MARiO: predicting cancer variant pathogenicity by integrating in silico evaluation and patient-level mutational contexts

Comprehensive genomic profiling (CGP) supports precision medicine in cancer care, but accurate assessment of missense variant pathogenicity, especially for variants without established consensus, remains challenging. Various computational tools have been developed for variant functional prediction, but most current tools rely solely on variant-level features and do not capture the clinical context of individual patients. To address this limitation, we developed MARiO (Missense Alteration Risk for Oncogenicity), a machine-learning model that integrates variant-level features and patient-level clinical and genomic contexts to effectively predict the pathogenicity of missense variants in cancer. We collected a total of 10,642 missense variants from 1271 patients, and evaluated candidate features for their association with variant pathogenicity, identifying informative features including in silico functional predictions, population allele frequency, variant allele frequency, and tumor mutational burden. Using these selected features, MARiO was developed with extreme gradient boosting. The model integrates multiple in silico prediction tools and patient-specific genomic contexts while accommodating missing values frequently observed in real-world CGP datasets. MARiO outperformed existing tools, achieving an area under the receiver operating characteristic curve of 0.942. The model demonstrated strong generalizability across multiple external datasets and showed consistency with real-world molecular treatment proposals. MARiO offers a robust and clinically relevant approach for missense variant pathogenicity assessment by integrating variant- and patient-level features and serves as a valuable tool to support clinical decision-making.