Hence, although cell-free experiments show comparable effects of the somatic hotspot POLE mutation p.(Val411Leu) and the recurrent germline mutation p.(Leu424Val) on exonuclease activity [12], the detection of p.(Val411Leu) as a constitutional mutation in this 14-year-old cancer patient suggests that this POLE mutation confers a more severe phenotype than the previously reported POLE and POLD1 germline mutations [3]. The gene discussed is POLE; the disease is cancer.