Secondary and Incidental Findings

Secondary and incidental findings are genetic results that fall outside the original reason for testing. Incidental findings are encountered unexpectedly, while secondary findings are actively looked for in a defined set of genes regardless of the test's primary indication. Both raise the question of what results to seek and return when broad sequencing inevitably reveals more than was asked.

Definition

Secondary findings are results in a predefined set of genes that are deliberately analyzed and reported independent of the indication for testing, whereas incidental findings are clinically relevant results encountered unexpectedly during analysis aimed at another question.

Scope

The topic distinguishes incidental from secondary findings, describes the rationale for maintaining a defined, periodically updated list of genes considered for deliberate secondary analysis, and outlines the criteria, such as actionability, used to decide which genes belong on such a list. It addresses the interpretive and policy structure around unsought results, not individual clinical decisions about returning them.

Core questions

• How do secondary findings differ from incidental findings?
• Why maintain a defined list of genes for deliberate secondary analysis?
• What criteria, such as actionability, decide which genes are included?
• How does the list change as evidence evolves?

Key concepts

• Incidental versus secondary findings
• Defined secondary-findings gene list
• Clinical actionability
• Opt-out and patient choice
• Periodic list revision
• Reporting scope in broad sequencing

Mechanisms

When exome or genome sequencing is performed for one indication, the data inevitably contain information about many other genes. To handle this systematically, professional recommendations defined a minimum list of genes in which known pathogenic variants should be deliberately sought and reported as secondary findings, chosen largely because the associated conditions are considered medically actionable (Green et al., 2013). The list is not fixed: it has been revised and expanded across successive versions as evidence and consensus change (Miller et al., 2021; Miller et al., 2023). Incidental findings, by contrast, are not pre-specified but arise unexpectedly in the course of the primary analysis.

Clinical relevance

The handling of unsought results is a central interpretive and counseling issue in broad genomic testing, including how the scope of reporting is defined and how patient choice is respected. The topic describes the framework and criteria for secondary and incidental findings; it is a reference account and does not direct whether or how to return any particular finding to an individual.

Epidemiology

Because secondary findings are sought in a defined gene set, the proportion of individuals with a reportable secondary finding depends on the genes included and the population tested; expansion of the list across versions changes the expected yield (Miller et al., 2021; Miller et al., 2023).

History

As clinical exome and genome sequencing grew, the question of unsought results became unavoidable, and a 2013 policy statement introduced a defined minimum list of genes to be examined for reportable secondary findings, selected for actionability (Green et al., 2013). The list has since been maintained and periodically updated through successive versions, reflecting accumulating evidence and shifting consensus on which genes warrant inclusion (Miller et al., 2021; Miller et al., 2023).

Debates

Which genes should be on the secondary-findings list, and should patients be able to decline?

Deciding which genes meet the bar of actionability for deliberate reporting, and how to honor patient preferences to opt out, has been contested since the list was introduced and has shaped its successive revisions.

Key figures

• Robert C. Green
• David T. Miller
• Leslie Biesecker

Seminal works

• green-2013
• miller-2021
• miller-2023

Frequently asked questions

What is the difference between a secondary and an incidental finding?

A secondary finding is deliberately looked for in a predefined set of genes regardless of why the test was ordered, whereas an incidental finding is one encountered unexpectedly while analyzing for the original question.

Why is there a defined list of genes for secondary findings?

Broad sequencing reveals far more than the original question, so a defined list, chosen largely for medical actionability, gives a consistent, evidence-based scope for which additional results are deliberately examined and reported.