The putative mutations might include (1) point mutations in the PMS2 gene that are known to have a lower cancer risk (Truninger et al, 2005; Worthley et al, 2005; Hendriks et al, 2006); (2) germline methylation of the MSH2 promoter as was recently described (Chan et al, 2006); (3) mutations in regulatory sequences or missence variants that might lead to a lower risk of tumour development in relatives because the complete inactivation of the affected MMR gene might be more dependent on modifier genes; and (4) a type of mutation that frequently arises de novo. The gene discussed is MSH2; the disease is cancer.