ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1576del (p.Thr526fs) (rs63750094)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076199 SCV000107216 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
GeneDx RCV000479550 SCV000568630 pathogenic not provided 2016-12-06 criteria provided, single submitter clinical testing This deletion of one nucleotide in MSH2 is denoted c.1576delA at the cDNA level and p.Thr526ProfsX17 (T526PfsX17) at the protein level. The normal sequence, with the base that is deleted in brackets, is TGTA[delA]CCTG. The deletion causes a frameshift which changes a Threonine to a Proline at codon 526, and creates a premature stop codon at position 17 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. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). MSH2 c.1576delA has been reported in patients with Muir-Torre syndrome and Lynch syndrome (Kruse 1998, Bonadona 2011, Kovac 2011, Limburg 2011). We consider this variant to be pathogenic.
Invitae RCV001230571 SCV001403055 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr526Profs*17) 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 individual(s) with Lynch syndrome (PMID: 9634524, 21671081,21056691). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90702). 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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