The phenotypic expression of three MSH2 mutations in large Newfoundland families with Lynch syndrome

Fam Cancer. 2007;6(1):1-12. doi: 10.1007/s10689-006-0014-8.


To compare the phenotypic expression of three different MSH2 mutations causing Lynch syndrome, 290 family members at 50% risk of inheriting a mutation were studied. Two truncating mutations of the MSH2 gene have been identified in Newfoundland: an exon 8 deletion in five families (N=74 carriers) and an exon 4-16 deletion in one family (N=65 carriers). The third mutation was an intron 5 splice site mutation resulting in deletion of exon 5 in RNA and occurred in 12 families (N=151 carriers). Age to onset of first cancer, first colorectal cancer (CRC), first extracolonic cancers and death were compared. By age 60, 89% of family members with the intron 5 mutation, 81% with the exon 8 deletion, and 85% with the exon 4-16 deletion had developed cancer. For all three mutations males had a higher age-related risk of CRC and death compared to females. In the intron 5 splice site mutation carriers, the number of transitional cell cancers of the urinary tract was significantly lower and time to first ovarian cancer was significantly higher than in the carriers of the genomic deletions. The incidence of CRC in MSH2 mutation carriers, exposed to the same environment, is not modified by the specific mutation, although there is a suggestion that type of mutation may influence development of some extracolonic cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor*
  • Causality
  • Colorectal Neoplasms, Hereditary Nonpolyposis / epidemiology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Comorbidity
  • DNA Mutational Analysis
  • Endometrial Neoplasms / epidemiology
  • Endometrial Neoplasms / genetics
  • Female
  • Founder Effect
  • Gene Deletion*
  • Gene Expression
  • Genetic Predisposition to Disease
  • Germ-Line Mutation / genetics
  • Humans
  • Male
  • Middle Aged
  • MutS Homolog 2 Protein / genetics*
  • Newfoundland and Labrador / epidemiology
  • Ovarian Neoplasms / epidemiology
  • Ovarian Neoplasms / genetics
  • Pedigree
  • Phenotype
  • Point Mutation / genetics*
  • Prevalence
  • Rectal Neoplasms / epidemiology
  • Rectal Neoplasms / genetics
  • Risk Factors
  • Sequence Analysis, DNA
  • Sex Distribution


  • Biomarkers, Tumor
  • MSH2 protein, human
  • MutS Homolog 2 Protein