Variant Classification Concordance using the ACMG-AMP Variant Interpretation Guidelines across Nine Genomic...

Area of Science:

• Genomics
• Clinical Genetics
• Bioinformatics

Background:

• Harmonizing variant pathogenicity classification is essential for advancing clinical genomics.
• Discordance in variant classification can impact patient care and genetic testing interpretation.

Purpose of the Study:

• To explore current sources of discordance in variant pathogenicity classification across multiple laboratories.
• To assess the level of concordance in variant classification using standardized guidelines.

Main Methods:

• Eight CLIA-accredited laboratories submitted 158 classified variants in ACMG secondary finding genes.
• Variants were independently re-annotated and classified by two additional laboratories using ACMG-AMP guidelines.
• Discordant variants underwent teleconference and email review for further assessment.

Main Results:

• Overall five-category concordance was achieved for 54% of variants.
• Eleven percent of variants showed discordance that could alter clinical recommendations (Pathogenic/Likely Pathogenic vs. VUS/Likely Benign/Benign).
• Post-review concordance reached 84% for initially discordant variants.

Conclusions:

• This study provides an updated estimate of variant concordance in clinical genomics.
• Identified discordance highlights the need for improved sharing of variant classifications and evidence.
• Ongoing efforts by ClinGen and inter-laboratory collaboration are vital for increasing concordance and standardizing clinical genomics practices.