11599 Background: Immune checkpoint inhibitors have therapeutic benefit in the treatment of various cancers; however, an elucidation of the molecular determinants of response to such therapy is needed. A high nonsynonymous mutation burden in tumors is associated with improved response to checkpoint blockade. In this study we determined the relationship of several altered genes/pathways in solid tumor samples that appeared to be significantly mutated (SM). Methods: Comprehensive genomic profiling was performed on 374 advanced solid tumor samples. Targeted sequencing was performed on 562 cancer associated genes, and analysis of matched tumor-normal DNA was performed to filter out germline variants and identify true somatic mutations. Samples with greater than 17 mutations were considered SM based on extrapolation from other reports and considering the number of genes interrogated by our panel. Results: Our analysis revealed that 13% (48/374) of tumors were significantly mutated, exhibiting 17 or greater nonsynonymous mutations occurring in a wide variety of solid tumors including but not limited to lung, CRC and melanoma. Over 90% of mutations were either frameshift, missense or splice site alterations, which may result in tumor-specific neoantigens and increased amounts of tumor-infiltrating lymphocytes (TILs). Loss of function mutations in MMR genes indicative of MMR deficiency which has been associated with increased response to immune checkpoint blockade were present in 21% (10/48) of SM cases. Mutations in polymerase e (POLE), indicative of high neoantigen load, were identified in 17% (8/48) of SM cases. Genes in SWI/SNF pathway were mutated in 65% (31/48) of SM cases, which included loss of function mutations in ARID1A. Mutations in DNA repair genes, including homologous recombination, base excision and nucleotide excision repair pathway, were noted in over half of the cases with the hypermutant phenotype. Conclusions: Our findings suggest that 13% of solid tumors have high nonsynonymous mutation burden which may be associated with benefit from checkpoint inhibitor therapy. Targeted gene panel sequencing may identify significantly mutated cases that are potential candidates for clinical trials with immune-therapeutics.