SPINK1-related chronic pancreatitis: A model that encapsulates the spectrum of variant effects, genetic complexity, and classificatory challenges.

Abstract

The widely used American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) variant classification system is inherently limited by its binary categorization of variants as "pathogenic" or "benign," failing to account for the full spectrum of variant effects within the complex genetic architecture of human disease. Although various refinements have been proposed, a framework that adequately captures this continuum remains to be established. To address this limitation, we conducted an in-depth analysis of SPINK1 variants associated with chronic pancreatitis (CP), a disorder ranging from Mendelian to environmentally influenced forms. We collated and reviewed SPINK1 variants identified in both genome-wide association studies (GWASs) and non-GWASs. Focusing on predicted loss-of-function (LoF) and experimentally characterized variants, we demonstrated through aggregation analysis that complete- or near-complete-LoF SPINK1 variants cause autosomal-dominant disease with moderate penetrance (∼55%). This finding establishes a critical baseline for comprehensively deciphering the genetic complexity underlying SPINK1-related CP. Concentrating on two well-characterized partial-LoF (hypomorphic) variants, c.194+2T>C and c.-4141G>T (enhancer), we present converging evidence for a distinct variant category that neither aligns with the ACMG/AMP binary classifications nor fits the recently proposed "risk alleles" category. Although some variants remain classified as variants of uncertain significance (VUSs), we propose a refined classificatory framework that integrates "risk," "predisposing," and "pathogenic" variants to accommodate the full spectrum of clinically relevant SPINK1 variants. This refined framework is expected to serve as a model for variant interpretation beyond SPINK1, providing insights into the issue of "missing heritability" and fostering further exploration of variant effects and genetic complexity across different contexts of human disease.