Chapter 3: The ACMG/AMP 5-Tier Variant Classification Framework
Chapter 3: The ACMG/AMP 5-Tier Variant Classification Framework
In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standards to unify clinical variant interpretation into five standardized tiers: Pathogenic, Likely Pathogenic, Uncertain Significance (VUS), Likely Benign, and Benign.
The 28 ACMG/AMP Evidence Criteria
Evidence is divided into Pathogenic (P) and Benign (B) categories with calibrated weight levels:
- PVS1 (Very Strong Pathogenic): Null variant (nonsense, frameshift, canonical \(\pm 1, 2\) splice site, initiation codon) in a gene where loss-of-function (LoF) is a known mechanism of disease.
- PS1–PS4 (Strong Pathogenic): Same amino acid change as previously established pathogenic variant (PS1); De novo without confirmation (PS2); Well-established functional in vitro assay showing damaging effect (PS3); Prevalence in affected probands significantly increased over controls (PS4).
- PM1–PM6 (Moderate Pathogenic): Located in critical mutational hotspot or active site domain without benign variation (PM1); Absent or extremely rare in population databases (gnomAD) (PM2); Novel missense change at an established pathogenic residue (PM5).
- PP1–PP5 (Supporting Pathogenic): Multiple computational in silico predictors (REVEL, CADD, AlphaMissense) agree on damaging effect (PP3); Phenotype matches specific gene (PP4).
- BA1 (Stand-Alone Benign): Allele frequency >5% in gnomAD across any continental subpopulation.
1. Combining Evidence: The Bayesian Point System
Modern clinical genomics maps ACMG qualitative criteria into quantitative Bayesian point systems (Tavtigian et al., ClinGen):
# ClinGen / ACMG Bayesian Point Calibration:
# Supporting = 1 point, Moderate = 2 points, Strong = 4 points, Very Strong = 8 points
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# Classification Tier Total Point Threshold Certainty
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# Pathogenic (P) >= +10 points > 99% probability of disease causality
# Likely Pathogenic (LP) +6 to +9 points > 90% probability
# Uncertain Significance 0 to +5 points Insufficient / conflicting evidence
# Likely Benign (LB) -1 to -6 points > 90% probability of being benign
# Benign (B) <= -7 points or BA1 > 99% probability
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