One question frequently asked is: “How many actionable genes do you report?” While this sounds like a simple question, it is really asking something much broader: “Under what circumstances can genomic information inform patient care?”
The true value of genomic testing is not measured by the number of genes labeled as actionable. Instead, it depends on whether a particular finding, considered together with the patient’s clinical circumstances, may provide information relevant to diagnosis, treatment, prevention, surveillance, risk reduction, or long-term disease management.
Clinical actionability in genomics extends beyond the availability of disease-specific therapies. Within the ACMG (American College of Medical Genetics and Genomics)1 and ClinGen2 frameworks, a genomic finding is considered actionable when it supports a clinical intervention that has the potential to improve health outcomes. Such interventions may include disease surveillance, diagnostic follow-up, risk-reduction strategies, imaging, family-based screening, or therapeutic measures. ClinGen evaluates the clinical actionability of gene–disease associations using a semiquantitative framework that incorporates disease severity, penetrance, intervention effectiveness, and the risks or burdens of intervention3,4.
Clinical actionability is not synonymous with treatment. It encompasses any intervention that improves patient care—including medication selection, disease surveillance, risk reduction, family planning, and targeted therapy.
Clinical validity, Clinical Utility, and Clinical Actionability
Before discussing actionability, it is important to distinguish it from clinical validity and clinical utility. A gene may be strongly associated with disease (clinically valid) but offer few immediate interventions. Conversely, a finding may have substantial clinical utility by informing diagnosis, prognosis, or family risk even when no targeted therapy exists.
Clinical validity refers to whether a gene or variant is truly associated with a disease or health outcome. In other words, does the genetic finding reliably predict, contribute to, or explain a clinical condition?
Clinical utility refers to whether the information provides value in patient care. A result may be clinically useful because it improves diagnosis, refines prognosis, ends a diagnostic odyssey, or informs family counseling—even when no specific treatment exists.
Clinical actionability goes a step further and asks what actions become possible because the information is known. Those actions may include targeted treatment, medication selection, avoidance of harmful drugs, increased surveillance, risk reduction strategies, reproductive planning, cascade testing of relatives, or enrollment in clinical trials.
For example, a pathogenic LDLR variant may prompt earlier statin therapy and more aggressive cholesterol management, while a high-risk BRCA1 variant may lead to enhanced cancer screening or consideration of preventive surgery.
A genetic finding may be clinically valid without being actionable, and it may be clinically useful even when no targeted intervention exists. For example, a variant associated with an untreatable rare disease may be both clinically valid and clinically useful because it establishes a diagnosis, yet currently offers limited opportunities for medical intervention. Conversely, a pharmacogenomic variant in the SLCO1B1 gene may be highly actionable because it provides information relevant to medication selection, dosing, and the potential risk of certain adverse drug reactions.
| Concept | Example | Can Exist Without Actionability? |
| Clinical Validity asks whether the result is true | Pathogenic BRCA1 variants are well-established causes of hereditary breast and ovarian cancer susceptibility. | Yes. A gene may be strongly associated with disease even if no intervention exists. |
| Clinical Utility asks whether the result is useful | A pathogenic variant causing a rare neurodevelopmental disorder may provide a definitive diagnosis and end a lengthy diagnostic odyssey. | Yes. Information may be useful even when no treatment or prevention strategy is available. |
| Clinical Actionability asks whether the result changes what you do | An LDLR variant may lead to earlier statin therapy; a DPYD variant may alter chemotherapy dosing; a BRCA1 variant may trigger enhanced cancer surveillance. | No. By definition, actionability requires a potential intervention or management change. |
Actionability refers to a genetic finding’s ability to inform a clinical, preventive, or personal health decision.
Examples include aiding a healthcare provider in selecting or avoiding specific medications, guiding surveillance and screening strategies, reducing modifiable risk factors, informing reproductive planning, identifying at-risk relatives, and consideration in determining eligibility for targeted therapies or clinical trials.
ACMG Secondary Findings
Perhaps the best-known example of medical actionability is the ACMG Secondary Findings list5. The American College of Medical Genetics and Genomics (ACMG) recommends that laboratories performing clinical exome or genome sequencing actively evaluate a curated set of genes associated with serious, potentially preventable, or treatable conditions. For individuals found to carry pathogenic or likely pathogenic variants in these genes, established medical interventions may reduce morbidity or mortality. The list is reviewed and updated regularly as new evidence emerges and additional therapeutic options become available.
Hereditary cardiovascular disorders and cancer predisposition syndromes comprise the majority of conditions included on the ACMG Secondary Findings list. The identification of pathogenic variants in these genes can prompt well-established, evidence-based medical management strategies intended to reduce the risk of serious outcomes, including sudden cardiac death or advanced malignancy.
It is important to understand that inclusion on the ACMG Secondary Findings list does not imply that genes outside the list are not medically actionable. Rather, the list represents a minimum set of genes for which there is broad professional consensus that the identification and reporting of pathogenic variants provide a clear opportunity for clinical intervention and patient benefit. Many other genes may also be actionable in specific clinical contexts but may not yet meet ACMG criteria for inclusion as secondary findings.
This distinction highlights an important principle: clinical actionability is multifaceted. The ACMG Secondary Findings list represents one important application of actionability, but many other forms of clinically meaningful actionability may exist beyond secondary findings.
Clinical Actionability in Practice
Medication Selection
For patients with a CYP2C19 poor metabolizer phenotype, a physician may consider an alternative to clopidogrel because impaired CYP2C19 function can reduce conversion of clopidogrel to its active metabolite, potentially resulting in decreased therapeutic efficacy.
Medication Toxicity
A patient carrying a pathogenic variant in the DPYD gene, for example, can dramatically increase the risk of life-threatening toxicity from fluoropyrimidine chemotherapy. Variants in the DPYD, TPMT, and NUDT15 genes may help identify individuals at increased risk of severe, and potentially life-threatening, adverse drug reactions. When supported by applicable drug labeling or evidence-based professional guidelines, this information may assist healthcare professionals in evaluating dosing, alternative therapy, or other appropriate precautions before treatment begins.
Surveillance and Lifestyle Modification
Individuals with pathogenic variants in genes associated with hereditary cancer syndromes, such as BRCA1, BRCA2, MLH1, MSH2, or TP53, may undergo earlier and more frequent cancer screening and may be eligible for additional risk-reducing interventions.
A patient carrying pathogenic variants in cardiomyopathy-associated genes such as MYBPC3, MYH7, TNNT2, or LMNA may undergo periodic echocardiography, cardiac MRI, and rhythm monitoring to detect disease before symptoms develop. A person with increased genetic risk (LDLR, APOB, PCSK9) for coronary artery disease may benefit from aggressive management of cholesterol, blood pressure, smoking cessation, and exercise.
Family Planning and Carrier Risk
Two individuals who carry pathogenic CFTR variants may consider preimplantation genetic testing or prenatal diagnostic testing to better understand or manage the likelihood of having a child with cystic fibrosis. When a pathogenic LDLR variant causing familial hypercholesterolemia is identified, relatives can undergo cascade testing to determine whether they also require treatment and monitoring.
Targeted Therapies
Some genetic findings may be considered in determining eligibility for precision therapies. A patient diagnosed with breast cancer having a somatic gain-of-function HER2 variant or amplification defect may be eligible for HER2-targeted therapies, while the presence of a pathogenic germline BRCA1 or BRCA2 variant may contribute to the assessment of eligibility for PARP inhibitor treatment, subject to the applicable approved indication and consideration of the patient’s complete clinical circumstances.
The emergence of RNA therapeutics—including siRNA and antisense oligonucleotide therapies—has fundamentally changed the landscape of actionability by transforming previously untreatable inherited disorders into diseases with mechanism-based therapies. For patients with an appropriate clinical diagnosis, certain genetic findings may help determine whether such therapy should be considered. For example, a patient carrying a pathogenic TTR variant associated with amyloidosis may be eligible for RNA interference (siRNA) therapies, such as patisiran or vutrisiran, or a patient with an AGXT gene pathogenic variant may be eligible for treatment of primary hyperoxaluria type I with siRNA therapy that suppresses hepatic oxalate production.
Clinical Trials and Research
Identification of certain variants may help patients and healthcare professionals identify potentially relevant clinical trials. For example, patients with rare genetic variants associated with amyotrophic lateral sclerosis (ALS) or inherited retinal disease may qualify for genotype-specific clinical trials evaluating novel therapies. Actual eligibility is determined under each trial’s inclusion and exclusion criteria.
Summary
Clinical actionability in genetics refers to whether a genetic finding can inform meaningful health-related decisions, not simply whether a cure or specific treatment exists. A result is considered actionable when it can influence medical management, medication selection, surveillance, risk-reduction strategies, reproductive planning, family screening, participation in clinical trials, or other preventive and personal health decisions. Therefore, actionability is not an inherent property of a gene but depends on how genetic information may be used to guide care and decision-making.
Clinical actionability is a dynamic concept that changes over time as new evidence, technologies, and interventions become available. Two decades ago, RNA therapeutics were largely absent from clinical practice, pharmacogenomics was seldom used in patient care, polygenic risk scores did not exist, multi-cancer blood tests had yet to emerge, and whole-body MRI screening was rarely performed. Consequently, the range of actionable genomic findings continues to expand, reflecting ongoing advances in precision medicine and preventive healthcare.
Clinical genetics has evolved far beyond its traditional role in diagnosing rare diseases. Today, it plays a central role in enabling personalized healthcare across the lifespan by providing information that healthcare providers may consider when making recommendations involving medication selection, disease prevention, early detection, targeted treatment, and family planning.
Asking “How many actionable genes do you report?” assumes actionability is a fixed property of a gene. Modern clinical genetics tells a different story. Actionability lies not within the gene itself, but depends on the specific gene and variant, the strength of the supporting evidence, the individual’s clinical circumstances, and the availability and appropriateness of an intervention.
As therapies, diagnostics, and preventive strategies continue to evolve, genomic data may serve as a valuable longitudinal clinical resource rather than a one-time diagnostic test. However, it is important to note that not every gene or finding will be actionable for every patient, and updated analysis, confirmatory testing, or additional clinical evaluation may be necessary before information is used in patient care. From this perspective, asking “How many actionable genes do you report?” becomes the wrong question. The number of genes described as actionable does not, by itself, fully represent the potential clinical relevance of genomic testing.
Disclaimer: This educational article discusses clinical actionability as a general concept and provides examples from published medical literature and professional frameworks. These examples do not necessarily represent findings, indications, or services included in tests offered by Simplify Genomics and do not mean that every gene or result will lead to a change in care. The clinical relevance and actionability of a genetic finding depend on the specific variant, the strength of the supporting evidence, the individual’s clinical circumstances, and the availability and appropriateness of an intervention. Test results should be evaluated by a qualified healthcare professional together with other relevant clinical information.
References
- American College of Medical Genetics and Genomics – https://www.acmg.net
- National Institutes of Health ClinGen – https://clinicalgenome.org
- Webber EM, et al. 2018. Evidence-based assessments of clinical actionability in the context of secondary findings: Updates from ClinGen’s Actionability Working Group. Hum Mutat. 39(11):1677-1685.
- Burke W. 2014. Genetic tests: clinical validity and clinical utility. Curr Protoc Hum Genet. 24;81:9.15.1-9.
- Lee K et al. 2025. ACMG SF v3.3 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 27(8):101454.