ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2647del (p.Ile883fs) (rs63750084)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160633 SCV000580441 pathogenic Hereditary cancer-predisposing syndrome 2017-10-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000497287 SCV000211234 pathogenic not provided 2014-10-20 criteria provided, single submitter clinical testing This deletion of one nucleotide in MSH2 is denoted c.2647delA at the cDNA level and p.Ile883LeufsX9 (I883LfsX9) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GAAAAA[A]TTATT. The deletion causes a frameshift, which changes an Isoleucine to a Leucine at codon 883, and creates a premature stop codon at position 9 of the new reading frame resulting in the loss of 52 correct amino acids and the gain of 8 incorrect amino acids. This variant is predicted to cause loss of normal protein function through protein truncation. MSH2 c.2647delA has been observed in a family meeting Amsterdam criteria (Percesepe 2001). we consider this variant to be pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076532 SCV000107561 pathogenic Lynch syndrome I 2018-06-13 reviewed by expert panel curation This variant is before the cutoff (codon 888) and therefore Class 5
Invitae RCV000537212 SCV000625400 pathogenic Hereditary nonpolyposis colon cancer 2017-07-14 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MSH2 gene (p.Ile883Leufs*9). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acids of the MSH2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a single family fulfilling Amsterdam criteria (PMID: 11579115). It has also been reported to segregate with Lynch syndrome cancers in five individuals from a single family (PMID: 14970868). ClinVar contains an entry for this variant (Variation ID: 91030). While this variant is not expected to result in nonsense mediated decay, it is expected to disrupt nearly the entire C-terminal portion of the MSH6 and MSH3 interaction domains of the MSH2 protein, as well as the helix-turn-helix domain (disrupted residues Ile883-Thr934) (PMID: 9774676, 18822302, 17531815). Although functional studies have not been done for this particular variant, loss of the C-terminal region of the protein likely impairs MSH2 function (PMID: 9774676, 18822302, 17531815). This suggests that deletion of this region of the MSH2 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

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