The infrequent combination of MSI‐H with POLE EDM led us to investigate the clinical significance of this association. Only 1/23 (4%) tumours with non‐EDM showed these genomic alterations, indicating that a large majority of mutations outside the exonuclease domain are not pathogenic. A scoring system to assess these alterations (POLE‐score) was developed based on their scores, 7/18 (39%) additional tumours with EDM were classified as POLE‐ultramutated ECs, and the six POLE mutations present in these tumours were considered pathogenic. Of these, 41 had one of five known pathogenic POLE exonuclease domain mutations (EDM) and showed characteristic genomic alterations: C>A substitution > 20%, T>G substitutions > 4%, C>G substitutions 100 mut/Mb. To address this, we examined base changes, tumour mutational burden (TMB), DNA microsatellite instability (MSI) status, POLE variant frequency, and the results from six in silico tools on 82 ECs with whole‐exome sequencing from The Cancer Genome Atlas (TCGA). However, clinical implementation of this classifier requires systematic evaluation of the pathogenicity of POLE mutations. Pathogenic somatic missense mutations within the DNA polymerase epsilon ( POLE) exonuclease domain define the important subtype of ultramutated tumours (‘ POLE‐ultramutated’) within the novel molecular classification of endometrial carcinoma (EC).
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