Does a Positive Secondary Finding Mean Disease Will Develop? | SF Series Part 3

You have received a result showing that a secondary finding was identified on exome sequencing.

Does that mean the condition has already developed, or that it will certainly develop in the future?

The short answer is: not necessarily.

A positive secondary finding does not necessarily mean that the condition is currently present or that it will inevitably develop. Depending on penetrance, the same variant can be associated with differences in whether, when, and how severely the condition manifests.

What are secondary findings? Secondary findings are medically important genetic results that are unrelated to the original indication for exome or genome sequencing but are intentionally analyzed because identifying them may enable prevention, surveillance, or early treatment. The American College of Medical Genetics and Genomics (ACMG) maintains and periodically updates a recommended list of genes associated with such medically actionable conditions. Whether secondary findings are analyzed and reported may depend on the testing laboratory, clinical setting, and the individual’s consent or preferences.

What does a pathogenic variant mean?

Genetic variants are generally classified according to the strength of the supporting evidence.

• Pathogenic
• Likely Pathogenic
• Variant of Uncertain Significance (VUS)
• Likely Benign
• Benign

For ACMG secondary findings, reporting generally focuses on Pathogenic or Likely Pathogenic variants.

Such a result means that the risk of the associated condition may be significantly increased.

However, depending on the gene, not everyone who carries a pathogenic variant will actually develop the condition.

Is it possible to carry a pathogenic variant and never develop the condition?

Yes, it is.

Penetrance refers to the proportion of people with a disease-associated variant who actually develop the associated condition.

If penetrance is less than 100%, some people carrying the same variant may never develop symptoms in their lifetime.

Even within the same family, and even with the same variant, the presentation can differ:

• Age of onset may differ
• Severity of symptoms may differ
• Clinical features may differ
• Symptoms may never appear at all

So the identification of a pathogenic variant alone does not allow precise prediction of when the condition will develop or how severe it will be.

What it does allow is this: knowing that the risk is increased makes it possible to begin appropriate surveillance and management.

Is a VUS also a concerning result?

A VUS (Variant of Uncertain Significance) is a variant for which the currently available evidence is insufficient to determine whether it causes disease.

In other words, it cannot currently be classified as either pathogenic or benign.

A VUS alone should not be used as the basis for major medical decisions such as:

• Prophylactic surgery
• Long-term drug therapy
• Confirming a diagnosis in family members
• Major reproductive decisions, including pregnancy planning

Because secondary findings can lead directly to preventive medical action, strict reporting criteria are applied.

For this reason, a VUS is not considered a reportable secondary finding

What should you do if the result is positive?

1. Review exactly what the report says

Look beyond the gene name and confirm the following:

• Which variant was identified?
• What is the pathogenicity classification?
• Which condition is the variant associated with?
• What is the mode of inheritance?

A single gene can be associated with more than one condition, so a diagnosis should never be assumed from the gene name alone.

2. Revisit personal and family history

Symptoms or family history that previously seemed unimportant may turn out to be connected to the test result.

For example, it is worth checking whether any family member had:

• Cancer at a young age
• Unexplained sudden death
• Cardiomyopathy or arrhythmia
• Aortic dissection
• Very high LDL cholesterol

3. Undergo evaluation in the relevant specialty

Genetic risk alone cannot tell you whether the condition is currently present.

Depending on the condition, additional evaluation may be required, such as:

• Electrocardiography and echocardiography
• Blood tests
• Cancer screening, including breast and colorectal
• Aortic imaging
• Other organ-specific investigations

Even if current results are normal, regular follow-up may still be necessary.

4. Consider family testing

The implications of a genetic finding can extend beyond the individual who was tested.

When a pathogenic variant is identified, biological relatives such as parents, siblings, and children may also carry the same variant.

Testing family members specifically for that variant is called family testing, or cascade testing.

This allows family members who have no symptoms yet to learn about their risk and begin appropriate surveillance or preventive care when indicated.

If the result is negative, is that reassuring?

A negative result for secondary findings means that no Pathogenic or Likely Pathogenic variant meeting the reporting criteria was identified in the genes examined.

It does not mean any of the following:

• The condition will never develop
• All genetic risk has been ruled out
• Every possible genetic variant has been detected or ruled out
• Routine health screening is no longer needed

Some variants are difficult to detect by exome sequencing, and some genes are not included on the ACMG list.

In addition, many diseases can occur for reasons unrelated to the genetic variants assessed in secondary findings.

A negative result is therefore not a guarantee that risk is absent.

Results must always be interpreted alongside clinical information

A genetic test result does not stand on its own.

Accurate diagnosis and management also require:

• The patient’s current symptoms
• Past medical history
• Family history
• Physical examination
• Blood tests and imaging
• Gene-specific penetrance and age of onset

For this reason, searching the gene name online after receiving a report and concluding a diagnosis on your own is not appropriate.

The result and the clinical information should be evaluated together by a clinical genetics specialist and the relevant treating physicians.

In one sentence

A positive secondary finding does not mean the condition will certainly develop. It means that an increased risk has been identified, allowing appropriate evaluation, surveillance, and preventive management to begin.

The greatest value of secondary findings does not lie in predicting the future with precision.

It lies in the opportunity to begin surveillance before symptoms or complications develop, to intervene when necessary, and to identify family members who may also be at risk.

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