Pitfalls in molecular analysis for mismatch repair deficiency in a family with biallelic pms2 germline mutations

Clin Genet. 2011 Dec;80(6):558-65. doi: 10.1111/j.1399-0004.2010.01608.x. Epub 2011 Jan 13.


Heterozygous germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause Lynch syndrome. Biallelic mutations in the MMR genes are associated with a childhood cancer syndrome [constitutional mismatch repair deficiency (CMMR-D)]. This is predominantly characterized by hematological malignancies and tumors of the bowel and brain, often associated with signs of neurofibromatosis type 1 (NF1). Diagnostic strategies for selection of patients for MMR gene analysis include analysis of microsatellite instability (MSI) and immunohistochemical (IHC) analysis of MMR proteins in tumor tissue. We report the clinical characterization and molecular analyses of tumor specimens from a family with biallelic PMS2 germline mutations. This illustrates the pitfalls of present molecular screening strategies. Tumor tissues of five family members were analyzed for MSI and IHC. MSI was observed in only one of the analyzed tissues. However, IHC analysis of brain tumor tissue of the index patient and his sister showed absence of PMS2 expression, and germline mutation analyses showed biallelic mutations in PMS2: p.Ser46IIe and p.Pro246fs. The same heterozygous mutations were confirmed in the father and mother, respectively. These data support the conclusion that in case of a clinical phenotype of CMMR-D, it is advisable to routinely combine MSI analysis with IHC analysis for the expression of MMR proteins. With inconclusive or conflicting results, germline mutation analysis of the MMR genes should be considered after thorough counselling of the patients and/or their relatives.

Publication types

  • Case Reports

MeSH terms

  • Adenosine Triphosphatases / genetics*
  • Adult
  • Aged, 80 and over
  • Brain Neoplasms / diagnosis
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Child
  • DNA Mismatch Repair
  • DNA Repair Enzymes / genetics*
  • DNA Repair-Deficiency Disorders / genetics
  • DNA-Binding Proteins / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genetic Testing
  • Germ-Line Mutation*
  • Heterozygote
  • Humans
  • Immunohistochemistry
  • Male
  • Microsatellite Instability
  • Middle Aged
  • Mismatch Repair Endonuclease PMS2
  • MutS Homolog 2 Protein / genetics
  • Neoplastic Syndromes, Hereditary / diagnosis
  • Neoplastic Syndromes, Hereditary / genetics
  • Pedigree


  • DNA-Binding Proteins
  • Adenosine Triphosphatases
  • PMS2 protein, human
  • MSH2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • MutS Homolog 2 Protein
  • DNA Repair Enzymes