Residency · Residency · Medical Genetics Genomics

Incidental and Secondary Findings in Genomic Sequencing

Introduction

Broad genomic testing such as exome and genome sequencing can reveal medically actionable genetic variants unrelated to the primary indication for testing. The management of these findings has been a defining ethical and practical challenge of the genomic medicine era. The ACMG has issued evolving recommendations that shape current practice, and understanding the distinction between incidental and secondary findings, along with the clinical infrastructure needed to manage them, is essential for all practitioners of genomic medicine.

Terminology

Incidental findings are pathogenic or likely pathogenic variants discovered unintentionally during analysis directed at the primary clinical question. They are not actively sought but emerge as a byproduct of broad genomic interrogation. Secondary findings, by contrast, are pathogenic or likely pathogenic variants identified through deliberate, systematic analysis of a predefined list of medically actionable genes, independent of the primary indication. The ACMG uses the term secondary findings for their recommended gene list, reflecting the active, intentional nature of the analysis. Although some laboratories and guidelines use the terms interchangeably, the distinction is conceptually important because it determines whether discovery is a passive consequence of sequencing or an active clinical intervention.

ACMG Secondary Findings Recommendations

Evolution of the List

The ACMG first published its secondary findings list (SF v1.0) in 2013, recommending analysis of 56 genes when clinical exome or genome sequencing is performed. SF v2.0 in 2017 updated the list to 59 genes with refined inclusion criteria. SF v3.0 in 2021 expanded it substantially to 73 genes, adding genes for hereditary cancer, cardiovascular, and metabolic conditions. SF v3.1 in 2022 further expanded the list to 78 genes encompassing 81 gene-condition pairs. SF v3.2 in 2023 represents the current version with continued refinements. This progressive expansion reflects the growing body of evidence supporting clinical actionability for additional gene-condition pairs.

Inclusion Criteria

For a gene to be included on the ACMG secondary findings list, the gene-disease association must be well-established, with ClinGen definitive or strong evidence. The condition must be medically actionable, meaning available interventions such as surveillance, preventive measures, or treatments can reduce morbidity or mortality. Penetrance must be sufficient to warrant clinical action upon identification. The condition must be clinically significant with meaningful health impact that justifies the implications of an unsolicited positive result.

Major Gene Categories on the ACMG SF List

The hereditary cancer category includes BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, APC, biallelic MUTYH, TP53, PTEN, RB1, MEN1, RET, VHL, SDHB/C/D, SMAD4, BMPR1A, STK11, and others. The cardiovascular category encompasses sarcomeric cardiomyopathy genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1), dilated cardiomyopathy genes (LMNA, FLNC), arrhythmogenic cardiomyopathy genes (DSP, PKP2, DSG2, DSC2), channelopathy genes (KCNQ1, KCNH2, SCN5A), aortopathy genes (FBN1, TGFBR1/2, SMAD3, COL3A1, ACTA2, MYH11), and familial hypercholesterolemia genes (LDLR, APOB, PCSK9). The metabolic and other category includes RYR1 and CACNA1S for malignant hyperthermia susceptibility, HFE for homozygous C282Y hereditary hemochromatosis, BTD for biotinidase deficiency, and GAA for Pompe disease.

Prevalence of Secondary Findings

Approximately 1-3% of individuals undergoing exome or genome sequencing harbor a reportable secondary finding in ACMG SF genes. Rates are higher in populations with founder mutations, such as BRCA1/2 pathogenic variants in Ashkenazi Jewish individuals. The probability of identifying a secondary finding increases with expanding gene lists and broader sequencing approaches. The most common findings are in hereditary cancer and cardiovascular genes, reflecting the representation of these categories on the list.

Consent and Return of Results

Pre-Test Consent Process

Patients must be informed about the possibility of secondary findings before testing is undertaken. The consent process should explain what types of conditions may be identified, that these findings are unrelated to the primary testing indication, the available options to opt in or opt out of secondary findings analysis, and the implications for family members. The ACMG recommends that laboratories offer SF analysis but recognizes the patient's right to decline.

The Opt-Out Debate

The ACMG's initial position in 2013 recommended against allowing patients to opt out, stating that all laboratories should analyze and report secondary findings. This position was revised in 2014 and onward to acknowledge that patients should have the right to opt out of SF analysis after informed consent. Most clinical laboratories now offer opt-out as standard practice. Some professional organizations advocate for granular opt-out options, allowing patients to accept certain categories of findings while declining others, such as opting out of cancer genes but accepting cardiovascular genes.

