Diversity of the clinical presentation of the MMR gene biallelic mutations

Fam Cancer. 2014 Mar;13(1):131-5. doi: 10.1007/s10689-013-9676-1.


Constitutional mismatch repair-deficiency, due to biallelic mutations of MMR genes, results in a tumour spectrum characterized by leukaemias, lymphomas, brain tumours and adenocarcinomas of the gastro-intestinal tract, occurring mostly in childhood. We report here two families illustrating the phenotypic diversity associated with biallelic MMR mutations. In the first family, two siblings developed six malignancies including glioblastoma, lymphoblastic T cell lymphoma, rectal and small bowel adenocarcinoma with onset as early as 6 years of age. We showed that this dramatic clinical presentation was due to the presence of two complex genomic PMS2 deletions in each patient predicted to result into complete PMS2 inactivation. In the second family, the index case presented with an early form of Lynch syndrome with colorectal adenocarcinomas at ages 17 and 20 years, and urinary tract tumours at the age of 25 years. We identified in this patient two MSH6 mutations corresponding to a frameshift deletion and an in frame deletion. The latter was not predicted to result into complete inactivation of MSH6. These reports show that the clinical expression of biallelic MMR mutations depends on the biological impact of the second MMR mutation and that, in clinical practice, the presence of a second MMR mutation located in trans should also be considered in patients suspected to present a Lynch syndrome with an unusual early-onset of tumours.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenosine Triphosphatases / genetics*
  • Adolescent
  • Age of Onset
  • Child
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • DNA Mismatch Repair / genetics*
  • DNA Repair Enzymes / genetics*
  • DNA-Binding Proteins / genetics*
  • Female
  • Haplotypes
  • Humans
  • Lymphoma, T-Cell / genetics
  • Male
  • Microsatellite Instability
  • Mismatch Repair Endonuclease PMS2
  • Mutation*
  • Pedigree
  • Rectal Neoplasms / genetics
  • Young Adult


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