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.
Lemert et al. (Wed,) studied this question.