ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5467+2T>C (rs80358009)

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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 RCV000162889 SCV000213376 likely pathogenic Hereditary cancer-predisposing syndrome 2017-05-08 criteria provided, single submitter clinical testing The c.5467+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 21 in the BRCA1 gene. This alteration has been previously reported in 1/110 unrelated families suspected of having hereditary breast and ovarian cancer (HBOC) syndrome (Tommasi S et al. Mutat Res. 2008 Sep 26;644(1-2):64-70). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112659 SCV000326320 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586131 SCV000699241 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-03-24 criteria provided, single submitter clinical testing Variant summary: The c.5467+2T>C in a BRCA1 gene is a splice-site variant that alters a conserved nucleotide. 5/5 in silico tools via Alamut predict this variant to disrupt a canonical donor sequence, however these predictions have yet to be confirmed by functional assay. The variant is absent from ExAC and been reported in affected individual(s) via publications and/or reputable database/clinical laboratory as Likely Pathogenic. Taken together, the variant was classified as Likely Pathogenic until additional information becomes available.
Invitae RCV000586131 SCV001415044 pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-11 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 22) of the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with a personal or family history of BRCA1-related conditions (PMID: 29446198, 18694767). This variant is also known as IVS23+2T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 125851). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 29750258). This variant disrupts the C-terminus of the BRCA1 protein. Other variant(s) that disrupt this region (p.Tyr1853*) have been determined to be pathogenic (PMID: 24504028, 20104584, 7894493, 21922593, 10811118, 11739404, 12400015). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories RCV001657694 SCV001877812 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2021-05-01 criteria provided, single submitter curation
Breast Cancer Information Core (BIC) (BRCA1) RCV000112659 SCV000145522 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112659 SCV001237491 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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