ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1738A>T (p.Lys580Ter) (rs267608169)

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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) RCV000076824 SCV000108311 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000129628 SCV000184421 pathogenic Hereditary cancer-predisposing syndrome 2017-06-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000260402 SCV000329709 pathogenic not provided 2017-09-26 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1738A>T at the cDNA level and p.Lys580Ter (K580X) at the protein level. The substitution creates a nonsense variant, which changes a Lysine to a premature stop codon (AAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one individual with colon cancer diagnosed before the age of 50 whose tumor showed isolated loss of PMS2 on immunohistochemistry (IHC) analysis (Senter 2008, Rosty 2016). Based on currently available evidence, we consider PMS2 Lys580Ter to be pathogenic.
Invitae RCV000524446 SCV000551932 pathogenic Hereditary nonpolyposis colon cancer 2018-12-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys580*) in the PMS2 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 particular variant has been reported in the literature in an individual with colon cancer (PMID: 18602922). ClinVar contains an entry for this variant (Variation ID: 91312). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.

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