Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation

Hum Mutat. 2007 Nov;28(11):1084-90. doi: 10.1002/humu.20569.


Since the first report by our group in 1999, more than 20 unrelated biallelic mutations in DNA mismatch repair genes (MMR) have been identified. In the present report, we describe two novel cases: one carrying compound heterozygous mutations in the MSH6 gene; and the other, compound heterozygous mutations in the PMS2 gene. Interestingly, the inactivation of one PMS2 allele was likely caused by gene conversion. Although gene conversion has been suggested to be a mutation mechanism underlying PMS2 inactivation, this is the first report of its involvement in a pathogenic mutation. The clinical features of biallelic mutation carriers were similar to other previously described patients, with the presence of café-au-lait spots (CALS), early onset of brain tumors, and colorectal neoplasia. Our data provide further evidence of the existence, although rare, of a distinct recessively inherited syndrome on the basis of MMR constitutional inactivation. The identification of this syndrome should be useful for genetic counseling, especially in families with atypical hereditary nonpolyposis colon cancer (HNPCC) associated with childhood cancers, and for the clinical surveillance of these mutation carriers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics*
  • Adult
  • Base Pair Mismatch
  • Base Sequence
  • Brain Neoplasms / genetics
  • Colorectal Neoplasms / genetics
  • DNA Primers
  • DNA Repair / genetics
  • DNA Repair Enzymes / genetics*
  • DNA-Binding Proteins / genetics*
  • Female
  • Gene Conversion*
  • Gene Silencing*
  • Genetic Carrier Screening
  • Humans
  • Male
  • Mismatch Repair Endonuclease PMS2
  • Mutation*
  • Pedigree
  • Pigmentation Disorders / genetics


  • DNA Primers
  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • Adenosine Triphosphatases
  • PMS2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • DNA Repair Enzymes