Universal versus guideline-based germline multigene panel testing in solid tumors: Diagnostic yield, variant of uncertain significance burden, and clinical actionability - A systematic review with meta-analysis.

PURPOSE: To compare diagnostic yield, variant of uncertain significance (VUS) burden, and clinical actionability of universal versus guideline-based germline multigene panel testing in adults with solid tumors.

METHODS

PubMed, Embase, Web of Science, and Scopus were searched from inception to January 30, 2026. Studies reporting germline multigene testing outcomes in adult solid tumor populations were included. Risk of bias was assessed with validated tools. Proportions were pooled using random-effects models.

RESULTS

Among 144 included studies, 14 formed the comparative evidence set. In unselected cohorts, pooled diagnostic yield was 0.13 (95% confidence interval [CI], 0.11-0.17; I2 = 98%), and pooled VUS burden was 0.40 (95% CI: 0.33-0.48; I2 = 97%). In a two-study synthesis, National Comprehensive Cancer Network (NCCN) criteria sensitivity was 0.72 (95% CI: 0.67-0.76), indicating that approximately 28% of individuals with pathogenic or likely pathogenic variants would not meet the tested criteria.

CONCLUSION

Universal germline multigene testing detects additional hereditary cancer predisposition beyond phenotype-based criteria but increases uncertain findings. Standardized actionability definitions and prospective comparative studies are needed to guide implementation.