ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.425+2T>C (rs876661045)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000663046 SCV000786091 likely pathogenic Breast-ovarian cancer, familial 2 2018-02-20 criteria provided, single submitter clinical testing
GeneDx RCV000221962 SCV000279339 likely pathogenic not provided 2018-03-21 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.425+2T>C or IVS4+2T>C and consists of a T>C nucleotide substitution at the +2 position of intron 4 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 653+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. This variant has not, to our knowledge, been published in the literature. Based on the currently available information, we consider BRCA2 c.425+2T>C to be a likely pathogenic variant.
Invitae RCV000697192 SCV000825789 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-07 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 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 not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 234487). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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). 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.

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