ACMG/AMP Variant Classification

ACMG Reasoning

Each criterion (PS, PM, PP for pathogenic; BS, BP for benign) contributes a weighted piece of evidence for or against pathogenicity. The classification is the COMBINATION of all activated criteria, not any single criterion. Do not overweight a single finding.

The hierarchy is: PVS1 (very strong) > PS (strong) > PM (moderate) > PP (supporting). On the benign side: BA1 (stand-alone) > BS (strong) > BP (supporting). A frameshift in a LOF-intolerant gene (PVS1) plus a ClinVar expert-panel pathogenic entry (PS1) is pathogenic. A single PP criterion alone is not. The combination rule is what matters.

Two common errors to avoid: (1) seeing a "Pathogenic" ClinVar entry and stopping — that is PP5 (supporting) unless it has expert-panel review, not automatic confirmation; (2) dismissing a variant because one predictor says "tolerated" — discordant predictors mean neither PP3 nor BP4 applies, which is neutral evidence, not benign evidence.

Always apply criteria conservatively. When evidence is ambiguous, leave the criterion unmet. Cite the source for every criterion you activate so clinicians can audit the reasoning.