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

Abstract

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 schemeprime or minutes 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 thePKD1gene and ″variants of varying clinical consequence″ in theCFTRgene. 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.

Classification of PRSS1 variants responsible for chronic pancreatitis: An expert perspective from the Franco-Chinese GREPAN Study Group

“…Employing CP as a disease model, and focusing on the four most studied CP-related genes (i.e., PRSS1, CFTR (encoding cystic fibrosis transmembrane conductance regulator) [13,14], SPINK1 (encoding pancreatic secretory trypsin inhibitor) [15] and CTRC (encoding chymotrypsin C [16,17]), we have recently proposed a seven-category system (i.e., "pathogenic", "likely pathogenic", "predisposing", "likely predisposing", "unknown significance", "likely benign" and "benign") for classifying variants in any disease-causing gene [10]. In a preprint, we have provided evidence to support our contention that the newly added "predisposing" variant classificatory category J o u r n a l P r e -p r o o f is an appropriate repository for the many intermediate variants that fall somewhere between "pathogenic" and "benign" [18].…”

“…Variant classification is an important, complex and evolving issue in the field of human genetics, and this is reflected in the constantly refined variant classification standards/guidelines and the ever increasing number of reports of reclassified variants (for examples in both contexts, see [18]). In this vein, our proposed allele frequency threshold and functional phenotype-based classification criterion for distinguishing PRSS1 "pathogenic" variants from "predisposing" variants (as well as our proposed classifications for some rare PRSS1 missense variants) may need to be refined as more data become available.…”