ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1700_1704del (p.Lys567fs) (rs63750474)

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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 RCV000490820 SCV000580459 pathogenic Hereditary cancer-predisposing syndrome 2017-05-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000483742 SCV000565803 pathogenic not provided 2015-03-16 criteria provided, single submitter clinical testing This deletion of 5 nucleotides in MSH2 is denoted c.1700_1704delAAACA at the cDNA level and p.Lys567ArgfsX3 (K567RfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AATA[AAACA]GAAT. The deletion causes a frameshift, which changes a Lysine to an Arginine at codon 567, and creates a premature stop codon at position 3 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 Lys567ArgfsX3 has been observed in at least one family presenting with the Muir-Torre variant of Lynch syndrome (Kruse 1996, Mangold 2004). we consider this variant to be pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076252 SCV000107271 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
Invitae RCV000076252 SCV000548263 pathogenic Lynch syndrome 2016-04-09 criteria provided, single submitter clinical testing This sequence change deletes 5 nucleotides from exon 11 of the MSH2 mRNA (c.1700_1704delAAACA), causing a frameshift at codon 567. This creates a premature translational stop signal (p.Lys567Argfs*3) and is expected to result in an absent or disrupted protein product. Truncating variants in MSH2 are known to be pathogenic. This particular truncation has been reported in individuals with suspected Lynch syndrome or Muir-Torre syndrome (PMID: 8931714, 11606497, 11208710). This variant is also known as 1699delAAACA and 1700-4del in the literature. For these reasons, this variant has been classified as Pathogenic.

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