HNPCC mutation MLH1 P648S makes the functional protein unstable, and homozygosity predisposes to mild neurofibromatosis type 1

Genes Chromosomes Cancer. 2004 Jul;40(3):261-5. doi: 10.1002/gcc.20040.


Heterozygous germ-line mutations in DNA mismatch repair (MMR) genes predispose individuals to hereditary nonpolyposis colorectal cancer (HNPCC), whereas with homozygous MMR gene mutations children are diagnosed at an early age with de novo neurofibromatosis type 1 (NF1) and/or hematological malignancies. Here, we describe a mutation, MLH1 P648S, which was found in a typical HNPCC family, with one homozygous child displaying mild features of NF1 and no hematological cancers. To evaluate the pathogenicity of the mutation, we studied both the expression and the function of the mutated protein. It generally has been assumed that the predisposing mutations prevent the production of a functional protein. The mutated MLH1 P648S protein was found to be unstable but still functional in mismatch repair, suggesting that the cancer susceptibility in the family and possibly also the mild disease phenotype in the homozygous individual are linked to shortage of the functional protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Substitution / genetics
  • Amino Acid Substitution / physiology*
  • Carrier Proteins
  • Cell Line, Tumor
  • Child
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Germ-Line Mutation / genetics
  • Germ-Line Mutation / physiology*
  • HCT116 Cells
  • Homozygote
  • Humans
  • Male
  • MutL Protein Homolog 1
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / physiology*
  • Neurofibromatosis 1 / genetics*
  • Nuclear Proteins
  • Proline / genetics
  • Proline / physiology*
  • Serine / genetics
  • Serine / physiology*


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