Background: Tumor mutation burden (TMB), as measured by whole exome sequencing, has been shown to strongly correlate with objective responses to immune checkpoint inhibition (ICI), in several tumor types. Consequently, the ability to accurately measure TMB, in a clinical setting, may guide patient treatment decisions. We investigate whether TMB can be accurately measured using a comprehensize genomic profiling (CGP) assay targeting several hundred cancer genes (~1.25 Mb). We also describe the landscape of TMB observed from > 60,000 advanced clinical cancer specimens, across > 400 cancer types. Methods: CGP by hybridization capture and high-coverage sequencing (median > 500x) of the full coding regions from 236 or 315 cancer-related genes was performed. Base substitutions, indels, copy number alterations and gene fusion/rearrangements were assessed. TMB was calculated as the number of somatic, coding, base sub. and indel alterations, excluding known driver mutations, per megabase of genome examined. This metric correlates with response to anti-PD-1 in melanoma. Results: We validate that targeted sequencing of 1.25 Mb does provide an accurate measurement of genome-wide TMB. We describe the spectrum of TMB observed across a diversity of tumor types. Lower grade and pediatric malignancies tend to have the lowest TMB ( < 1 mut/MB), while epithelial cancers, associated with environmental DNA damage, were most highly mutated ( > 10 mut/MB). Mutations in mismatch-repair genes (MSH2, MSH6, MLH1, PMS2 and RAD50), DNA replication genes (POLD1, POLE) and TP53BP1 were associated with > 2x increases in TMB, though some specimens with high TMB lacked identifiable causative alterations. Several tumor types, in which ICI are not yet approved, had many cases with high TMB ( > 20 mut/MB), including intestinal type stomach adenocarcinoma (20%), and uterine endometrial adenocarcinoma (16%). Conclusions: These data demonstrate that TMB can be accurately assessed using a clinically available CGP assay, allowing assessment for current patients. Examining the landscape of TMB across a diversity of tumor types provides new data to expand the population that can potentially benefit from immunotherapy.