ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2459-1G>A (rs1060501991)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001201394 SCV000548134 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-20 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 14 of the MSH2 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 MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 408455). 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 MSH2 are known to be pathogenic (PMID: 15849733, 24362816). 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000465186 SCV000887428 likely pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH2 NM_000251.2:c.2459-1G>A has a 98.7% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 1.56 and 1.56 to 1, generated from evidence of seeing this as a somatic mutation in two independent tumors without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.

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