ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.81-9C>G (rs80358127)

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Total submissions: 5
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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) RCV000111718 SCV001161638 pathogenic Breast-ovarian cancer, familial 1 2019-06-18 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 5 based on posterior probability = 0.996447
Invitae RCV000049152 SCV000077165 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-08-12 criteria provided, single submitter clinical testing This sequence change falls in intron 2 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with breast cancer (PMID: 18704682). This variant is also known as IVS2-9C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 55719). Based on a multifactorial likelihood algorithm using genetic and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 30415210). Experimental studies have shown that this variant disrupts mRNA splicing and protein function (PMID: 20614180, 23893897, 30209399). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV001027266 SCV001189799 pathogenic Hereditary cancer-predisposing syndrome 2019-04-19 criteria provided, single submitter clinical testing The c.81-9C>G intronic pathogenic mutation results from a C to G substitution 9 nucleotides upstream from coding exon 2 in the BRCA1 gene. This nucleotide position is poorly conserved in available vertebrate species, however, thymidine is the only other observed alternate nucleotide. Using the BDGP and ESEfinder splice site prediction tools predicts a weakening in the native splice acceptor site efficiency and the creation of a new alternate splice acceptor site 8 nucleotides upstream from the native. RNA studies have confirmed this cryptic splice site is used resulting in abnormal splicing in the set of samples tested (Ambry internal data; Joosse SA et al. Breast Cancer Res. Treat., 2012 Apr;132:379-89). In addition, this alteration was shown to be functionally deleterious in a high-throughput haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on the majority of evidence available to date, this alteration is interpreted as a disease-causing mutation.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111718 SCV000144229 uncertain significance Breast-ovarian cancer, familial 1 2002-06-20 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000111718 SCV001242306 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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