Universal Germline Genetic Testing in a Precision Oncology and Rare Cancer Clinic: Implementation and Outcomes.

Abstract

PURPOSE: Current National Comprehensive Cancer Network (NCCN) guidelines for germline testing are complex and often miss patients with cancer susceptibility. We evaluated results of universal germline genetic testing in a Precision Medicine and Rare Cancer clinic, focusing on the prevalence of pathogenic/likely pathogenic (P/LP) variants and the proportion of affected patients who would have been missed by NCCN guidelines, comparing patients with rare and common cancer. METHODS: All consenting patients with cancer seen at Froedtert Hospital's Precision Oncology and Rare Cancer clinic (June 2023 to January 2025; N = 120 patients; 55, common cancers, 65 rare cancers), who had not previously had germline testing, met with a clinic-embedded genetic counselor and underwent germline testing. Key variables included cancer type (rare v common), germline test results (penetrance/clinical actionability), and whether patients met NCCN guidelines for testing. RESULTS: The positive rate for P/LP germline variants was 15% (n = 18; 13%, patients with common cancer; 17%, patients with rare cancer). Notably, 29% and 64%, respectively, of patients with positive common and rare cancer did not meet NCCN guidelines at the time of testing. Among patients with common and rare cancer with positive results, 83% and 42% of P/LP variants were in high/moderate penetrance genes (eg, BRCA2, PMS2, SDHB, ATM, CHEK2). CONCLUSION: Universal germline testing identified a substantial number of patients with clinically valuable germline variants, many of whom would be missed by NCCN guidelines, exposing guideline-based testing limitations. Overall, 50% of patients positive for germline variants did not meet NCCN testing criteria. A clinic-embedded genetic counselor facilitated testing and post-test counseling as part of a comprehensive cancer management approach. These findings emphasize the need for inclusive testing strategies to better identify cancer predisposition, including in rare cancers.