During the proof reading process, DNA polymerase epsilon (POLE) and DNA polymerase delta (POLD1) have central roles in replicating the leading and lagging DNA strands, respectively.3, 4, 5 Mutations in the exonuclease domain in POLE lead to impaired proofreading function, resulting in massively increased tumor mutation burden (TMB).1, 6, 7. The gene discussed is POLE; the disease is neoplasm.