This multicenter retrospective study defines the population of patients with pancreatic cysts whose outcomes benefit most from the molecular testing that is part of PancraGEN and PanDNA. The incremental predictive value of molecular testing was evaluated in a patient cohort who had clinically characterized high-risk stigmata (HRS), worrisome features (WFs), or the lack thereof. The probability that patients would remain cancer-free based on these clinical characteristics was examined. These patient groups were further risk-stratified by results of DNA analysis that examined 3 key DNA abnormalities: i) loss of heterozygosity mutations among a panel of tumor suppressor genes; ii) Kras mutation; and iii) elevated DNA quantity. These 3 key DNA abnormalities provided the most significant incremental risk stratification to patients with WFs. Among patients with WFs, the presence of multiple DNA abnormalities significantly increased malignancy risk (relative risk, 5.2; P=0.002) and the absence of all DNA abnormalities significantly decreased risk (relative risk, 0.4; P=0.040).