When a person undergoes comprehensive genetic sequencing, such as whole-exome or whole-genome sequencing, the primary goal is often to find a genetic cause for a specific medical condition. This search involves analyzing thousands of genes to pinpoint the source of a known or suspected disorder. However, these expansive tests also generate data on genes entirely unrelated to the original reason for testing.
The American College of Medical Genetics and Genomics (ACMG) developed a standardized framework to handle these unexpected results, formally called ACMG Secondary Findings. These findings are genetic variants that indicate a high risk for a serious health condition for which preventative measures or treatments are available. The ACMG formalized the reporting of these results to ensure that relevant health information is not inadvertently withheld from patients undergoing advanced genetic testing.
Defining Secondary Findings
ACMG Secondary Findings (SFs) are formally defined as pathogenic or likely pathogenic variants discovered in a specific set of genes during a clinical genetic test ordered for a completely different reason. These findings are considered “secondary” because they are an unexpected discovery, distinct from the primary variant sought to explain the patient’s symptoms. The terms “secondary findings” and “incidental findings” are often used interchangeably in clinical practice.
The core principle underpinning the reporting of these variants is medical actionability. The ACMG recommendations identify high-penetrance conditions, meaning the genetic variant has a strong likelihood of causing the disease in the person’s lifetime. For a finding to be reported, it must relate to a condition that is serious, highly penetrant, and one for which early detection or intervention can significantly reduce morbidity or mortality. Laboratories are directed to report only genetic variants classified as pathogenic or likely pathogenic, ensuring a high degree of certainty. This strict filtering is necessary because the presence of a secondary finding, which occurs in an estimated 1% to 6% of tested individuals, mandates a clinical follow-up that can be complex and emotionally challenging.
The Criteria for Inclusion
The specific genes that qualify as ACMG Secondary Findings are contained within a highly curated and regularly updated list, such as the ACMG SF v3.2 list, which includes 81 distinct genes. This list is the result of a rigorous consensus process by experts, who select only those gene-disease pairs that meet the criteria of being serious and medically actionable. The diseases covered by the list are limited to those where a clear, established intervention exists to mitigate the risk.
The diseases represented generally fall into categories of hereditary cancer predisposition syndromes, specific cardiovascular conditions, and certain inborn errors of metabolism. For example, the list includes genes like BRCA1 and BRCA2, which increase the lifetime risk for breast and ovarian cancers, and LDLR, associated with Familial Hypercholesterolemia. Also included are genes such as MYH7 and ACTA2, linked to serious cardiac conditions like hypertrophic cardiomyopathy and familial thoracic aortic aneurysm. The inclusion of a gene signifies a determination that the benefit of knowing the risk outweighs the potential burden of the information.
The Patient’s Right to Decline
Receiving unexpected health information can have profound psychological, social, and financial impacts, making patient autonomy a central component of the ACMG framework. Patients undergoing whole-exome or whole-genome sequencing have the right to “opt out,” or dissent, from the analysis and reporting of secondary findings. This choice must be presented and discussed during the informed consent process before the genetic test is performed.
Pre-test genetic counseling is crucial for ensuring this decision is informed. The counselor explains the nature of the secondary findings, the specific diseases involved, and the implications of both receiving and declining the results. While the ACMG recommends the return of these findings due to their potential benefit, the policy respects the patient’s “right not to know.” The patient’s decision to opt out means the laboratory will not analyze or report variants in the designated ACMG secondary findings genes, even if the raw data suggests a significant health risk.
Medical Actionability and Follow-Up
The purpose of reporting an ACMG Secondary Finding is to enable medical actionability. This refers to the availability of established and effective interventions to prevent or significantly reduce the severity of the associated disease. Actionable steps can include increased surveillance, prophylactic surgery, lifestyle modifications, or the initiation of specific medications. These interventions are generally well-defined, distinguishing these findings from risks for conditions where no reliable preventative strategies exist.
When a pathogenic or likely pathogenic variant is reported, the initial step involves confirmatory testing, often using a different laboratory method, to ensure the accuracy of the result. Following confirmation, the patient is immediately referred to the appropriate specialist, such as a cardiologist for an arrhythmia variant or an oncologist for a hereditary cancer risk. For instance, a positive finding in BRCA1 prompts a referral to a high-risk cancer clinic to discuss intensified screening, such as annual breast MRIs, or risk-reducing surgeries. The goal of this structured follow-up is to transition the patient to active preventative medical management.