ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5407-4C>G (rs876660347)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222294 SCV000277702 likely benign Hereditary cancer-predisposing syndrome 2020-03-05 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);RNA Studies
Illumina Clinical Services Laboratory,Illumina RCV001073214 SCV000403053 uncertain significance Breast-ovarian cancer, familial 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV001697223 SCV000532626 likely benign not provided 2019-04-10 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 30209399)
Invitae RCV000343466 SCV000636039 likely benign Hereditary breast and ovarian cancer syndrome 2020-07-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000222294 SCV000906438 likely benign Hereditary cancer-predisposing syndrome 2016-02-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000433879 SCV001370707 uncertain significance not specified 2020-05-07 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5407-4C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251444 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5407-4C>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=3) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Brotman Baty Institute,University of Washington RCV001073214 SCV001238731 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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