ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4600G>A (p.Val1534Met) (rs55815649)

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Total submissions: 17
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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) RCV000112362 SCV000244363 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 = 0.000000000074
Invitae RCV000195319 SCV000076615 benign Hereditary breast and ovarian cancer syndrome 2020-12-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120259 SCV000202263 benign not specified 2014-04-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162668 SCV000213115 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.
Counsyl RCV000112362 SCV000220303 benign Breast-ovarian cancer, familial 1 2014-05-10 criteria provided, single submitter literature only
Michigan Medical Genetics Laboratories,University of Michigan RCV000112362 SCV000267713 benign Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000195319 SCV000494388 benign Hereditary breast and ovarian cancer syndrome 2014-05-02 criteria provided, single submitter clinical testing Variant summary: (1) Variant is found in a non-conserved region with a high prevalence in control individuals (22/7,595), (2) Variant is reported to co-occur with other potentially pathogenic variants in BRCA1 (p.Glu1413AspfsX2, 2 - p.Gln1240X) and 1 BRCA2 (p.Ile1874ArgfsX34)(UMD), (3) Functional studies suggest comparable activity levels to wild type (Carvalho_BRCA1_CR_2007) and (4) multiple databases and publications classify variant as benign/neutral (Emory genetics, UMD, ARUP, Easton_2007, Carvalho_2007, Chenevix-Trench_2006 and Lindor_2012) .
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000120259 SCV000538431 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: 0.5% (52/10406) African chromosomes; ClinVar: 2 labs classify as LB; 5 papers describe as nonpathogenic
Genetic Services Laboratory, University of Chicago RCV000120259 SCV000593658 likely benign not specified 2015-09-02 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000112362 SCV000744612 benign Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120259 SCV000806954 benign not specified 2017-01-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282537 SCV000885073 benign none provided 2019-12-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162668 SCV000902629 benign Hereditary cancer-predisposing syndrome 2015-10-15 criteria provided, single submitter clinical testing
ITMI RCV000120259 SCV000084411 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000112362 SCV000145125 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120259 SCV000591527 benign not specified no assertion criteria provided clinical testing The p.Val1534Met variant has been observed in the literature in 5/5288 proband chromosomes of individuals with hereditary breast cancer, ovarian cancer and prostate cancer. It was not detected in any of the 360 control chromosomes evaluated (Abkevich 2004, Carvalho 2007, Chenevix-Trench 2006, Hondow 2011, Iversen 2011, Leongamornlert 2012, Velasco 2005, Millot 2012). The variant was also observed by our lab in one unaffected individual in a family where a different pathogenic variant was reported, increasing the likelihood this variant does not have clinical significance. The variant was also identified in ClinVar by GeneDx (benign), and by Invitae and ITMI (significance not provided). It is listed in the dbSNP database (ID#: rs55815649) as coming from a clinical source with a global minor allele frequency (MAF) of 0.001, having been observed thrice in 3,000 chromosomes. It has been reported in the UMD (x8 as neutral), BIC (x26 as VUS), and EVS (ACMG 3) databases. This residue is not conserved in mammals and the variant amino acid Methionine (Met) is present in the dog. Computational analyses (PolyPhen, SIFT, AlignGVGD) does not predict any effect on the protein function, increasing the likelihood this variant does not have functional significance. In addition, in one of the functional studies that measured the transactivation activity of BRCA1, the activity level of the variant was comparable to the wild-type protein in mammalian cells (Carvalho 2007). In summary, based on the above information, this variant is classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000656628 SCV000778737 benign not provided 2017-03-31 no assertion criteria provided clinical testing

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