Phenotypic POLE variant classification identifies patients who may have favorable prognosis and benefit from immunotherapy

Pathogenic POLE mutations (pPOLE) undermine mismatch error correction by POLε during DNA replication and resulting somatic ultramutation predicts response to immunotherapy. Beyond frequently recurrent alleles, historical pPOLE classification has been largely based on exonuclease domain localization. A POLE-specific phenotypic classification model was developed encompassing tumor mutational burden (TMB), mutational signatures, germline frequency, and consideration of co-mutation with other POLE mutations to identify pPOLE.