ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.736T>G (p.Leu246Val) (rs28897675)

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Total submissions: 25
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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) RCV000112779 SCV000244410 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 = 0.000000531
Invitae RCV000049113 SCV000077126 benign Hereditary breast and ovarian cancer syndrome 2020-11-27 criteria provided, single submitter clinical testing
GeneDx RCV000157724 SCV000167234 benign not specified 2013-10-17 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.
Michigan Medical Genetics Laboratories,University of Michigan RCV000112779 SCV000195886 benign Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162555 SCV000212965 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 RCV000112779 SCV000220389 likely benign Breast-ovarian cancer, familial 1 2014-06-08 criteria provided, single submitter literature only
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000049113 SCV000267857 likely benign Hereditary breast and ovarian cancer syndrome 2016-04-25 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000049113 SCV000324818 likely benign Hereditary breast and ovarian cancer syndrome 2015-12-22 criteria provided, single submitter clinical testing Interpretation was last updated within 1 year from 12/22/2015 8:42 AM
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000157724 SCV000538445 uncertain significance not specified 2017-01-24 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: This variant has been reported in HGMD in 1 individual, showing that it leads to loss of expression of BRCA1. This variant is present in ExAC with a Max MAF of 0.04% (25/65600 chrs). It is classified in ClinVar with 3 stars as benign by 5 submitters (including expert panel ENIGMA), Likely benign by 3 submitters, and VUS by 3 submitters.
Genetic Services Laboratory, University of Chicago RCV000157724 SCV000593663 likely benign not specified 2016-07-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283578 SCV000602736 benign none provided 2019-10-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162555 SCV000683352 benign Hereditary cancer-predisposing syndrome 2015-01-13 criteria provided, single submitter clinical testing
Mendelics RCV000112779 SCV001140623 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000112779 SCV001280988 uncertain significance Breast-ovarian cancer, familial 1 2017-04-27 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000148400 SCV001333444 likely benign Breast and/or ovarian cancer 2018-12-14 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034762 SCV001501183 likely benign not provided 2020-11-01 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034762 SCV000043184 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112779 SCV000145673 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148400 SCV000190099 uncertain significance Breast and/or ovarian cancer 2014-06-01 no assertion criteria provided research
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000112779 SCV000493711 uncertain significance Breast-ovarian cancer, familial 1 2015-06-04 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353473 SCV000591299 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1, p.Leu246Val variant was identified in 7 of 7716 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancer (Akbari 2011, Capanu 2011, Diez 2003). The variant was also identified in dbSNP (ID: rs28897675) “With Uncertain significance allele”, with a minor allele frequency of 0.0002 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, LOVD, the ClinVar database (classified as a benign variant by the Invitae, GeneDx and Ambry genetics; classified as Likely benign by Counsyl; classified as Uncertain significance by BIC, by Biesecker Laboratory and by CSER_CC_NCGL), GeneInsight COGR database (1X, classified as “Benign” by a clinical laboratory), the BIC database (80X with unknown clinical importance), and UMD (17X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (BRCA1 c.3901_3902delAG (p.Ser1301X); BRCA2 c.5984dup (p.Asn1995delinsLys)), increasing the likelihood that the p.Leu246Val variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002), Exome Variant Server project in 3 of 8600 European American alleles, the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 26 of 76950 chromosomes (frequency: 0.0003) from a population of European (Non-Finnish) and Latino individuals, increasing the likelihood this could be a low frequency benign variant. The p.Leu246 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In addition, the Val residue is also present in opossum, which would increase the likelihood this variant may not have functional significance. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. RNA based analysis by Sharp (2004) suggest that the mutation is associated with either constitutive skipping of exon 11, or monoallelic BRCA1 expression. However, two functional studies characterized the variant as neutral (Abkevich 2004, Gómez García 2009). In addition, this variant have been observed with two or more known deleterious mutations, increasing the likelihood this variant does not have clinical significance (Tavtigian 2006, Judkins 2005). 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 RCV000112779 SCV000733666 benign Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000034762 SCV000778774 likely benign not provided 2017-04-03 no assertion criteria provided clinical testing
True Health Diagnostics RCV000162555 SCV000787913 likely benign Hereditary cancer-predisposing syndrome 2017-10-25 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000148400 SCV000863627 uncertain significance Breast and/or ovarian cancer 2002-03-15 no assertion criteria provided clinical testing

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