Evaluation of Bayesian Point-Based System on the Variant Classification of Hereditary Cancer Predisposition Genes

Purpose To assess the differences in variant classifications using the ACMG/AMP 2015 guidelines and the Bayesian point-based classification system (here referred to as the point system) in 115 hereditary cancer predisposition genes and explore the utility of the point system in variant sub-tiering. Methods Germline variant classifications for 721 pediatric patients from an in-house panel were retrospectively evaluated using the two scoring systems. Results 2376 unique variants were identified. The point system exhibited a lower rate of unique variants of uncertain significance (VUS) of ∼15% compared to ∼36% using the ACMG/AMP 2015 guidelines (p-value < 0.001). This reduction is attributed to the classification of variants as likely benign with one benign supporting evidence (∼12%) or one benign strong evidence (∼4%) using the point system. In addition, the point system resolves conflicting criteria/evidence not recognized by the ACMG/AMP 2015 guidelines (∼5%). Sub-tiering unique VUS calls by the point system indicates ∼11.5% were VUS-Low (0-1 points), while the remaining ∼3.5% were VUS-Mid (2-3 points) and VUS-High (4-5 points). Conclusion The point system reduces the VUS rate and facilitates sub-tiering. Future large-scale studies are warranted to explore the impact of the point system on improving VUS reporting and/or VUS clinical management. ### 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I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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.