The American College of Medical Genetics and Genomics (ACMG) curates a list of genes associated with certain medical conditions. This resource, often called the ACMG 59 list based on a previous version, is a tool used in clinical genetics to identify individuals who may have an increased risk for specific health problems. The list serves as a guide for clinical laboratories performing broad genetic sequencing and is periodically updated to reflect new scientific understanding.
Criteria for Inclusion on the List
A gene’s inclusion on the ACMG list is determined by a strict set of criteria centered on medical actionability. This means that if a person is found to have a pathogenic variant in one of these genes, there are established and effective interventions available. These interventions, such as increased surveillance, preventative surgeries, or specific therapies, can help prevent the associated disease or significantly reduce its severity. The selection process also requires that the potential disease has serious health consequences and that the genetic tests used to identify variants are reliable and accurate.
Associated Genes and Conditions
The list has evolved and now includes more genes than the original 59. The current version, ACMG SF v3.2, contains 81 genes associated with a range of preventable or treatable conditions. These conditions are grouped into several major categories, providing a framework for understanding the types of health risks the list covers.
One of the largest categories is hereditary cancers. Early identification of variants in these genes allows for enhanced screening protocols and risk-reducing measures. This group includes genes such as:
- BRCA1 and BRCA2, linked to an increased risk for breast, ovarian, and other cancers.
- MLH1, MSH2, MSH6, and PMS2, associated with Lynch syndrome, which predisposes individuals to colorectal and other cancers.
- TP53, related to Li-Fraumeni syndrome.
Cardiovascular conditions represent another portion of the list. This category covers disorders like cardiomyopathies, which affect the heart muscle, and arrhythmias, which cause irregular heart rhythms. Examples include:
- LDLR, APOB, and PCSK9, responsible for familial hypercholesterolemia, a disorder causing high cholesterol and early-onset heart disease.
- KCNQ1 and SCN5A, linked to long QT syndrome, a heart rhythm condition that can cause fainting and sudden cardiac death.
A smaller group on the list relates to metabolic disorders. An example is malignant hyperthermia susceptibility, linked to genes such as RYR1. This condition causes a severe reaction to certain anesthetic drugs, so prior knowledge allows medical teams to use alternatives. The list also covers a few other miscellaneous conditions.
Role in Genetic Testing
The ACMG list is used in broad-scale genetic testing, such as whole exome sequencing (WES) or whole genome sequencing (WGS). These tests analyze many genes at once to find a genetic explanation for a patient’s existing health problem, known as a primary finding. During this analysis, a laboratory may uncover genetic variants unrelated to the initial reason for testing.
These unrelated results are referred to as secondary or incidental findings. The ACMG recommends that clinical laboratories specifically look for and report pathogenic variants in the genes on its actionable list, as discovering these variants offers an opportunity for medical intervention.
The process is an opportunistic screening that leverages data from the primary test and is not a substitute for diagnostic testing if a specific condition is suspected. Reporting is standardized to include variants classified as “pathogenic” or “likely pathogenic,” while variants of uncertain significance are not reported. About 5-6% of individuals who undergo this type of testing will have a positive secondary finding.
Patient Autonomy and Next Steps
A core principle of the ACMG’s recommendations is patient autonomy. Before genetic sequencing, individuals have the right to decide whether they want to receive information about secondary findings. This choice, often called “opting out,” allows patients to decline the analysis of these genes if they prefer not to know about risks unrelated to their primary medical concern.
To facilitate an informed decision, pre-test genetic counseling is standard. A genetic counselor explains the nature of secondary findings, the types of conditions on the ACMG list, and the potential implications of learning this information.
If a pathogenic variant from the ACMG list is identified, the next steps involve follow-up with a medical professional. The patient will typically have a post-test consultation with a genetic counselor to discuss the result, what it means for their health, and implications for family members. This may lead to confirmatory testing and the development of a personalized management plan.