Genetics in medicine : official journal of the American College of Medical Genetics · 2024
Evaluation of Bayesian point-based system on the variant classification of hereditary cancer predisposition genes.
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Eldomery Mohammad K, Maciaszek Jamie L, Cain Taylor, Loyola Victor Pastor, Mothi Suraj Sarvode, Wheeler David A, Tang Li, Wang Lu, Klco Jeffery M, Blackburn Patrick R
Аннотация
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.
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.