A large-scale, prospective clinical sequencing initiative using the MSK-IMPACT assay was conducted to profile 10,945 tumors from 10,336 patients with advanced cancer. The study identified clinically relevant somatic mutations, novel non-coding alterations, and mutational signatures across various tumor types. The data, publicly available through the cBioPortal for Cancer Genomics, enabled the discovery of biomarkers and deeper investigation into rare alterations. The study demonstrated the feasibility of large-scale clinical sequencing to guide treatment decisions. Key findings included the high prevalence of TP53 mutations, frequent mutations in genes like KRAS and PIK3CA, and the identification of TERT promoter mutations associated with poor prognosis. The study also highlighted the importance of mutation signatures in predicting response to therapies, including immune checkpoint inhibitors. Additionally, the study found that a significant proportion of patients had actionable mutations, with 36.7% harboring at least one actionable alteration. The results underscore the value of comprehensive genomic profiling in identifying potential therapeutic targets and improving patient outcomes. The study also emphasized the need for broader molecular profiling and novel clinical trial designs to evaluate the efficacy of targeted therapies in diverse cancer types. The data is publicly available for further research and analysis.A large-scale, prospective clinical sequencing initiative using the MSK-IMPACT assay was conducted to profile 10,945 tumors from 10,336 patients with advanced cancer. The study identified clinically relevant somatic mutations, novel non-coding alterations, and mutational signatures across various tumor types. The data, publicly available through the cBioPortal for Cancer Genomics, enabled the discovery of biomarkers and deeper investigation into rare alterations. The study demonstrated the feasibility of large-scale clinical sequencing to guide treatment decisions. Key findings included the high prevalence of TP53 mutations, frequent mutations in genes like KRAS and PIK3CA, and the identification of TERT promoter mutations associated with poor prognosis. The study also highlighted the importance of mutation signatures in predicting response to therapies, including immune checkpoint inhibitors. Additionally, the study found that a significant proportion of patients had actionable mutations, with 36.7% harboring at least one actionable alteration. The results underscore the value of comprehensive genomic profiling in identifying potential therapeutic targets and improving patient outcomes. The study also emphasized the need for broader molecular profiling and novel clinical trial designs to evaluate the efficacy of targeted therapies in diverse cancer types. The data is publicly available for further research and analysis.