Clinical Variant Reclassification in Hereditary Disease Genetic Testing.

Area of Science:

• Genetics
• Bioinformatics
• Clinical Diagnostics

Background:

• Accurate classification of DNA sequence variants is fundamental for germline genetic testing.
• Understanding variant classification (VC) and reclassification patterns is vital for improving methods and ensuring equity across race, ethnicity, and ancestry (REA) groups.

Purpose of the Study:

• To assess the accuracy of initial variant classifications against professional guidelines.
• To quantify the rates, factors, and impact of variant reclassifications in a large cohort.

Main Methods:

• Analysis of clinical multigene panel and exome sequencing data from over 3.2 million individuals tested between 2015 and 2023.
• Classification of DNA variants into five categories: benign, likely benign, VUS, likely pathogenic, or pathogenic.
• Statistical analysis including ANOVA and Pearson chi-squared tests to evaluate classification accuracy and reclassification rates.

Main Results:

• Over 2 million variants were analyzed, with 4.60% undergoing reclassification.
• Most reclassifications (61.65%) were from VUS to definitive categories; 37.66% increased certainty.
• VUS reclassification rates were higher in underrepresented REA populations; computational modeling contributed significantly to VUS resolution.

Conclusions:

• Initial variant classifications generally met certainty thresholds, suggesting a need to re-evaluate classification definitions.
• Strategies for resolving VUS, including computational methods and family testing, offer insights for improving VC methods and patient outcomes.