A proposed general variant classification framework using chronic pancreatitis as a disease model

The widely used ACMG-AMP variant classification categories (pathogenic, likely pathogenic, uncertain significance, likely benign and benign) were specifically developed for variants in Mendelian disease genes, classifying variants discretely with respect to a simple causal versus benign dichotomy. A general variant classification framework taking into account the continuum of clinical phenotypes, the continuum of the variants genetic effects and the different pathological roles of the genes implicated, is however lacking. Herein, we used chronic pancreatitis (CP), which clinically manifests as hereditary, familial, idiopathic or alcoholic forms, as a disease model. Based upon cross-gene and cross-variant comparisons, we firstly assigned the four most studied CP genes (PRSS1, CFTR, SPINK1 and CTRC) to two distinct categories in terms of causality: CP-causing (PRSS1 and SPINK1) and CP-predisposing (CFTR and CTRC). We then employed two new classificatory categories, "predisposing" and "likely predisposing", to replace ACMG-AMPs "pathogenic" and "likely pathogenic" categories in CP-predisposing genes, thereby classifying all pathologically relevant variants in these genes as "predisposing". In the case of CP-causing genes, the two new classificatory categories served to expand the five ACMG-AMP categories whilst two thresholds (allele frequency and functional) were introduced to discriminate pathogenic from predisposing variants. Our proposed five-category (predisposing, likely predisposing, uncertain significance, likely benign and benign) and seven-category (pathogenic, likely pathogenic, predisposing, likely predisposing, uncertain significance, likely benign and benign) frameworks (with respect to disease-predisposing and disease-causing genes, respectively) retain the backbone of the five ACMG-AMP categories while rendering them readily applicable to variant classification in other disease contexts.