ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2588dup (p.Tyr863Ter) (rs1553370435)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657824 SCV000779580 likely pathogenic not provided 2017-06-23 criteria provided, single submitter clinical testing This duplication of one nucleotide is denoted MSH2 c.2588dupA at the cDNA level and p.Tyr863Ter (Y863X) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GGAT[dupA]TGAT. The duplication creates a nonsense variant, which changes a Tyrosine to a premature stop codon. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through protein truncation. The disrupted region at the end of the gene includes the Helix-turn-helix domain and a region that interacts with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). Based on currently available evidence, we consider this variant to be likely pathogenic.
Invitae RCV000809827 SCV000950006 pathogenic Hereditary nonpolyposis colon cancer 2018-10-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr863*) 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 not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 546053). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001016027 SCV001176933 pathogenic Hereditary cancer-predisposing syndrome 2018-09-25 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)

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