ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.213-2A>G

dbSNP: rs397508940
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University RCV000240728 SCV000265870 pathogenic Breast neoplasm 2015-11-01 criteria provided, single submitter research
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000258171 SCV000325259 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001853354 SCV002132485 pathogenic Hereditary breast ovarian cancer syndrome 2021-05-28 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this variant affects BRCA1 protein function (PMID: 30209399). This variant has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 29446198, 30702160). ClinVar contains an entry for this variant (Variation ID: 224426). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 4 of the BRCA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584).
Ambry Genetics RCV004020571 SCV005025801 pathogenic Hereditary cancer-predisposing syndrome 2023-11-14 criteria provided, single submitter clinical testing The c.213-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 4 in the BRCA1 gene. This alteration was identified in 1/507 unselected Chinese breast cancer patients (Zhong X et al. PLoS One, 2016 Jun;11:e0156789). One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation of a novel splice acceptor site. RNA studies have shown this variant to result in an acceptor gain which includes 59 nucleotides of intron and results in a transcript subject to nonsense-mediated mRNA decay (Ambry internal data, Houdayer C et al. Hum Mutat 2012 Aug;33(8):1228-38). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Brotman Baty Institute, University of Washington RCV000258171 SCV001241697 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro

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