Background: Primary CNST demonstrate remarkable intra-tumoral and inter-tumoral heterogeneity contributing to therapeutic resistance. We report implementation of a PMRP for patients with primary CNST. Methods: An Institutional Review Board approved prospective registration protocol was activated in September 2014 as a data repository for cancer patients undergoing genomic evaluation. NGS profiling of CNST was performed using a 68-gene alteration panel. Mutations (M) were classified as Actionable (approved clinical indication), Applicable (clinical trials or off-label indication) and Unknown significance. Results: As of December 2015, sequencing was completed on 98 primary CNST. Diagnoses included glioblastoma (51), anaplastic glioma (25), low-grade glioma (7), neuronal-glial tumors (4), DLBCL (3), medulloblastoma (3), ependymoma (1), hemangiopericytoma (1), meningioma (2), pituitary adenoma (1). Mutations were identified in 97% of cases. 308 M were identified: 0 Actionable, 128 (42%) Applicable, and 180 (58%) of Unknown significance. The most common Applicable M included: TP53 (33), IDH1 (31), PTEN (14), TYMS (10), EGFR (8), TPMT (8), PIK3CA (6), BRAF (3), APC (2), CDKN2A (2), MYD88 (2), TET2 (2), KRAS (2) ATM (1), DPYD (1), IDH2 (1), JAK3 (1), and RET (1). The number of Applicable M in each case was: 0 (20%), 1 (38%), 2 (27%), 3 (10%), 4 (1%), 5 (1%). Impact of NGS testing was assessed: new therapy started (3%), declined off-label treatment option (1%), no actionable information (26%), stable on current therapy (58%), transitioned to hospice (7%). Clinical decisions were impacted by lack of evidence to change the treatment plan (36%) and off-label access and insurance coverage (68%). Conclusions: Primary CNST demonstrate a significant number of actionable mutations associated with sensitivity to targeted inhibitors along the PI3K/AKT/mTOR, EGFR, CDK, and BRAF pathways amongst others and matching to clinical trial therapies. CNST represent a unique opportunity for investigation of targeted therapies, however access to such therapies remains a barrier.