ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.862_863del (p.Gln288fs) (rs63750246)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165221 SCV000215935 pathogenic Hereditary cancer-predisposing syndrome 2014-07-03 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)
Color RCV000165221 SCV000686248 pathogenic Hereditary cancer-predisposing syndrome 2017-01-06 criteria provided, single submitter clinical testing
Counsyl RCV000411556 SCV000488646 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2016-05-13 criteria provided, single submitter clinical testing
GeneDx RCV000657185 SCV000778907 pathogenic not provided 2017-11-24 criteria provided, single submitter clinical testing This deletion of two nucleotides in PMS2 is denoted c.862_863delCA at the cDNA level and p.Gln288ValfsX10 (Q288VfsX10) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CAGA[delCA]GTTT. The deletion causes a frameshift which changes a Glutamine to a Valine at codon 288, and creates a premature stop codon at position 10 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. PMS2 c.862_863delCA has been reported in an individual with colon cancer and suspected Lynch syndrome; the colon tumor demonstrated microsatellite instability (MSI) and loss of PMS2 protein on mismatch repair immunohistochemistry (MMR IHC) (Clendenning 2006, Senter 2008). We consider this variant to be pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076895 SCV000108391 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000627706 SCV000218667 pathogenic Hereditary nonpolyposis colon cancer 2018-12-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln288Valfs*10) 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 an individual affected with Lynch syndrome (PMID: 16619239, 18602922). ClinVar contains an entry for this variant (Variation ID: 91376). 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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