ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.802dup (p.Tyr268fs) (rs267608149)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076888 SCV000108384 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000815163 SCV000955610 pathogenic Hereditary nonpolyposis colon cancer 2018-12-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr268Leufs*31) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs267608149, ExAC 0.007%). This variant has been observed in an individual affected with colorectal cancer (PMID: 18602922). This variant is also known as c.802_803insT in the literature. ClinVar contains an entry for this variant (Variation ID: 91369). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000076888 SCV000966983 pathogenic Lynch syndrome 2017-12-14 criteria provided, single submitter clinical testing The p.Tyr268fs variant in PMS2 has been reported in at least 1 individual with P MS2-associated cancer and absence of PMS2 by IHC in the tumor (Senter 2008, Rost y 2016). It was also identified in 1/30264 South Asian and 1/110626 European chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut e.org). This variant is predicted to cause a frameshift, which alters the protei n?s amino acid sequence beginning at position 268 and leads to a premature termi nation codon 31 amino acids downstream. This alteration is then predicted to lea d to a truncated or absent protein. Heterozygous loss of function of the PMS2 ge ne is an established disease mechanism in Lynch syndrome. In addition, this vari ant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved In SIGHT expert panel (ClinVar SCV000108384.2). In summary, this variant meets crit eria to be classified as pathogenic for Lynch syndrome in an autosomal dominant based upon predicted impact on protein. ACMG/AMP Criteria applied: PVS1, PM2, PP 4.

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