Background: Pathogenic POLE (pPOLE) variants interfere with the exonuclease activity of POLε during DNA replication, resulting in somatic ultramutation and conferring susceptibility to ICI. Historical classification of pPOLE relies on localization to the exonuclease domain (ED). We present the landscape of pPOLE variants in CRC according to a proposed phenotypic classification model. Methods: Comprehensive genomic profiling was performed on tissue (TBx) and liquid (LBx) biopsies during the course of clinical care. A POLE-specific variant classification model including tumor mutational burden (TMB), mutational signatures, and germline frequency was used to differentiate pPOLE from benign POLE (bPOLE) variants. Results:POLE variant status was evaluated in 455,965 TBx and 41,804 LBx pan-tumor. POLE alterations, including pPOLE and variants of unknown significance, were detected in 3.9% of samples with 7,404 discrete alleles observed. After applying the classification model, 30 variants were classified as pPOLE, representing 3.6% (751/20,601) of observed POLE variants. All pPOLE were localized to the ED and a majority were missense substitutions (29/30). There were an additional 620 ED variants categorized as bPOLE. CRC had the second highest prevalence of pPOLE variants (0.5%, 302/60,547). pPOLE variants were associated with ultramutation in CRC where the median tissue TMB was 183.0 mut/Mb, 1-2 orders of magnitude higher than for CRC harboring bPOLE variants (7.8 mut/Mb) or without POLE variants (3.5 mut/Mb). 32.2% of pPOLE CRC also had evidence of high microsatellite instability (MSI-H). Combined pPOLE + MSI-H was associated with markedly elevated TMB compared to either signature alone (344.4 versus 53.1 and 151.3 mut/Mb for bPOLE + MSI-H and pPOLE + MS-Stable, respectively). A small minority of CRC tumors with pPOLE variants (7/298, 2.3%) had low TMB (<10 mut/Mb). However, this was associated with a low pPOLE variant allele frequency (VAF; median 2.8% versus 24.0% for tumors w/ TMB ≥10, p < .0001) pointing to low tumor purity and likely an underestimation of TMB. While targetable alterations (e.g., homologous recombination repair [HR] gene variants) were enriched in pPOLE tumors, these tumors had a low rate of HR deficiency (HRD) as determined by a computational algorithm (HRDsig), suggesting these are likely incidental monoallelic variants. Conclusions: A POLE phenotype-specific classification model identified pPOLE variants associated with ultramutation in CRC. Co-occurrence of pPOLE and MSI-H in CRC is common and has a synergistic effect leading to even higher TMB. We hypothesize that pPOLE detection predicts ultramutation and response to ICI even when TMB is under-detected due to low tumor purity. Caution is advised for therapy selection based on co-alterations in the setting of pPOLE due to an abundance of incidental variants.