ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2458+2T>C

gnomAD frequency: 0.00001  dbSNP: rs1278858560
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Department of Laboratory Medicine, University of Washington RCV000758658 SCV000887426 likely pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH2 NM_000251.2:c.2458+2T>C has a 98.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.
Ambry Genetics RCV001015600 SCV001176449 likely pathogenic Hereditary cancer-predisposing syndrome 2022-05-23 criteria provided, single submitter clinical testing The c.2458+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 14 in the MSH2 gene. Using a Bayesian analysis that incorporates tumor mutation data, this variant was classified as likely pathogenic (Shirts BH et al. Am J Hum Genet. 2018 Jul 5;103(1):19-29). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, 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. As such, this alteration is classified as likely pathogenic.
Myriad Genetics, Inc. RCV003453555 SCV004186596 likely pathogenic Lynch syndrome 1 2023-08-08 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.

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