For example, central nervous system tumors with rare pLoF mutations in the DNA mismatch repair genes MSH2 and MLH1 exhibited significantly increased global mutation rates across 213 targeted sequenced genes (MSH2: mean 30.1 mutations in carriers versus 3.0 in non-carriers; P = 3.8×10−7, one-sided Mann–Whitney U-test; MLH1: mean 35.3 mutations in carriers versus 3.1 in non-carriers; P = 8.8×10−6, one-sided Mann–Whitney U-test). Here, MLH1 is linked to central nervous system cancer.