Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes

Hum Mutat. 2010 May;31(5):588-93. doi: 10.1002/humu.21230.


Germline mutation detection in PMS2, one of four mismatch repair genes associated with Lynch syndrome, is greatly complicated by the presence of numerous pseudogenes. We used a modification of a long-range PCR method to evaluate PMS2 in 145 clinical samples. This modification avoids potential interference from the pseudogene PMS2CL by utilizing a long-range product spanning exons 11-15, with the forward primer anchored in exon 10, an exon not shared by PMS2CL. Large deletions were identified by MLPA. Pathogenic PMS2 mutations were identified in 22 of 59 patients whose tumors showed isolated loss of PMS2 by immunohistochemistry (IHC), the IHC profile most commonly associated with a germline PMS2 mutation. Three additional patients with pathogenic mutations were identified from 53 samples without IHC data. Thirty-seven percent of the identified mutations were large deletions encompassing one or more exons. In 27 patients whose tumors showed absence of either another protein or combination of proteins, no pathogenic mutations were identified. We conclude that modified long-range PCR can be used to preferentially amplify the PMS2 gene and avoid pseudogene interference, thus providing a clinically useful germline analysis of PMS2. Our data also support the use of IHC screening to direct germline testing of PMS2.

MeSH terms

  • Adenosine Triphosphatases / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • DNA Mutational Analysis
  • DNA Repair Enzymes / genetics*
  • DNA-Binding Proteins / genetics*
  • Germ-Line Mutation / genetics
  • Humans
  • Mismatch Repair Endonuclease PMS2
  • Pseudogenes / genetics


  • DNA-Binding Proteins
  • Adenosine Triphosphatases
  • PMS2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • DNA Repair Enzymes