Clinical yield and utility of germline multigene panel testing across hereditary cancer syndromes: A systematic review of real-world evidence.

Abstract

e22664 Background: Germline multigene panel testing (MGPT) is widely used for hereditary cancer risk assessment , but real-world diagnostic yield and clinical utility vary across clinical contexts and populations . Published data from routine practice are fragmented and heterogeneous. We conducted a systematic review to synthesize evidence on MGPT performance across hereditary cancer syndromes. Methods: PubMed and related databases were searched through 2025 for observational studies of germline MGPT in hereditary cancer evaluation. We excluded somatic tests, population screening studies, single-gene analyses, and variant-only case reports. Data extracted included testing indications, panel gene content, pathogenic/likely pathogenic (P/LP) and variant-of-uncertain-significance (VUS) rates, and reported downstream clinical actions. Study quality was assessed using the ROBINS-I tool for non-randomized studies. Results: 209 studies met inclusion criteria (median cohort 215 patients; IQR 96–879). Panels ranged from 1 to 1,021 genes (median 25 genes; IQR 14–72); most panels targeted only BRCA1/2. Median P/LP detection was 13.4% (IQR 8.7%–20.1%). Individual median detection rates were illustrated in the table . Notably, 10–30% of patients harbored clinically actionable variants outside BRCA1/2. For example, panel testing in breast and colorectal cancer cohorts identified P/LP variants in CHEK2, PALB2, APC, and DNA mismatch repair genes . VUS rates were substantial (median 25%; IQR 14%–44%) and were highest in studies using larger panels and in underrepresented populations . 22 reported on management outcomes; among these, the median proportion of patients with documented management changes was 14.5%. For instance, one report found that 69% of patients with panel-identified mutations had revised clinical recommendations . Overall risk of bias was moderate-to-serious in most studies due to retrospective design, referral patterns, and incomplete follow-up. Conclusions: MGPT frequently uncovers actionable pathogenic variants beyond BRCA1/2, but diagnostic yields vary and are offset by a high burden of VUS . The impact of these findings on patient management remains poorly defined because outcome reporting is limited. These results underscore the need for prospective, standardized real-world data collection to clarify how MGPT results influence hereditary cancer care. Summary of included studies and median germline pathogenic/likely pathogenic (P/LP) variant detection rates stratified by hereditary cancer syndrome. Hereditary Cancer Syndrome Number of Studies Median P/LP Detection rate Breast & Ovarian (HBOC) 87 14.8% Colorectal & Polyposis 39 17.2% Pancreatic Cancer 22 15.2% Endometrial/Uterine 16 11.4% Others 45 13.3%