For the five most common POLE mutations (P286R, V411L, S297F, A456P, and S459F), pathogenicity (in this sense meaning causal for tumor ultramutation) has been confirmed (18); however, the classification of other, less frequent POLE variants is currently challenging and variants of unknown significance (VUS) include the following: A465V, L424V, T278M, and A428T (18). Here, POLE is linked to neoplasm.