Evaluation of Bayesian Classification Framework on the Variant Classification of Hereditary Cancer Predisposition Genes

Purpose: To assess the differences in the variants classifications using the ACMG/AMP 2015 guidelines and the Bayesian point-based classification system (here referred to as point system) in 115 hereditary cancer predisposition genes and explore the utility of the point system in variant reanalysis. Methods: Germline variant classifications from 721 pediatric patients were evaluated using the two scoring systems and compared with our reported classification. Results: 2376 unique variants were identified. The point system exhibited a propensity to decrease the rate of variants of unknown significance (VUS) to 15% compared to 36% by the ACMG/AMP 2015 (Cochran-Armitage with Z-score of -16.686; p-value < 0.001). This reduction in VUS rate is attributed to 1) single benign supporting evidence (12%); 2) single benign strong evidence (4%), each of which independently could downgrade a VUS to likely benign in the point system; and 3) resolving conflicting evidence or evidence not recognized by the ACMG/AMP 2015 guidelines (5%). Examination of the point system scores of the reported VUS (28%) facilitated tiering and prioritizing the variants for reanalysis. Conclusion: The point system facilitates the reduction of the VUS rate and provides a systematic way for periodic reanalysis of VUS in hereditary cancer predisposition genes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the American Lebanese and Syrian Associated Charities of SJCRH. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was reviewed by the St. Jude Children Research Hospital Institutional Review Board, which determined that this project did not meet the criteria for human subjects research and, therefore, did not require full institutional review board approval. All patients consented to clinical analysis and individual reporting of germline sequencing data. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All of the relevant data used in this study has been provided in the tables, or relevant supplementary information.