Context:Sixty to 80% of multiple endocrine neoplasia type 1 (MEN1) patients develop pancreatic neuroendocrine neoplasias (pNENs), which reveal an aggressive behavior in 10%-20% of patients. Causative MEN1 mutations in the interacting domains of the encoded Menin protein directly alter its regulation abilities and may influence the phenotype.Objective:The objective of the study was the evaluation of an association between MEN1 mutations in different interacting domains of Menin and the phenotype of pNENs.Design:This was a retrospective analysis of a prospectively collected cohort of 71 genetically confirmed MEN1 patients at a tertiary referral center.Main Outcome Measures:Analysis of patients' characteristics and clinical phenotype of pNENs regarding the mutation type and its location in Menin interacting domains was measured.Results:Sixty-seven patients (93%) developed pNENs after a median follow-up of 134 months. Patients with mutations leading to loss of interaction (LOI) with the checkpoint kinase 1 (CHES1) interacting domain codons (428–610) compared with patients with mutations resulting in LOI with other domains (eg, JunD, Smad3) had significantly higher rates of functioning pNENs (70% vs 34%), malignant pNENs (59% vs 16%), and aggressive pNENs (37% vs 9%), respectively. Patients with CHES1-LOI also had an increased pNEN-related mortality (20% vs 4.5%). Neither gender, age, nor the ABO blood types were associated with the phenotype of pNENs.Conclusions:MEN1 patients with MEN1 mutations leading to CHES1-LOI have a higher risk of malignant pNENs with an aggressive course of disease and disease-related death.