title: Genetic testing is important in families with a history suggestive of hereditary non-polyposis colorectal cancer even if the Amsterdam criteria are not fulfilled.
abstract: BACKGROUND
  Clinical screening is still the first-line approach to identification of families with hereditary non-polyposis colorectal cancer (HNPCC). The need for uniformity of diagnosis of the syndrome, particularly in multicentre studies, led to the establishment of a set of minimum diagnostic criteria, the 'Amsterdam criteria'. It is now known that HNPCC is caused by germline defects in the human mismatch repair genes and DNA predictive testing is possible. Defects in two of the known mismatch repair genes, namely hMSH2 and hMLH1, account for over 90 per cent of mutations found in HNPCC families.
  
  
  METHODS
  Ten families were identified with pedigrees suggestive of HNPCC (that is with a possible dominant inheritance of HNPCC), but in which the Amsterdam criteria were not fulfilled. Using the technique of single-strand conformational polymorphism analysis, samples were screened from an affected member of each of these ten kindreds for germline mutations in the genes hMSH2 and hMLH1.
  
  
  RESULTS
  Mutations were identified in six families. Of these, there were three missense, one nonsense, one frameshift and one putative splice-site mutation. Three of the mutations were in hMSH2 and three in hMLH1.
  
  
  CONCLUSIONS
  This study demonstrates that all families with a pedigree suggestive of HNPCC should be referred to a geneticist even if the Amsterdam criteria are not fulfilled. A knowledge of the gene carrier status enables targeted surveillance and the possibility of early surgical intervention that could be curative.
authors.affiliation: Cancer Genetics and Immunology Laboratory, John Radcliffe Hospital, Oxford, UK.
authors.forename: N E
authors.initials: NE
authors.lastname: Beck
authors.forename: I P
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: T
authors.initials: T
authors.lastname: Homfray
authors.forename: S V
authors.initials: SV
authors.lastname: Hodgson
authors.forename: C J
authors.initials: CJ
authors.lastname: Harocopos
authors.forename: W F
authors.initials: WF
authors.lastname: Bodmer
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree