Background: Whole exome sequencing in WD pNETs demonstrated an increased number of mutations in chromatin modeling genes (MEN1, DAXX, and ATRX), and in the mTOR pathway. NGS brings this technology to the clinic but its relevance in practice has been questioned. In this prospective, IRB-approved study (NCT01775072), we used the MSK-IMPACT assay to perform NGS on WD pNETs in a routine practice setting. MSK-IMPACT, performed in a CLIA-compliant laboratory, is a multiplexed assay (Illumina HiSeq) providing full exon coverage of 410 cancer related genes, detecting base substitutions, small indels, copy number and select gene rearrangements. Methods: After written consent, tumor and germline DNA were analyzed. Genomic alterations were catalogued. Results: MSK-IMPACT results are available in 44 patients (pts). Actionable alterations were identified in 19/44 pts (43.2%). These actionable alterations included BRAF V600E (1 pt; 2.3%), and mutations in TSC1 (1 pt; 2.3%), TSC2 (7 pts; 15.9%), PTEN (5 pts; 11.4%), CDKN1B (2 pts; 4.5%), CDKN2A (4 pts; 9.1%), CDKN2B (4 pts; 9.1%), CDKN2C (1 pt; 2.3%), and ARID1A (6 pts; 13.6%). Other recurrently altered genes included MEN1 (27 pts, 61.4%), DAXX (18 pts, 40.9%), and ATRX (11 pts, 25.0%). Notably, 9 pts (20.5%) had alterations in the histone methyltransferase SETD2. All 9 pts presented with metastatic liver disease. 1/9 (11.1%) tumors were low grade; 6/9 (66.7%) were intermediate grade and 2/9 (22.2%) were high grade. All 9 pts received alkylating agents (temozolomide or dacarbazine); 8 pts (88.9%) had disease shrinkage and 1 pt (11.1%) had stable disease. Conclusions: The mutational landscape in our study was in line with prior work in pNET whole exome sequencing. In almost half of our cohort, potentially actionable alterations were identified through NGS but have not yet been shown to be therapeutically relevant. In addition, we report a novel finding of SETD2 alterations in pNETs. Most pts with SETD2 alterations had intermediate to high grade tumors and all pts responded to alkylating agents. Investigation is ongoing to clarify the relevance of the alterations identified through MSK-IMPACT and the clinical significance of SETD2 in WD pNETs.