Complex genetic predisposition to cancer in an extended HNPCC family with an ancestral hMLH1 mutation

J Med Genet. 1996 Aug;33(8):636-40. doi: 10.1136/jmg.33.8.636.


Hereditary non-polyposis colorectal cancer (HNPCC) is characterised by a genetic predisposition to develop colorectal cancer at an early age and, to a lesser degree, cancer of the endometrium, ovaries, urinary tract, and organs of the gastrointestinal tract other than the colon. In the majority of families the disease is linked to mutations in one of the two mismatch repair genes, hMSH2 or hMLH1. We have found a novel hMLH1 nonsense mutation in a Swiss family with Lynch syndrome, which has been transmitted through at least nine generations. A different tumour spectrum of neoplasms of the skin, soft palate, breast, duodenum, and pancreas was observed in three branches of this family, where there was a virtual absence of colonic tumours. The hMLH1 mutation could not be detected in members of these branches suggesting that at least a second genetic defect predisposing to cancer is segregating in part of the kindred.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Carrier Proteins
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • DNA
  • DNA Mutational Analysis
  • Female
  • Genetic Predisposition to Disease
  • Genetics
  • Germ-Line Mutation / genetics*
  • Humans
  • Male
  • Microsatellite Repeats / genetics
  • Middle Aged
  • MutL Protein Homolog 1
  • Neoplasm Proteins / genetics*
  • Nuclear Proteins
  • Pedigree
  • Point Mutation / genetics*
  • Switzerland


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • DNA
  • MutL Protein Homolog 1