OncoKB: Automated annotation of the pathogenicity and treatment implications of germline mutations in cancer.

e22604 Background: The success of PARP inhibitors in BRCA1/2 mutant tumors represents the convergence of germline and somatic molecular profiling as part of routine management of clinical cancer care. Other predictive molecular alterations with matched precision oncology drugs in the germline setting have also emerged. The expansion of germline genetic testing to guide therapy selection has increasingly shifted the burden of germline cancer risk assessment to the point-of-care oncologists who now have the additional challenge of ensuring appropriate interpretation of genetic test results. We therefore sought to expand OncoKB, MSK’s FDA-recognized precision oncology knowledge base, to incorporate annotations for germline variants by partnering with MSK’s Clinical Genetics and Diagnostic Molecular Genetics (DMG) services to provide clinicians and researchers worldwide with an automated, evidence-based tool for interpreting the pathogenicity and clinical actionability of germline variants. Methods: We reviewed data compiled by MSK’s DMG for over 2,600 unique germline variants in known cancer susceptibility genes. For each variant, we standardized information on pathogenicity, penetrance, mechanism of inheritance, and associated inherited syndromes to enable integration into OncoKB. Using the OncoKB therapeutic levels of evidence framework, we assigned clinical actionability to individual germline variants based on supporting evidence as to whether the variant is predictive of response to standard care or investigational targeted therapy. Additionally, we expanded the OncoKB API to include endpoints for germline variants, enabling the programmatic annotation of germline sequencing reports and research cohorts. Results: To date, OncoKB has incorporated information on 2631 unique germline variants across 91 genes implicated in germline cancer predisposition and detected by MSK-IMPACT. 24 genes across >10 cancer types are considered Level 1 standard care biomarkers in the germline setting. To date, more than 3400 patients in the MSK-IMPACT cohort have germline alterations that can be annotated with germline OncoKB. Conclusions: OncoKB’s new annotation of germline variants provides a novel and easily accessible tool for clinicians who utilize germline genetic testing to programmatically determine the effect of the variant based on MSK clinical expertise. Public release of this data is expected in 2025.