Editor—Hereditary non-polyposis colorectal cancer (HNPCC) is a heterogeneous autosomal dominant disease with incomplete penetrance. The frequency is estimated at 1:200/1:1000. HNPCC results from constitutional mutation in one of the five human mismatch repair genes (MMR) that have so far been implicated:hMSH2, hMLH1,hPMS1, hPMS2, andhMSH6.1 2 hMSH2 and hMLH1account for the majority of mutations found in HNPCC families (25-70%). The function of MMR genes is to maintain genetic stability and tumour DNA from HNPCC patients shows an accumulation of replication errors exhibiting an instability phenotype at microsatellite loci (MSI).3 4

Standard criteria have been established to define HNPCC clinically. These are known as the “Amsterdam criteria” and require that at least two generations be affected by colorectal cancer (CRC), that three or more relatives with histologically verified CRC be present, one of whom is a first degree relative of the other two, and at least one case of CRC be diagnosed before the age of 50.5 The syndrome is characterised by synchronous and metachronous CRC tumours and by association of certain types of extracolonic tumours, especially endometrial neoplasia.6

In 45-86% of cases,7 genetic testing characterises the mutation in the index patient for each HNPCC family identified and predicts a possible predisposition to colon and/or related syndrome cancer in at risk subjects of the same kindred. In clinical practice, however, besides HNPCC families, there are families with multiple CRC patients that do not fulfil the Amsterdam criteria, or with a single case of early onset CRC, or with multiple primary tumours. These features can suggest an HNPCC syndrome. In these instances, the percentage of germline mutations of MMR genes is low and the lifetime incidence of colorectal cancer is lower than in Amsterdam families.8 9 …