Evaluation of Bayesian point-based system on the variant classification of hereditary cancer predisposition genes

Abstract

Purpose: To assess the differences in variant classifications using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology 2015 guidelines and the Bayesian point-based classification system (here referred to as the point system) in 115 hereditary cancer predisposition genes and explore variant sub-tiering by the point system.

Methods: Germline variant classifications for 721 pediatric patients from an in-house panel were retrospectively evaluated using the 2 scoring systems.

Results: A total of 2376 unique variants were identified, with ∼23.5% exhibiting discordant classifications. Unique variants classified by the point system demonstrated a lower rate of variants of uncertain significance (VUS; ∼15%) compared with American College of Medical Genetics and Genomics and the Association for Molecular Pathology 2015 guidelines (∼36%). This change is attributed to unique variants with 1 benign supporting evidence (∼12%) or 1 benign strong evidence (∼4%) being classified as likely benign by the point system. Additionally, variants with conflicting/modified evidence (∼5% of 2376) are also resolved by the point system. Sub-tiering unique variants classified by the point system as VUS (n = 354) indicates ∼77.4% were VUS-Low (0-1 points), whereas the remaining ∼22.6% were VUS-Mid (2-3 points) and VUS-High (4-5 points).

Conclusion: The point system reduces the VUS rate and facilitates their sub-tiering. Future large-scale studies are warranted to explore the impact of the point system on improving VUS reporting and/or VUS clinical management.

Keywords: ACMG/AMP 2015 guidelines; Bayesian point-based classification system; Hereditary cancer predisposition; Sub-tiering; Variant classification.