ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.426-2A>G (rs398122779)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160018 SCV000210237 pathogenic not provided 2018-11-02 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.426-2A>G or IVS4-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 4 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 654-2A>G. The variant destroys a canonical splice acceptor 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 been reported in association with hereditary breast and ovarian cancer (Wei 2018). Based on the current evidence, we consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077725 SCV000327000 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000503210 SCV000591679 pathogenic Hereditary breast and ovarian cancer syndrome 2013-05-13 criteria provided, single submitter clinical testing
Invitae RCV000503210 SCV000952603 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-12 criteria provided, single submitter clinical testing This sequence change affects an acceptor 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 been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 91817). 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.
Sharing Clinical Reports Project (SCRP) RCV000077725 SCV000109528 pathogenic Breast-ovarian cancer, familial 2 2008-04-28 no assertion criteria provided clinical testing

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