Splice site mutations in mismatch repair genes and risk of cancer in the general population.

We tested the hypothesis that splice site variations in MSH2 and MLH1 are associated with increased risk of hereditary non-polyposis colorectal cancer (HNPCC) and of cancer in general in the general population. In a cohort of 154 HNPCC patients with sequenced MSH2 and MLH1, we identified four possible splice-site mutations, which we subsequently genotyped in more than 9,000 individuals from the general population. Allele frequencies in the general population were 0 % for 942+3A>T in MSH2, 0.05 % for 307-19A>G, 0.005 % for 1,667+(2-8)del(taaatca);ins(attt), and 4.4 % for 1039-8T>A in MLH1. Odds ratios for HNPCC in a case-control design were 419 (95 % CI: 53-18,900) for 942+3A>T in MSH2, 19 (5-72) for 307-19A>G, 194 (21-1,768) for 1,667+(2-8)del(taaatca); ins(attt), and 0.3 (0.1-0.7) for 1,039-8T>A in MLH1. In the general population, incidence rate ratios for 1,039-8T>A carriers versus noncarriers were 0.70 (0.51-0.96) for HNPCC-related cancers combined and 0.82 (0.71-0.94) for all cancers combined in a prospective design. The three rare mutations were associated with increased risk of HNPCC. In contrast, the more common 1,039-8T>A associated with a decreased risk of HNPCC, of HNPCC-related cancers and of all cancers combined in the general population. These findings are novel and important in the counseling of HNPCC patients and their relatives.