Challenges in PMS2 variant classification: a critical analysis of conflicting data in ClinVar

Abstract

Objective: To characterize conflicting variants of the PMS2 gene recorded in ClinVar, describing their distribution by molecular and temporal type, and to analyze the magnitude and patterns of interlaboratory discordance in order to identify curatorial gaps and standardization needs. Methods: Cross-sectional, analytical, and exploratory study based on 432 conflicting PMS2 variants deposited in ClinVar. Only submissions from recognized institutions with public and clinically relevant information were included. Variants were categorized according to ACMG/AMP criteria and analyzed in terms of molecular type and year of submission. Results: Missense variants were predominant (68.3%), followed by intronic (15.1%) and synonymous (12.5%) variants. A progressive increase in missense submissions was observed from 2017 onwards. Classifications as variants of uncertain significance (VUS) remained stable, pathogenic variants showed gradual growth, and benign variants maintained a constant frequency. The main conflicts occurred between VUS and pathogenic variants (n=161), followed by VUS and benign variants (n=33). Conclusion: The study demonstrates the persistence of discordances in the classification of PMS2 variants, highlighting the complexity of their curation. These findings reinforce the need for classification standardization to ensure more consistent diagnoses and greater safety in genetic counseling.