ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1487G>A (p.Arg496His) (rs28897677)

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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) RCV000111630 SCV000244304 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 = 0.00000188
Invitae RCV000047494 SCV000075507 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000120286 SCV000167242 benign not specified 2013-12-12 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 RCV000162601 SCV000213022 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 RCV000120286 SCV000219208 likely benign not specified 2016-10-26 criteria provided, single submitter clinical testing
Counsyl RCV000111630 SCV000220299 likely benign Breast-ovarian cancer, familial 1 2014-05-08 criteria provided, single submitter literature only
Pathway Genomics RCV000111630 SCV000223749 benign Breast-ovarian cancer, familial 1 2014-10-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047494 SCV000494349 benign Hereditary breast and ovarian cancer syndrome 2014-09-29 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000120286 SCV000538438 likely benign not specified 2016-03-29 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: ExAC: 0.1% (51/66708) European; ClinVar: 5 B/LB, 3 VUS
Genetic Services Laboratory, University of Chicago RCV000120286 SCV000593685 likely benign not specified 2017-03-29 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283236 SCV000602714 benign none provided 2020-05-13 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000162601 SCV000679700 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162601 SCV000682965 likely benign Hereditary cancer-predisposing syndrome 2015-02-11 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034727 SCV000806898 likely benign not provided 2017-07-07 criteria provided, single submitter clinical testing
Mendelics RCV000111630 SCV001140601 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034727 SCV001151335 likely benign not provided 2019-12-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000111630 SCV001287423 likely benign Breast-ovarian cancer, familial 1 2018-07-10 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170825 SCV001333443 likely benign Breast and/or ovarian cancer 2017-11-20 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034727 SCV000043181 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
ITMI RCV000120286 SCV000084438 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000111630 SCV000144110 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Medical Genetics, University Hospital of North Norway RCV000111630 SCV000301431 likely benign Breast-ovarian cancer, familial 1 2016-05-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353760 SCV000591336 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Arg496His variant was identified in at least 10 of 116730 proband chromosomes (frequency: 0.00009) from individuals or families with breast cancer, and was present in 2 of 1602 control chromosomes (frequency: 0.002) from healthy individuals (Arnold 2002, Bodian 2014, Capanu 2011, Horvath 2013, Schoumacher 2001, Soegaard 2008, Spitzer 2000). The variant was also identified in HGMD, LOVD, the ClinVar database (classified through clinical testing as a benign variant by Invitae and GeneDX), the BIC database (86X with unknown clinical importance), and UMD (15X as a neutral variant). In UMD the variant was identified with a 6 different co-occurring pathogenic BRCA1 variants, and Judkins (2005) also found the variant in trans with a known deleterious variant in BRCA1, increasing the likelihood that the p.Arg496Hisvariant does not have clinical significance. In The variant was identified by the Exome Variant Server project in 8 of 8600 European American alleles (frequency: 0.0009), and in dbSNP (ID: rs28897677) with an allele frequency of 0.002 in the ClinSeq project, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Arg496 residue is not conserved in mammals and the variant amino acid histidine (His) is present in dog and opossum, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein, and in silico studies assessing evolutionary conservation, amino acid properties, or multifactorial probability based models all suggest that the variant is not pathogenic or neutral/of little clinical significance (Abkevich 2004, Capanu 2011, Lee 2008, Lindor 2011, Tavtigian 2006). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000111630 SCV000733657 benign Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing

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