SCV000682964 likely benign Hereditary cancer-predisposing syndrome 2014-12-16 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656641 SCV000806897 likely benign not provided 2017-02-20 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000148399 SCV000902231 benign Breast and/or ovarian cancer 2016-07-22 criteria provided, single submitter clinical testing
Mendelics RCV000111629 SCV001140602 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000047493 SCV001159073 benign not specified 2018-10-03 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111629 SCV000144109 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 RCV000047493 SCV000587141 benign not specified 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353852 SCV000591335 benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Arg496Cys variant is identified in the literature in 6 out of 7356 proband chromosomes (frequency 0.001) with breast and ovarian cancers, however a limited number of control chromosomes were analyzed (0 out of 700, frequency=0), and so the frequency of this variant in the general population could not adequately be assessesed (Infante 2006, Chenevix-Trench 2006, Van-Hassel 2010, Borg 2010, German consortium 2002, Arnold 2002). It is listed in dbSNP database as coming from a "clinical source" (ID#: rs28897676) with an average heterozygosity of 0.000+/-0.015 from one population. The BIC database reports this variant 46X with unknown clinical importance. It is reported 52 times in the myriad database "in trans" and therefore likely to be neutral (Chenevix-Trench 2006). In the UMD database, this variant has been identified in 12 individuals with breast or ovarian cancers, and in 4 of these cases a second pathogenic BRCA1 or BRCA2 mutation was also detected, therefore increasing the likelihood this variant is benign. The p.Arg496 residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein, and other in silico analysis do not show any impact on the function (Lovelock 2007, Lindor 2011, Capanu 2011, Waddel 2008, Lee 2008, Mark_2005_15571721, Judkins_2005_16267036). Another variant at the same location, p.Arg496His, is also found 12 times in UMD database, with a second pathogenic variant co-occurring in 5 individuals with beast and ovarian cancer phenotype, decreasing the likelihood the p.Arg496Cys variant has clinical significance. In summary, based upon the above information, this variant is classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000656641 SCV000778768 likely benign not provided 2017-03-30 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000148399 SCV000863586 uncertain significance Breast and/or ovarian cancer 2001-10-10 no assertion criteria provided clinical testing

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