Validation of the ACMG/AMP guidelines-based seven-category variant classification system

Background One shortcoming of employing the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP)-recommended five-category variant classification scheme (“pathogenic”, “likely pathogenic”, “uncertain significance”, “likely benign” and “benign”) in medical genetics lies in the scheme’s inherent inability to deal properly with variants that fall midway between “pathogenic” and “benign”. Employing chronic pancreatitis as a disease model, and focusing on the four most studied chronic pancreatitis-related genes, we recently expanded the five-category ACMG/AMP scheme into a seven-category variant classification system. With the addition of two new classificatory categories, “predisposing” and “likely predisposing”, our seven-category system promises to provide improved classification for the entire spectrum of variants in any disease-causing gene. The applicability and practical utility of our seven-category variant classification system however remains to be demonstrated in other disease/gene contexts, and this has been the aim of the current analysis. Results We have sought to demonstrate the potential universality of pathological variants that could be ascribed the new variant terminology (‘predisposing’) by trialing it across three Mendelian disease contexts (i.e., autosomal dominant, autosomal recessive and X-linked). To this end, we firstly employed illustrative genes/variants characteristic of these three contexts. On the basis of our own knowledge and expertise, we identified a series of variants that fitted well with our “predisposing” category, including “hypomorphic” variants in the PKD1 gene and “variants of varying clinical consequence” in the CFTR gene. These examples, followed by reasonable extrapolations, enabled us to infer the widespread occurrence of “predisposing” variants in disease-causing genes. Such “predisposing” variants are likely to contribute significantly to the complexity of human genetic disease and may account not only for a considerable proportion of the unexplained cases of monogenic and oligogenic disease but also for much of the “missing heritability” characteristic of complex disease. Conclusion Employing an evidence-based approach together with reasonable extrapolations, we demonstrate both the applicability and utility of our seven-category variant classification system for disease-causing genes. The recognition of the new “predisposing” category not only has immediate implications for variant detection and interpretation but should also have important consequences for reproductive genetic counseling. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any specific financial support. ### 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 used ONLY openly available human data that were originally located at PubMed, ClinVar, gnomAD, the ADPKD Variant Database () and the Clinical and Functional TRanslation of CFTR (CFTR2) databse (). 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All supporting data are available within the article.