title: Recurrent germline mutation in MSH2 arises frequently de novo.
abstract: BACKGROUND
  An intronic germline mutation in the MSH2 gene, A-->T at nt942+3, interferes with the exon 5 donor splicing mechanism leading to a mRNA lacking exon 5. This mutation causes typical hereditary non-polyposis colorectal cancer (HNPCC) and has been observed in numerous probands and families world wide. Recurrent mutations either arise repeatedly de novo or emanate from ancestral founding mutational events. The A-->T mutation had previously been shown to be enriched in the population of Newfoundland where most families shared a founder mutation. In contrast, in England, haplotypes failed to suggest a founder effect. If the absence of a founder effect could be proven world wide, the frequent de novo occurrence of the mutation would constitute an unexplored predisposition.
  
  
  METHODS
  We studied 10 families from England, Italy, Hong Kong, and Japan with a battery of intragenic and flanking polymorphic single nucleotide and microsatellite markers.
  
  
  RESULTS
  Haplotype sharing was not apparent, even within the European and Asian kindreds. Our marker panel was sufficient to detect a major mutation arising within the past several thousand generations.
  
  
  CONCLUSIONS
  As a more ancient founder is implausible, we conclude that the A-->T mutation at nt942+3 of MSH2 occurs de novo with a relatively high frequency. We hypothesise that it arises as a consequence of misalignment at replication or recombination caused by a repeat of 26 adenines, of which the mutated A is the first. It is by far the most common recurrent de novo germline mutation yet to be detected in a human mismatch repair gene, accounting for 11% of all known pathogenic MSH2 mutations.
authors.affiliation: Division of Surgical Oncology, The Ohio State University, 410 W 10th Avenue, N-924 Doan Hall, Columbus, OH 43210, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Desai
authors.forename: J C
authors.initials: JC
authors.lastname: Lockman
authors.forename: R B
authors.initials: RB
authors.lastname: Chadwick
authors.forename: X
authors.initials: X
authors.lastname: Gao
authors.forename: A
authors.initials: A
authors.lastname: Percesepe
authors.forename: D G
authors.initials: DG
authors.lastname: Evans
authors.forename: M
authors.initials: M
authors.lastname: Miyaki
authors.forename: S T
authors.initials: ST
authors.lastname: Yuen
authors.forename: P
authors.initials: P
authors.lastname: Radice
authors.forename: E R
authors.initials: ER
authors.lastname: Maher
authors.forename: F A
authors.initials: FA
authors.lastname: Wright
authors.forename: A
authors.initials: A
authors.lastname: de La Chapelle
mesh_terms: D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins; D005192:Family Health; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D051718:MutS Homolog 2 Protein; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D004247:DNA; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein