Germline pathogenic variants in early-onset colorectal cancer and limitations of tumor-based screening.

e15719 Background: In the United States, the incidence of early-onset colorectal cancer (EOCRC) is increasing, yet real-world utilization of genetic counseling and germline testing remains variable. Historically, tumor mismatch repair (MMR) and microsatellite instability (MSI) testing have guided evaluation for Lynch syndrome; however, this approach may fail to identify the broader spectrum of hereditary cancer syndromes now recognized in EOCRC. Methods: We performed a retrospective analysis of patients diagnosed with colorectal cancer before age 50 who presented to Moffitt Cancer Center between 2016-2025 (n = 140). Rates of genetic counseling referral, tumor MSI/MMR testing, and germline testing results were abstracted from the electronic medical record. Pathogenic or likely pathogenic germline variants and variants of uncertain significance (VUS) were categorized by gene and associated hereditary cancer syndrome. Descriptive statistics were used to assess mutation prevalence and identify gaps in genetic counseling referral and completion of germline testing. Results: Of the 140 patients with EOCRC, 77 (55%) were referred for genetic counseling, of whom 66 (85.7%) completed germline genetic testing. Referral for genetic counseling in this cohort rose significantly over time, from 56.4% in 2019-2022 to 80.6% in 2023-2025 (p = 0.013). Pathogenic germline variants were identified in 12 of 66 tested patients (18%), all of whom had MSI-stable/pMMR tumors. Detected variants included APC (6.1%), MUTYH (6.1%), BRCA2 (1.5%), MSH2 (1.5%), MLH1 (1.5%), and NF1 (1.5%). Alterations in APC or MUTYH accounted for 66.7% of the detected pathogenic variants, compared to 16.7% involving mismatch repair genes, representing a 4:1 predominance of non–Lynch-associated hereditary colorectal cancer syndromes. Tumor MSI/MMR status was available for all tested patients; only 2 of 66 (3%) had MSI-high/dMMR tumors, neither of which harbored a pathogenic germline variant. An additional 10 patients harbored at least one VUS. Extrapolating from the observed mutation prevalence suggests that EOCRC patients who did not undergo genetic counseling or testing likely harbor undetected pathogenic germline variants. Conclusions: In this EOCRC cohort treated at a large tertiary referral center, nearly one in five tested patients carried a pathogenic germline variant, most involving non–Lynch-associated hereditary colorectal cancer syndromes. These findings support universal germline genetic testing for EOCRC regardless of tumor MSI/MMR status to reduce missed hereditary cancer diagnoses and improve cascade testing for at-risk relatives.