Documentation / Variant Analysis / ACMG/AMP Framework
ACMG/AMP Framework for Nuclear Variant Analysis
Folklore uses the ACMG/AMP five-tier framework for supported nuclear sequence variants. Evidence is recorded by direction and strength, then combined through published rules with additional safety checks for conflicting or incomplete evidence.
Evidence Model
The 28 ACMG/AMP criteria cover population, computational, functional, segregation, de novo, allelic, phenotype, and curated clinical evidence. Strength-modified criteria retain their original code with an explicit strength suffix, following ClinGen nomenclature.
| Direction | Strengths | Examples |
|---|---|---|
| Pathogenic | Very Strong, Strong, Moderate, Supporting | PVS1, PS1, PM2, PP3 |
| Benign | Stand-alone, Strong, Supporting | BA1, BS1, BP4 |
Automated and Review-Dependent Evidence
Nineteen criteria have active automated production paths. Eight criteria depend on case, family, functional, or segregation evidence that requires clinical review. PM5 has an implemented same-position evidence path but remains governed by deployment configuration. The interface distinguishes computed evidence from evidence that still needs expert assessment.
Gene-Specific Guidance
When an applicable ClinGen Variant Curation Expert Panel specification is available, Folklore can apply its gene- or disease-specific evidence refinements. The result records the panel and specification version so the reviewer can see when a general rule was modified.
Interpretation boundary
A reproducible rules engine can apply recorded evidence consistently, but it cannot replace assessment of phenotype fit, penetrance, inheritance, assay validity, or newly published evidence. The displayed class must be reviewed in the full clinical context.
Reference: Richards S, et al. Genetics in Medicine. 2015;17(5):405-424. PMID: 25741868