Mutation deep within an intron of MSH2 causes Lynch syndrome

Fam Cancer. 2011 Jun;10(2):297-301. doi: 10.1007/s10689-011-9427-0.


Lynch syndrome, a heritable form of cancer predisposition, is caused by germline mutations within genes of the DNA mismatch repair family, and can be rapidly identified in young onset cancer patients through the detection of loss of expression of at least one of these genes in tumour samples. To date, such causative mutations have only been identified within exonic and splice site regions. Though this approach has been successful in the majority of families, a considerable number remain in which no mutation has been found. To address this situation, we used an alternative mutation discovery procedure which involved haplotype analysis of the locus containing the gene lost in the tumour and delineation of segregating haplotypes, followed by an investigation of splicing aberrations to uncover cryptic splice sites which lay outside the genomic regions routinely examined for mutations. In this report, we show that an intronic mutation 478 bp upstream of exon 2 in the MSH2 gene causes Lynch syndrome through creation of a novel splice donor site with subsequent pseudoexon activation, thus highlighting the need for more extensive sequencing approaches in families where routine procedures fail to find a mutation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adolescent
  • Adult
  • Aged
  • Child
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Humans
  • Introns*
  • Middle Aged
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein / genetics*
  • Mutation*
  • Nuclear Proteins / genetics


  • Adaptor Proteins, Signal Transducing
  • MLH1 protein, human
  • Nuclear Proteins
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein