Updated recommendation for the benign stand-alone ACMG/AMP criterion

Area of Science:

• Genetics
• Genomic Medicine
• Bioinformatics

Background:

• The American College of Medical Genetics and Genomics/Association of Molecular Pathologists (ACMG/AMP) established variant pathogenicity guidelines.
• Stand-alone rule BA1 states that variants with a minor allele frequency (MAF) > 0.05 are considered benign.
• Previous application of BA1 lacked clarity, necessitating refinement.

Purpose of the Study:

• To refine the ACMG/AMP stand-alone rule BA1 for variant pathogenicity.
• To clarify the application of BA1 and identify exemptions.
• To ensure accurate interpretation of genetic variants with high MAF.

Main Methods:

• Cross-referencing ClinVar and Exome Aggregation Consortium data.
• Identifying variants with MAF > 0.05 and plausible pathogenicity.
• Applying ACMG/AMP criteria to assess identified variants.

Main Results:

• Nine variants with MAF > 0.05 and potential pathogenicity were identified.
• Four of these variants were classified as pathogenic.
• Five variants were classified as variants of uncertain significance.
• Refined guidelines for BA1 application, database recommendations, and assumptions were established.

Conclusions:

• The BA1 rule requires clarification and specific exemptions for accurate variant interpretation.
• A process for petitioning amendments to variant assertions and criteria for setting gene-specific MAF thresholds were established.
• Refined guidelines improve the reliable classification of genetic variants.