POLE and central nervous system cancer: In line with increasing evidence that variants outside of the exonuclease domain can also cause hypermutation [11, 44, 45], a TMB higher than 2.6 mut/Mb, the median of 10,294 gliomas according to Touat et al. [32], was detected in all 14 glioma DNAs from 10 POLE/POLD1 variant carriers analyzed here, three of which were definitely hypermutated (TMB > 17 mut/Mb [32]).