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AMP/ACMG Guidelines for Variant Classification

Overview​

The Association for Molecular Pathology (AMP) and American College of Medical Genetics and Genomics (ACMG) have established standardized guidelines for the interpretation of sequence variants. These guidelines provide a framework for classifying genetic variants based on their clinical significance.

Five-Tier Classification System​

  1. Pathogenic (P)

    • Strong evidence supporting disease-causing nature
    • Multiple lines of evidence indicating variant's role in disease

  2. Likely Pathogenic (LP)

    • Strong evidence suggesting disease-causing nature
    • Not enough evidence for definitive pathogenic classification

  3. Variant of Uncertain Significance (VUS)

    • Insufficient or conflicting evidence for classification
    • Cannot be definitively categorized as benign or pathogenic

  4. Likely Benign (LB)

    • Evidence suggests non-pathogenic nature
    • Not enough evidence for definitive benign classification

  5. Benign (B)

    • Strong evidence supporting non-pathogenic nature
    • Multiple lines of evidence indicating variant's harmless nature

Evidence Categories​

Population Data​

  • Allele frequency in population databases
  • Presence in healthy individuals
  • Ethnic-specific variations

Computational and Predictive Data​

  • In silico prediction tools
  • Conservation scores
  • Splice site predictions

Functional Data​

  • Functional studies
  • Expression studies
  • Animal models

Segregation Data​

  • Co-segregation with disease in families
  • De novo occurrence

Other Database Sources​

  • Disease-specific databases
  • Clinical databases
  • Literature reports

Specific Criteria​

Very Strong Evidence of Pathogenicity (PVS1)​

  • Null variant in a gene where LOF is a known mechanism of disease

Strong Evidence of Pathogenicity (PS1-PS4)​

  • PS1: Same amino acid change as established pathogenic variant
  • PS2: De novo variant with confirmed paternity and maternity
  • PS3: Well-established functional studies show damaging effect
  • PS4: Variant prevalence in affected individuals significantly higher than controls

Moderate Evidence of Pathogenicity (PM1-PM6)​

  • PM1: Located in mutational hot spot or functional domain
  • PM2: Absent from controls in population databases
  • PM3: For recessive disorders, detected in trans with pathogenic variant
  • PM4: Protein length changes
  • PM5: Novel missense change at amino acid where different change is pathogenic
  • PM6: Assumed de novo without confirmation of paternity and maternity

Best Practices​

  1. Documentation

    • Clearly document evidence used for classification
    • Note any limitations or uncertainties

  2. Regular Review

    • Periodically review classifications as new evidence emerges
    • Update classifications when necessary

  3. Communication

    • Clear reporting of classification and evidence
    • Appropriate clinical context

References​

  1. Richards S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015

  2. Li MM, et al. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2017