ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9433G>C (p.Val3145Leu) (rs587776476)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129373 SCV000184137 likely benign Hereditary cancer-predisposing syndrome 2019-05-02 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV001088631 SCV000283368 likely benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000499802 SCV000592287 uncertain significance not specified 2014-01-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000499802 SCV000695239 likely benign not specified 2020-10-26 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9433G>C (p.Val3145Leu) results in a conservative amino acid change located in the BRCA2, OB3 domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251342 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9433G>C has been reported in the literature in at-least one individual affected with cancer (example, McVeigh_2013). Theis report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory ( BRCA2 c.3847_3848delGT , p.V1283fs*2), providing supporting evidence for a benign role. Additionally, this variant was found to co-occur with a pathogenic BRIP1 variant (c.2392C>T; p.R798*) at our laboratory, however, this evidence is captured with caution as the pathogenicity of this specific loss of function (LOF) variant in BRIP1 (p.Arg798Ter) in addition to all other truncating BRIP1 variants in regards to their breast cancer risk has recently been called into question (PMID:26921362). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=4). Based on the evidence outlined above and to reflect the emerging majority consensus in the field, the variant was re-classified as likely benign.
GeneDx RCV000499802 SCV000715915 likely benign not specified 2017-04-13 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.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761164 SCV000891080 uncertain significance Anaplastic/large cell medulloblastoma 2017-04-03 criteria provided, single submitter clinical testing
Color RCV000129373 SCV000903031 benign Hereditary cancer-predisposing syndrome 2016-11-18 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000144220 SCV001267534 uncertain significance Breast-ovarian cancer, familial 2 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.
Illumina Clinical Services Laboratory,Illumina RCV001114170 SCV001272016 uncertain significance Fanconi anemia, complementation group D1 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sharing Clinical Reports Project (SCRP) RCV000144220 SCV000189323 benign Breast-ovarian cancer, familial 2 2012-01-04 no assertion criteria provided clinical testing

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