ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8331+2T>C (rs398122602)

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Total submissions: 7
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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 RCV000258355 SCV000327868 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000258355 SCV000605691 pathogenic Breast-ovarian cancer, familial 2 2015-11-12 criteria provided, single submitter clinical testing
GeneDx RCV000519723 SCV000617474 pathogenic not provided 2018-01-11 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8331+2T>C or IVS18+2T>C and consists of a T>C nucleotide substitution at the +2 position of intron 18 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 8559+2T>C. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Splicing assays have confirmed that this variant causes aberrant splicing (Fraile-Bethencourt 2017). This variant has been reported in at least one individual with epithelial ovarian cancer (Cunningham 2014). Based on the current evidence, we consider this variant to be pathogenic.
Color Health, Inc RCV000581266 SCV000689116 pathogenic Hereditary cancer-predisposing syndrome 2020-02-06 criteria provided, single submitter clinical testing
Invitae RCV000496246 SCV000759096 pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-03 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 18 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 in several individuals with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 24504028, 25186627, 29446198, 29487695, 29339979). ClinVar contains an entry for this variant (Variation ID: 267692). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 28339459). 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.
Ambry Genetics RCV000581266 SCV001178672 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-18 criteria provided, single submitter clinical testing The c.8331+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 17 in the BRCA2 gene. This alteration has been reported in multiple hereditary breast and/or ovarian cohorts (Cunningham JM, Sci Rep 2014; 4():4026; Heramb C et al. Hered Cancer Clin Pract 2018 Jan;16:3; Song H et al. Hum. Mol. Genet. 2014 Sep;23(17):4703-9; Kwong A et al. Oncotarget 2018 Jan;9(8):7832-7843). 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. Various RNA studies have supported that this variant causes a majority of coding exon 17 skipping (also refered to as Exon 18 in the literature); however, one quantitative study supports this variant as producing an incomplete splice defect (Ambry internal data; Fraile-Bethencourt E et al. PLoS Genet. 2017 Mar;13(3):e1006691; Gelli E et al. Cancers (Basel), 2019 Mar;11; Wangensteen T et al. Hered Cancer Clin Pract, 2019 May;17:14). 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. Based on the majority of available evidence, this alteration is classified as likely pathogenic.
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496246 SCV000587947 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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