ACMG

Over the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. With its introduction and use, clinical laboratories are now performing an ever-increasing number of genetic tests that include genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic diseases. Due to the increasing complexity, this change in genetic testing is accompanied by new challenges in sequence interpretation (Richards S et al. 2015).

The ACMG developed standards and guidelines for the interpretation of sequence variants. These recommendations apply primarily to the range of genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes and genomes. They are based on the use of specific standard terminology - "pathogenic", "probably pathogenic", "of uncertain significance", "probably benign" and "benign" - to describe variants identified in genes that cause Mendelian disorders. In addition, this recommendation describes a process for classifying variants into these five categories based on criteria that utilize typical types of variant evidence (e.g., population data, computational data, functional data, segregation data).

ACMG is the acronym for: American College of Medical Genetics and Genomics. The ACMG guidelines are internationally recognized standards for the interpretation of genetic variants and are primarily used in human genetic diagnostics. They were developed to enable consistent and clinically relevant decisions about the significance of genetic changes.

The ACMG criteria classify variants into five categories:

1. pathogenic (disease-causing)

2. likely pathogenic (probably disease-causing)

3. variant of uncertain significance (VUS)

4. probably benign (probably benign)

5. benign (benign)

The evaluation is based on a point system that takes into account different types of evidence:

1. pathogenic criteria

• Strong (PVS1): E.g. loss-of-function in a gene that has LoF as a disease mechanism.
• Moderate (PM1-PM6): E.g. hotspot region, known functional domain affected.
• Low (PP1-PP5): E.g. family cosegregation, in silico predictions support pathogenicity.

2. benign criteria

• High (BA1): High allele frequency in the population.
• Moderate (BS1-BS4): E.g. good functional data show no effect.
• Low (BP1-BP7): E.g. in silico data show no effect, silent mutation without splicing effect.

Example for classification as "pathogen":

- 1× PVS1 + 1× PM2 + 1× PP3 → results in sufficient evidence for "pathogenic".

In practice, each variant is evaluated on the basis of these criteria. The final classification depends on how many pathogenic or benign criteria are fulfilled (and how strong they are).

1. Richards S et al. (2015) ACMG Laboratory Quality Assurance Committee. 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 17:405-424.
2. Tavtigian SV et al. (2018) Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework. Genet Med 20:1054-1060.