Background: The germline I1307K mutation in the adenomatous polyposis coli (APC) gene is a well-known alteration identified in approximately 6% of the Ashkenazi Jewish population. This mutation confers an increased risk of developing colorectal and other cancers. We previously reported high prevalence of aggressive variant prostate cancer (AVPC) in patients with the germline APC (I1307K) mutation. Herein, we report a larger case control analysis evaluating the hypothesis that AVPC is enriched in these patients. Methods: We reviewed records from New York University, Johns Hopkins University and Sheba Medical Center to identify patients with the APC (I1307K) mutation. Eligibility criteria included the identification of the mutation either on germline or somatic tissue testing (when germline testing was not available). AVPC was defined using previously established criteria. Combined somatic alterations in two or more of following genes were assessed: RB1, TP53, PTEN. These somatic alterations have been previously associated with AVPC. We compared cases with 21 controls with APC frameshift mutations. For categorical variables, the odds ratios (OR) for cases compared to controls are provided with 95% confidence intervals (CI). Continuous variables were summarized with descriptive statistics and compared between the case and control groups using 2-sided nonparametric Wilcoxon Rank Sum tests. Results: From 2016-2022, 18 patients at 3 institutions with the germline APC (I1307K) mutation and 21 controls at NYU with frameshift APC mutations were identified. Median ages did not differ between cases (73.5 years) and controls (71 years). At the time of analysis 13 cases (72%) and 18 (86%) controls were alive (OR: 0.43, 95% CI: 0.09, 1.24). The odds of metastatic disease among cases is 2.03 times that of controls (95% CI: 0.56, 7.32). Median PSA at diagnosis was 8 ng/mL (0.4-780) in cases and 12 ng/mL (4.7-1500) in controls. The odds of small cell histology (either on initial or subsequent biopsy) was 18 times greater than in controls (5 cases; 28% and 1 control; 5%). The odds of clinically-defined AVPC was 9.5 times greater in cases than in controls (9 cases; 50% and 2 controls; 10%, 95% CI: 1.69-53.3). In patients with metastatic disease at diagnosis 7/10 cases (70%) vs 0/9 controls had AVPC. The odds of combined somatic alterations in two or more of RB1, TP53 or PTEN was 5.1 times greater in cases than in controls (4 cases; 22% and 1 control; 5%, 95% CI: 0.58, 56.73). Conclusions: Prostate cancers that develop in the presence of the germline APC (I1307K) mutation appear to be enriched for clinically-defined and molecularly-defined AVPC compared to patients with frameshift APC mutations. The odds of combined somatic alterations in two or more of RB1, TP53 and PTEN were more common in cases than in the controls. Larger studies to identify the impact of germline APC (I1307K) mutation in the somatic genomic and epigenomic landscape of prostate cancer are ongoing.