Pathogenic variants in POLE or POLD1 causing defective polymerase proofreading, and pathogenic variants in MMR genes causing defects in MMR can lead to a high TMB, i.e. hypermutation, in the DNA of human tumors, including brain tumors, when they occur in the germline or somatically [9, 11, 31, 33, 40–42]. This evidence concerns the gene POLD1 and brain neoplasm.