POLE and mismatch repair cancer syndrome 1: Pediatric GBMs with CMMRD exhibit ultra-high nonsynonymous mutations (>250/Mb) because of the complete ablation of two replication repair mechanisms, a biallelic germline MMR deficiency, and a somatically acquired proofreading defect in replicating DNA polymerase, most commonly in the POLE gene (Shlien et al. 2015; Campbell et al. 2017).