The American College of Medical Genetics and Genomics (ACMG) 59 list identifies genes for which pathogenic or likely pathogenic variants should be reported when a patient undergoes comprehensive genetic testing, such as whole exome sequencing (WES) or whole genome sequencing (WGS). This guideline, originally published in 2013 with 56 genes and updated to 59 in 2015, established a standard practice for clinical laboratories to analyze these genes regardless of the initial reason for the patient’s test. The list has since expanded beyond 59 genes, reflecting the growing understanding of genetic risk and medical interventions. This proactive screening aims to provide patients with early, life-saving information about conditions they may not have otherwise known about.
The Purpose and Scope of Incidental Findings
The genes on this list are formally known as Secondary Findings (SF), a term preferred by the ACMG over the older term “incidental findings.” A secondary finding is an unexpected result of a genetic test that is unrelated to the condition for which the testing was originally ordered; for example, a patient tested for a pediatric neurological disorder might receive a secondary finding indicating a high risk for adult-onset hereditary cancer.
The standardized list addresses the dilemma faced by laboratories performing broad genetic sequencing, which generates data on thousands of genes. The ACMG recognized that withholding information about highly penetrant, medically responsive conditions would compromise patient well-being, especially when the information could lead to preventative care. The list acts as a minimum reporting standard, establishing a consensus for opportunistic screening among clinical diagnostic laboratories.
Adherence to the ACMG list is a professional consensus guideline, not a legal mandate, though it is widely adopted in clinical practice. The guideline specifies that only variants classified as pathogenic (disease-causing) or likely pathogenic should be reported. Variants of Uncertain Significance (VUS) are specifically excluded from reporting to prevent unnecessary anxiety and medical intervention. This focused approach ensures that patients only receive results that are highly reliable and directly relevant to their future health management.
Criteria for Gene Inclusion
The selection of genes for the ACMG list is based exclusively on medical actionability, which is the cornerstone of the entire guideline. Actionability is defined as the availability of established medical interventions that can significantly reduce the morbidity or mortality associated with the genetic condition. If a pathogenic variant is discovered early, the patient must have clear medical options—such as heightened surveillance, prophylactic surgery, or specific medication—to prevent or mitigate the disease.
The ACMG Secondary Findings Working Group rigorously evaluates each nominated gene-disease pair against this standard. Conditions lacking effective preventative or therapeutic measures are intentionally excluded, regardless of disease severity. Therefore, the list focuses on high-penetrance conditions, meaning the genetic change is highly likely to lead to the disease during the patient’s lifetime.
Inclusion requires high evidence demonstrating both the clinical validity of the gene-disease link and the utility of the medical intervention. The list is continuously updated to reflect new scientific understanding and the development of new treatments.
Health Conditions Covered
The conditions represented on the ACMG list primarily fall into three categories: hereditary cancer syndromes, inherited cardiac conditions, and connective tissue disorders.
Hereditary Cancer Syndromes
Hereditary Cancer Syndromes account for a large portion of the list because preventative measures are well-established and highly effective. Genes like \(BRCA1\) and \(BRCA2\), associated with hereditary breast and ovarian cancer, are included because identifying a pathogenic variant allows for interventions such as increased screening with breast magnetic resonance imaging (MRI) or prophylactic surgery.
The list also includes genes responsible for Lynch Syndrome, such as \(MLH1\), \(MSH2\), \(MSH6\), and \(PMS2\). These variants significantly increase the lifetime risk for colorectal and endometrial cancers. Finding these variants enables preventative measures like frequent colonoscopies, which can detect and remove precancerous polyps before they become malignant.
Inherited Cardiac Conditions
This major category covers inherited Cardiac Conditions, which are often associated with sudden cardiac death. Examples include genes linked to Long QT Syndrome (\(KCNQ1\), \(KCNH2\), and \(SCN5A\)) and those for hypertrophic and dilated cardiomyopathies (\(MYBPC3\) and \(MYH7\)). Early detection of pathogenic variants allows for immediate management, which may involve medication like beta-blockers or the implantation of a cardioverter-defibrillator (ICD) to prevent fatal arrhythmias.
Connective Tissue Disorders
The list addresses conditions that affect connective tissue, most notably Marfan syndrome, caused by pathogenic variants in the \(FBN1\) gene. This condition is associated with a high risk of aortic dissection, a life-threatening rupture of the main artery. Identification of an \(FBN1\) variant allows for regular aortic imaging and medical management with blood pressure-lowering drugs to slow aortic dilation, preventing catastrophic cardiovascular events.
Patient Rights and Managing Results
The process of reporting secondary findings begins with pre-test genetic counseling, where the patient’s rights are thoroughly discussed. A fundamental component of the ACMG guideline is the patient’s right to choose whether or not to receive these secondary findings, often called the “right not to know.” Before the genetic test is performed, patients must be informed that a search for these actionable variants will be conducted, and they are given the explicit option to opt-out of receiving any results from the ACMG list.
If a pathogenic or likely pathogenic variant is found, post-test genetic counseling is necessary. The genetic counselor helps the patient interpret the complex information, including the calculated lifetime disease risk and the specific medical interventions available. This session is designed to manage the psychological impact of an unexpected diagnosis, which can include anxiety, uncertainty, and feelings of survivor guilt.
The counselor also facilitates the transfer of care to appropriate specialists, such as cardiologists or oncologists, for implementing the recommended screening or preventative plan. Furthermore, a positive secondary finding often has implications for the patient’s family members, who may also carry the same variant. This necessitates cascade screening to identify at-risk relatives who can also benefit from early intervention.