Return of Results

Only pathogenic and likely pathogenic variants in ACMG SF genes should be returned as secondary findings. Variants of uncertain significance in SF genes are generally not reported as secondary findings, as the clinical actionability that justifies unsolicited reporting requires high confidence in pathogenicity. Results should be delivered with genetic counseling to explain the finding, its implications, and recommended follow-up. Appropriate specialty referral for clinical management should follow, such as oncology for BRCA1/2 findings or cardiology for cardiomyopathy gene variants.

Clinical Management After a Secondary Finding

Actionability Framework

The defining characteristic of ACMG SF genes is clinical actionability. For each gene, specific surveillance and management recommendations exist. BRCA1/2 findings trigger enhanced breast screening with MRI, discussion of risk-reducing surgery, and ovarian cancer surveillance. FBN1 findings indicating Marfan syndrome lead to echocardiographic surveillance, beta-blocker or ARB therapy, and activity modifications. LDLR findings for familial hypercholesterolemia prompt lipid panel assessment, statin therapy initiation, and cascade family screening. Malignant hyperthermia susceptibility gene findings mandate avoidance of triggering anesthetic agents. The ClinGen Actionability Working Group has developed a semi-quantitative framework for evaluating clinical actionability that informs which genes meet the threshold for SF list inclusion.

Cascade Testing

Secondary findings have implications for biological relatives who may share the identified variant. Cascade testing of first-degree relatives should be offered following the same principles as primary genetic diagnoses. The proband has the responsibility to inform at-risk relatives, supported by the clinical team with family letters and genetic counseling resources.

Ethical Considerations

Autonomy and the Right Not to Know

Robust informed consent must include the option to decline secondary findings. Some individuals may not want information about conditions for which they have no symptoms, particularly when such information may generate anxiety, alter self-perception, or affect insurance eligibility. The balance between the potential health benefit and psychological burden must be navigated individually.

Pediatric Considerations

The ACMG recommends returning childhood-actionable secondary findings in minors undergoing exome or genome sequencing. Adult-onset conditions identified in children raise questions about the child's future autonomy to decide whether they wish to know their genetic status. Current ACMG guidance supports returning adult-onset findings in children to enable family cascade testing, but this position remains debated in the bioethics community.

Research vs. Clinical Contexts

Research participants may or may not receive secondary findings depending on the study protocol and consent. The National Academies of Sciences 2018 report recommended returning actionable findings to research participants when possible. However, research-grade sequencing results typically require clinical confirmation in a CLIA-certified laboratory before any clinical action is taken based on the finding.

Challenges and Future Directions

As knowledge grows, the SF list will continue to expand, increasing the frequency and complexity of secondary findings. Some advocate for offering SF analysis as population-level genomic screening decoupled from diagnostic testing. Equity concerns arise because access to post-finding management and surveillance varies by insurance status and geography. The laboratory burden of SF analysis adds cost and effort to every clinical sequencing test. The question of recontact obligation remains unresolved: as new genes are added to the SF list, it is unclear whether previously sequenced patients should be recontacted with newly relevant findings from their existing data.

Clinical Pearls

Secondary findings are medically actionable pathogenic or likely pathogenic variants deliberately sought in a defined gene list, distinct from incidental findings discovered during primary analysis. Approximately 1-3% of individuals undergoing clinical exome or genome sequencing will have a reportable secondary finding, and patients must be counseled about this possibility before testing. The right to opt out of secondary findings analysis is now standard practice, and informed consent should clearly present this option. Every secondary finding triggers a cascade of clinical obligations including genetic counseling, specialty referral, and family notification for cascade testing.

References

1. Miller DT, Lee K, Abul-Husn NS, et al. ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics. Genetics in Medicine. 2022;24(7):1407-1414.
2. Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in Medicine. 2013;15(7):565-574.
3. Kalia SS, Adelman K, Bale SJ, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0). Genetics in Medicine. 2017;19(2):249-255.
4. Hart MR, Biesecker BB, Blout CL, et al. Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study. Genetics in Medicine. 2019;21(5):1100-1110.

Read this lecture as Markdown