For the five most common POLE mutations (P286R, V411L, S297F, A456P, and S459F), pathogenicity (in this sense meaning causal for tumour ultramutation) has been confirmed 4, 5, 6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25; however, the classification of other, less frequent POLE variants is currently challenging. Here, POLE is linked to neoplasm.