ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2362dup (p.Thr788fs) (rs63750463)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076464 SCV000107493 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
GeneDx RCV000480512 SCV000568636 pathogenic not provided 2015-12-02 criteria provided, single submitter clinical testing This duplication of one nucleotide in MSH2 is denoted c.2362dupA at the cDNA level and p.Thr788AsnfsX11(T788NfsX11) at the protein level. The normal sequence, with the base that is duplicated in braces, is ACTT[A]CTGC. The duplication causes a frameshift, which changes a Threonine to an Asparagine at codon 788, and creates a premature stop codon at position 11 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 c.2362dupA has been identified in at least one individual meeting Amsterdam II criteria whose colon tumor showed absence of MSH2 protein by immunohistochemistry (Pedroni 2007). We consider this variant to be pathogenic.
Ambry Genetics RCV000490851 SCV000580625 pathogenic Hereditary cancer-predisposing syndrome 2019-08-22 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV001040813 SCV001204403 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-05-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr788Asnfs*11) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with an MSH2-related cancer (PMID: 17473388, 29348823). ClinVar contains an entry for this variant (Variation ID: 90962). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.

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