Germline multigene panel testing identifies pathogenic variants in 15.2% of colorectal cancer patientsGenetic testing reveals common cancer risks in colorectal cancer patients

BACKGROUND: Colorectal cancer can arise from an inherited genetic background, but the diagnostic yield of multigene germline panel testing in patients diagnosed with colorectal cancer remains uncertain. The aim of this study was to quantify such yield. METHODS: In this systematic review and meta-analysis, we searched PubMed (MEDLINE), Embase, Scopus, and the Cochrane Central Register of Controlled Trials from database inception to Aug 2, 2025, for studies published in English reporting the results of germline multigene panel testing of at least five genes using next-generation sequencing in unselected patients with colorectal cancer. Eligible study designs included cross-sectional and cohort studies, and clinic-based series in which all consecutive patients with colorectal cancer were offered multigene panel testing. Two independent reviewers, masked from each other's decisions, screened records and extracted summary data and individual participant data, with conflicts resolved by a third reviewer. Risk of bias was assessed using the Newcastle-Ottawa Scale. The primary outcome was the person-level prevalence (diagnostic rate) of at least one pathogenic or likely pathogenic variant in cancer predisposition genes. Analyses were stratified by age at colorectal cancer diagnosis and gene penetrance. Random-effects meta-analyses estimated pooled prevalence. Heterogeneity was quantified using the I statistic. Meta-regression evaluated the effect of age at colorectal cancer diagnosis, panel size, family history, and publication year on diagnostic rates. This study was registered in PROSPERO, CRD42025649177. FINDINGS: Of 2707 records identified, 1682 duplicates were removed and screening excluded a further 985 records. 40 articles underwent full-text review, of which 21 met eligibility criteria and were included (ten [48%] at low, nine [43%] at moderate, and two [10%] at high risk of bias). Across 6925 individuals with colorectal cancer, the pooled rate of any pathogenic or likely pathogenic variant was 15·2% (95% CI 12·8-18·1; 1061/6925; I=84·1%; k=12), with high-penetrance variants identified in 7·9% (5·9-10·5; 551/6909; I=88·4%; k=11) and high-penetrance colorectal cancer predisposition variants in 5·4% (3·5-8·6; 408/6909; I=93·4%; k=11). In early-onset colorectal cancer (age at diagnosis <50 years), yields were 17·7% (15·0-20·7; 1113/7444; I=85·7%; k=16) for any pathogenic or likely pathogenic variant, 14·2% (11·7-17·3; 917/7409; I=85·7%; k=15) for high-penetrance variants, and 12·2% (9·5-15·5; 788/7409; I=89·5%; k=15) for high-penetrance colorectal cancer predisposition variants. In late-onset colorectal cancer (age at diagnosis ≥50 years), yields were 13·0% (10·8-15·7; 711/5243; I=73·3%; k=11) for all variants, 6·5% (4·4-9·5; 349/5227; I=86·4%; k=10) for high-penetrance variants, and 3·8% (2·0-7·5; 234/5227; I=90·3%; k=10) for high-penetrance colorectal cancer predisposition variants. In meta-regression analyses, panel size and publication year did not affect yields. A higher prevalence of first-degree family history of colorectal cancer correlated with increased overall and colorectal cancer-specific variant yields, but not with non-colorectal variant yields. There was a progressive decline in yield with increasing age at colorectal cancer diagnosis, although the yield for high-penetrance variants remained greater than 5% up to age 67 years (95% CI 59-75). INTERPRETATION: The yield of multigene panel testing is considerable in unselected patients with colorectal cancer, even beyond early-onset disease. The yield of high-penetrance germline variants remains above recognised testing thresholds up to age 67 years, providing a benchmark of universal testing for further study. FUNDING: Italian Ministry of University, EU-Next Generation EU, and National Cancer Institute.