Comparison of the ABC and ACMG systems for variant classification

Area of Science:

• Clinical Genetics
• Molecular Diagnostics
• Bioinformatics

Background:

• Variant classification is crucial for clinical utility and reporting.
• Existing systems like ABC and ACMG have different primary purposes.
• ACMG guidelines influence variant reporting in many clinical laboratories.

Purpose of the Study:

• To compare the ABC and ACMG variant classification systems.
• To assess the impact of each system on clinical reporting decisions.
• To evaluate the concordance of ACMG criteria selection among laboratories.

Main Methods:

• European clinical laboratories classified 10 challenging cases using both ABC and ACMG systems.
• Laboratories reported whether variants would be reported as clinically relevant.
• ACMG criteria selection was compared across participating laboratories.

Main Results:

• In 7 out of 10 cases, classification system did not influence reporting likelihood when 'maybe report' ACMG variants were included.
• ABC classification favored reporting for population-frequent, disease-associated variants.
• Average concordance for ACMG criteria selection was 46% after excluding rarely used criteria.

Conclusions:

• The ABC system provides clearer, more adaptable variant classification than ACMG.
• ABC separates molecular and clinical information, allowing tailored reporting.
• ABC avoids clinically inappropriate labels for variants, unlike ACMG.