ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1759+2T>C

dbSNP: rs267607976
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076267 SCV000107288 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Invitae RCV000804797 SCV000944727 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-10-16 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 11 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). Disruption of this splice site has been observed in a family affected with Lynch syndrome (PMID: 11772966). ClinVar contains an entry for this variant (Variation ID: 90768). 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.
Ambry Genetics RCV001013049 SCV001173584 likely pathogenic Hereditary cancer-predisposing syndrome 2018-05-25 criteria provided, single submitter clinical testing The c.1759+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 11 in the MSH2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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.
All of Us Research Program, National Institutes of Health RCV000076267 SCV004838909 likely pathogenic Lynch syndrome 2024-01-08 criteria provided, single submitter clinical testing The c.1759+2T>C variant of the MSH2 gene is expected to affect mRNA splicing and result in an absent or disrupted protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncating variants in MSH2 are known to be pathogenic (PMID: 15849733, 19419416). Therefore, this variant is classified as likely pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000076267 SCV005045727 likely pathogenic Lynch syndrome 2023-09-22 criteria provided, single submitter clinical testing The c.1759+2T>C variant of the MSH2 gene is expected to affect mRNA splicing and result in an absent or disrupted protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncating variants in MSH2 are known to be pathogenic (PMID: 15849733, 19419416). Therefore, this variant is classified as likely pathogenic.

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