An Analytical Approach that Combines Knowledge from Germline and Somatic Mutations Enhances Tumor Genomic Reanalyses in Precision Oncology

<b><i>Background:</i></b> Expanded analysis of tumor genomics data enables current and future patients to gain more benefits, such as improving diagnosis, prognosis, and therapeutics. <b><i>Methods:</i></b> Here, we report tumor genomic data from 1146 cases accompanied by simultaneous expert analysis from patients visiting our oncological clinic. We developed an analytical approach that leverages combined germline and cancer genetics knowledge to evaluate opportunities, challenges, and yield of potentially medically relevant data. <b><i>Results:</i></b> We identified 499 cases (44%) with variants of interest, defined as either potentially actionable or pathogenic in a germline setting, and that were reported in the original analysis as variants of uncertain significance (VUS). Of the 7405 total unique tumor variants reported, 462 (6.2%) were reported as VUS at the time of diagnosis, yet information from germline analyses identified them as (likely) pathogenic. Notably, we find that a sizable number of these variants (36%-79%) had been reported in heritable disorders and deposited in public databases before the year of tumor testing. <b><i>Conclusions:</i></b> This finding indicates the need to develop data systems to bridge current gaps in variant annotation and interpretation and to develop more complete digital representations of actionable pathways. We outline our process for achieving such methodologic integration. Sharing genomics data across medical specialties can enable more robust, equitable, and thorough use of patient's genomics data. This comprehensive analytical approach and the new knowledge derived from its results highlight its multi-specialty value in precision oncology settings.