Our results now show that the ultra-mutator phenotype is shared by other yeast Pol ε EDM alleles orthologous to cancer-associated Pol ε mutations, most notably pol2-M459K (human POLE M444K), and that increased mutation accumulation in pol2-ultra cells compared to pol2–4 cells also occurs in the absence of MMR activity, strongly suggesting that differential repair of mismatches is not a major source of hypermutation. Here, POLE is linked to cancer.