M. Genuardi et al., Assessment of pathogenicity criteria for constitutional missense mutationsof the hereditary nonpolyposis colorectal cancer genes MLH1 and MSH2, EUR J HUM G, 7(7), 1999, pp. 778-782
To determine the role played by MLH1 and MSH2 missense variants in cancer s
usceptibility, we have investigated the following genetic and biological ch
aracteristics associated with six MLH1 and four MSH2 missense changes ident
ified in Italian hereditary nonpolyposis colorectal cancer (HNPCC) families
: co-segregation with disease phenotype and/or bona fide pathogenetic mutat
ions; presence of the variant in healthy control subjects; evolutionary con
servation of the involved aminoacid and type of aminoacid change; and prese
nce/absence of microsatellite instability (MSI) in tumour DNA, Overall, nin
e variants did not fulfil greater than or equal to 2 pathogenicity criteria
. MSI was investigated in tumour samples from carriers of nine different mi
ssense mutations. Only 3/9 variants were associated with MSI in tumour DNA,
In addition, four variants were not present in affected pedigree members,
and five variants were observed in the control population. Based upon these
results, we conclude that most MLH1 and MSH2 missense changes are unlikely
to act as major causative factors in colorectal cancer susceptibility and
development.