Glossary · Genetics
ACMG criteria
In one sentence
The ACMG criteria are the standards published in 2015 by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology for classifying genetic variants into five tiers, from pathogenic to benign.
Also known as: ACMG/AMP criteria · ACMG guidelines · ACMG/AMP guidelines · ACMG classification · ACMG/AMP
What are the ACMG criteria?
They are the internationally used framework for deciding whether a genetic variant causes a Mendelian disorder. They were published in 2015 in Genetics in Medicine as a joint consensus of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), with Sue Richards as first author, which is why they are often cited as the “ACMG/AMP criteria” or “Richards et al. 2015”.
Before the guideline, each laboratory classified variants with its own rules and vocabulary. The guideline introduced a shared language and a five-tier system.
How they work
The guideline sets out 28 criteria: 16 for pathogenic evidence and 12 for benign evidence. Each has a code and a weight:
- Pathogenic: very strong (PVS1), strong (PS1–PS4), moderate (PM1–PM6) and supporting (PP1–PP5).
- Benign: stand-alone (BA1), strong (BS1–BS4) and supporting (BP1–BP7).
The criteria capture different kinds of evidence: population frequency (for example in gnomAD), variant type and predicted effect, computational predictions, functional studies, segregation within families, de novo occurrence and data from resources such as ClinVar. Combining rules then assign one of five classes:
- Pathogenic
- Likely pathogenic
- Uncertain significance (VUS)
- Likely benign
- Benign
Limitations and updates
- Expert judgement: applying each criterion requires interpretation, and laboratories can reach different classes from the same data.
- Scope: the guideline was written for germline variants in Mendelian disease, not for somatic tumour variants or copy number variants, which have their own recommendations.
- Refinements: ClinGen and gene-specific expert panels have since published adjustments to individual criteria and specifications for particular genes and conditions.
Example
A laboratory finds a frameshift variant in a gene where loss of function is a recognised cause of disease. It applies PVS1 (null variant), PM2 (absent from population databases) and PP1 for co-segregation in the family. Under the 2015 combining rules, one very strong criterion plus one moderate and one supporting criterion is enough for “pathogenic”. The report still lists which criteria were applied, so the referring clinician can see how the conclusion was reached.
ACMG criteria at Xenogene
According to its product page, Xenogene’s Clinvar platform for genetic variant interpretation applies classification according to ACMG/AMP criteria within a workflow of VCF ingestion, annotation with public databases, classification and reporting. Its toolset includes InterVar for automated ACMG classification. Automated classification is a support: the final interpretation rests with the professional who requested the analysis.
Frequently asked questions
What are the five ACMG variant classifications?
Pathogenic, likely pathogenic, uncertain significance (VUS), likely benign and benign. The 'likely' categories are used when the evidence is strong but not conclusive.
What does PVS1 mean in ACMG classification?
It is the very strong pathogenic criterion: a null variant (nonsense, frameshift, canonical splice site and so on) in a gene where loss of function is a known mechanism of disease. Applying it involves nuance, and later recommendations have refined how it should be used.
Can two laboratories classify the same variant differently using ACMG criteria?
Yes. The criteria standardise the process, but weighing the evidence still requires expert judgement. Such disagreements show up, for example, as conflicting interpretations in ClinVar.
Related terms
- Genetic variant
A genetic variant is any difference in a person's DNA sequence compared with a reference sequence. Most have no effect on health; some are associated with disease or alter risk.
- ClinVar
ClinVar is a free public database run by the NCBI at the US National Institutes of Health that collects interpretations submitted by laboratories and experts on how human genetic variants relate to disease.
- NGS (next-generation sequencing)
NGS (next-generation sequencing) is a family of technologies that read millions of DNA or RNA fragments in parallel in a single run, making it possible to study whole genomes, targeted genes or entire microbial communities at scale.
Educational content for healthcare professionals and the general public. It does not replace assessment by a healthcare professional: ordering and interpreting any test is the responsibility of the requesting clinician.
Updated on