ACMG Criteria for Clinical Use

The American College of Medical Genetics and Genomics (ACMG) has established a framework for the interpretation of genetic variants in clinical settings. These criteria are critical for standardizing variant classification and ensuring consistent and accurate genetic diagnoses.

Overview of ACMG Guidelines

The ACMG framework classifies variants into five categories based on their pathogenicity:

  1. Pathogenic (P)
  2. Likely Pathogenic (LP)
  3. Uncertain Significance (VUS)
  4. Likely Benign (LB)
  5. Benign (B)

The classification process involves evaluating evidence from multiple sources, including population data, computational predictions, functional studies, and clinical observations.

Key Criteria Categories

1. Population Data

  • Benign Evidence: Variant frequency significantly higher than expected for a disorder (e.g., >5% in a population database).
  • Pathogenic Evidence: Variant absent or extremely rare in population databases (e.g., ExAC, gnomAD).

2. Computational and Predictive Data

  • Pathogenic Evidence: Multiple in silico tools predict a deleterious effect on protein function or splicing (e.g., SIFT, PolyPhen).
  • Benign Evidence: Predictive tools indicate a lack of impact on protein function.

3. Functional Data

  • Pathogenic Evidence: Well-established functional studies demonstrate a deleterious effect.
  • Benign Evidence: Studies show no functional impact.

4. Segregation and Co-Segregation

  • Pathogenic Evidence: Variant segregates with disease in multiple affected family members.
  • Benign Evidence: Lack of segregation in family studies.

5. De Novo Occurrence

  • Pathogenic Evidence: Variant arises de novo in an affected individual, with confirmed parentage.

6. Allelic Data

  • Pathogenic Evidence: Variant observed in trans with a pathogenic variant in recessive diseases or in cis with another pathogenic variant in dominant diseases.
  • Benign Evidence: Co-occurrence with a pathogenic variant in a different gene responsible for the observed phenotype.

7. Clinical Evidence

  • Pathogenic Evidence: Variant previously reported in multiple affected individuals or families with consistent phenotypes.
  • Benign Evidence: Variant consistently observed in unaffected individuals.

Strength of Evidence

Each criterion is assigned a strength level:

  • Very Strong (PVS1): Null variant in a gene where loss-of-function is a known mechanism of disease.
  • Strong (PS): E.g., functional evidence or co-segregation.
  • Moderate (PM): E.g., moderate population frequency, computational evidence.
  • Supporting (PP): E.g., specific phenotypic match.

The evidence is integrated using a structured framework to classify the variant.

Application in Clinical Practice

  1. Gather Evidence: Collect relevant genetic, clinical, and familial data.
  2. Evaluate Criteria: Assess each ACMG criterion systematically.
  3. Classify Variant: Assign a classification based on the weight of evidence.
  4. Report Results: Communicate findings with clear explanations and implications for patient care.

References

  • Richards, S., Aziz, N., Bale, S., et al. (2015). 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. Genetics in Medicine, 17(5), 405-424.
  • ACMG Official Website: https://www.acmg.net