Assessing Allele Frequency Information: A Study of Variant Curation Expert Panel Guidelines.

Area of Science:

• Genetics
• Bioinformatics
• Clinical Genomics

Background:

• The 2015 ACMG/AMP guidelines recommend large, diverse, race-matched reference databases for variant interpretation.
• Defining expectations for variant interpretation is subjective due to genetic diversity and penetrance.
• Clinical Genome Resource (ClinGen) Variant Curation Expert Panels (VCEPs) provide gene-specific interpretations of guidelines, including population data.

Purpose of the Study:

• To evaluate the VCEP guidelines concerning allele frequency information.
• To assess the consistency and variability in VCEP approaches to allele frequency thresholds.

Main Methods:

• Analysis of genetic databases across 39 VCEPs.
• Evaluation of variant frequency and pathogenicity.
• Consideration of allele frequency thresholds and disease prevalence.

Main Results:

• Significant variability in approved allele frequency cutoffs among VCEPs was observed.
• Diverse disease mechanisms contribute to the observed variations.
• Inconsistencies were noted in the methods for establishing cutoffs and necessary parameters.

Conclusions:

• Understanding allele frequency thresholds requires deep knowledge of genetics and specific diseases.
• VCEP guidelines can aid curators in identifying recommended thresholds.
• Enhanced guidance is necessary for consistent utilization of population evidence in variant curation.