Background: CGP through Next-Generation Sequencing (NGS) has substituted single-gene testing to identify more druggable gene aberrations. The simultaneous detection of broad spectrum predictive biomarkers and molecular signatures including tumor mutational burden (TMB), microsatellite instability (MSI) burden, somatic BRCA, homologous recombination repair genes (HRR) and RNA variants by CGP provides a more cost efficient and tissue-preserving approach than serial single-biomarker analyses. Methods: 750 biopsy proven patients of various cancer spectrum at HCG cancer center were consented and profiled using Illumina TruSight Oncology 500 (TSO500) assay that interrogates 523 cancer-related genes on NextSeq in an IRB-approved prospective study. The findings were discussed in molecular tumor board (MTB) and recommendations from treating physicians were documented in patient records for change in clinical management and follow up. Results: A total of 1291 genomic alterations were detected in 750 cases (mean 1.7 mutations/sample). CGP identified genetic alterations with therapeutic and prognostic implications in 77% patients (Tier I- 34%, Tier II-64%, Tier III-14%). CGP revealed higher number of druggable genes (47%) than small panels (14%).Tumor agnostic markers for immunotherapy (IO) were observed in 20% of the current cohort, based on which IO was initiated and are on follow up. In 20% of the cohort, HRR pathway alterations including sBRCA (7%) were detected providing an option to treat with platinum or PARP inhibitors. Other significant alterations like EGFR, RAS/RAF, ERBB2, PIK3CA, cKIT, PDGFRA, ARID1A, ARID2, POLE, and FGFR were found. RNA sequencing yielded 54 RNA alterations (38 translocations and 16 splice variants). Androgen receptor splice variants were observed in 50% prostate carcinoma patients for whom taxane therapy was initiated. Other frequent fusions detected were: TMPRSS-ERG, RPS6KB1-VMP1, EML4-ALK,NTRK, PDGFRA and EWSR. Conclusions: CGP reports actionable and prognostic genetic alterations in 77% of patients who could potentially benefit by tumor-matched targeted and immunotherapy. Post MDT patients were assigned to approved therapies (5-80%) or change in clinical management (5-25%) based on the cancer type (Table). 25% patients were enrolled for investigator initiated clinical trials and are on follow up for clinical outcome and analysis of independent prognostic and therapeutic value of novel biomarkers in a larger cohort of Indian patient.