DNA polymerase epsilon (POLe) is the leading strand replicative polymerase. POLe mutations located primarily in the proofreading domain cause replication errors and increase mutation burden in cancer cells. Consequently, POLe has been classified as a cancer driver gene. Certain POLe frameshift mutations that affect the proofreading domain are purified in cancer cells, but point mutations in other domains have also been reported. Here we use an artificial intelligence algorithm to determine what other mutations co-occur with POLe mutations in colorectal cancers. We partitioned POLe mutations into driver, passenger, and WT (no mutation), then assessed mutations in other genes in these three groups. We found that a driver POLe mutation is not likely to associate with driver mutations in other genes. Thus, driver mutations in colorectal cancers appear to purify in a manner that is independent of POLe. Mutations that affect POLe function do not necessarily increase the frequency of driver mutations in other genes. Structural analysis shows that many POLe driver mutations affect coordination of the Mg²⁺ ion in the active site. Our data show that the accumulation of colorectal cancer mutations is driven by complex factors.