ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9256+1G>A (rs81002883)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000114075 SCV000328086 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000114075 SCV000786406 likely pathogenic Breast-ovarian cancer, familial 2 2018-04-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV001019075 SCV001180385 pathogenic Hereditary cancer-predisposing syndrome 2018-12-07 criteria provided, single submitter clinical testing The c.9256+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 23 of the BRCA2 gene. This alteration was classified in one study as a class 4 or 5 alteration based on a multifactorial 5-tier system using both bioinformatics information and splicing assay information reviewed in the literature (Walker LC et al. Hum. Mutat. 2013 Oct;34(10):1424-31). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site. Additionally, both minigene assays and RNA studies on patient RNA have shown that this alteration leads to skipping of coding exon 23, leading to a frameshift and resultant premature stop codon (Claes K et al. Genes Chromosomes Cancer 2003 Jul;37(3):314-20; Acedo A et al. Hum. Mutat. 2015 Feb;36(2):210-21). 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 a disease-causing mutation.
Invitae RCV001381000 SCV001579248 pathogenic Hereditary breast and ovarian cancer syndrome 2019-02-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 24 of the BRCA2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with breast and prostate cancer in a family (PMID: 12759930). This variant is also known as IVS24+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 52787). Experimental studies have shown that this splice change results in the skipping of exon 24 (PMID: 12759930, 22632462). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000114075 SCV000147583 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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