These proofreading domain mutations in POLE and POLD1 are known to synergize with mismatch repair deficiency to cause a rapid burst of a massive number of substitution mutations causing “ultrahypermutation” of the cancer genome with a characteristic mutational signature that is predominated by C > A:G > T transversions specifically at cytosines with flanking thymine bases (TCT nucleotide sequence) [12, 43]. The gene discussed is POLD1; the disease is mismatch repair cancer syndrome 1.