ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8331+2T>C (rs398122602)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000581266 SCV000689116 likely pathogenic Hereditary cancer-predisposing syndrome 2018-07-29 criteria provided, single submitter clinical testing
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.
Invitae RCV000496246 SCV000759096 pathogenic Hereditary breast and ovarian cancer syndrome 2018-01-25 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 identified in individuals affected with either breast cancer or ovarian cancer (PMID: 25186627, 24504028).  ClinVar contains an entry for this variant (Variation ID: 267692). Experimental studies have shown that this variant in the donor splice site of intron 18 leads to aberrant 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.
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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