Skip to main content

How to address secondary findings from genomic testing

How to address secondary findings from genomic testing

How to address secondary findings from genomic testing

Consider this scenario: Jayne is 50 years old and has experienced progressing neurological symptoms over the past two years with no diagnosis. She recently had exome testing which show no genetic variants that explain her symptoms, but identifies a pathogenic variant (mutation) in MSH6. This gives her a diagnosis of Lynch syndrome which puts her at significantly increased risk for colon and endometrial cancer, among other cancer types. The specialist’s note indicates that she should follow up with her primary care provider (you) about this result. She is coming in for an appointment this week. What will you do?

The more you look, the more you see. It’s true for many medical tests, including genetic testing. It has become possible and often desirable to assess more of the genome in a cost-effective manner such as exome testing. Secondary findings, such as Jayne’s MSH6 mutation, are not related to the primary reason for ordering the test, but may be medically actionable.

Jayne is one of the approximately 2% of individuals identified with a secondary finding on exome testing. [Hart 2019] While receiving these results can be surprising for someone already dealing with another condition, they may provide an opportunity to reduce future disease risk. Clear communication about the risks and next steps will increase the likelihood that your patient will benefit from this information.

Why test for genes not associated with the patient’s symptoms?

Studies have demonstrated the clinical utility of exome testing for diagnosis. While comprising only 1-2% of the entire genome, the exome contains the majority of the variants associated with disease.

When broad testing, such as exome testing, is ordered, the American College of Medical Genetics and Genomics (ACMG) recommends reporting pathogenic variants for a list of 59 genes, regardless of the indication for testing. [Kalia 2017] A panel of experts identified these genes and associated conditions as medically actionable, meaning that management guidelines are available and, when applied, can improve health outcomes. Genes included on the ACMG list include those for several hereditary cancer syndromes, connective tissue disorders, cardiac syndromes, arrhythmic disorders, metabolic disorders, malignant hyperthermia and familial hypercholesterolemia. A list of all the conditions and their associated genes is available on the NCBI ClinVar website.

Did Jayne know her testing included genes unrelated to neurological conditions?

Jayne likely did know that the test might reveal risks for disease unrelated to her condition. The question is whether and how much of that pre-test discussion she remembers.

The potential for a secondary finding is one of the many topics that professional organizations, such as ACMG, recommend including in the pre-test counseling and informed consent discussion. [ACMG 2013] That said, there’s a lot that needs to be covered in pre-test counseling. Depending on how the discussion happens, as well as where the patient and family is physically, mentally, and emotionally during the discussion, receiving a secondary finding may be a shock.

In addition, what Jayne may have been told about the MSH6 result depends on the ordering provider’s familiarity with Lynch syndrome. During your consultation, you’ll need to assess what she knows, what she doesn’t, and how she is coping with the new information. All of these factors will impact your discussion and how likely Jayne is to engage in the recommended screening for Lynch syndrome.

What does Jayne need to know about the results?

Jayne is likely to have wide-ranging questions. There are some important messages about secondary results to share, regardless of the specific gene involved.

No additional testing is necessary. The test result is accurate and does not need to be confirmed;

Not everyone with the variant will develop the condition;

There are things that can be done to reduce risk and/or identify disease early; and

The result has implications for relatives.

Jayne will also need information specific to the MSH6 result, including what steps can be taken to mitigate her risk. There may be information about the result and Lynch syndrome in the test report itself, and there are resources that can provide additional information about Lynch syndrome, including the National Comprehensive Cancer Network (NCCN). In most cases, the next step will be to refer Jayne to a cancer genetic specialist who can discuss the diagnosis in more detail. It is important for you, the referring provider, to emphasize the importance of following through on that referral.

It is also important to acknowledge that Jayne has just received a new diagnosis on top of the diagnosis she is still searching for related to her neurologic symptoms. Be aware of factors that can influence a patient’s ability to understand or cope with the results, including emotional reactions to results, underlying psychosocial issues, and baseline understanding of genomic testing. Elicit, acknowledge, and validate unique feelings that arise from genomic results.

Your goal is for Jayne to leave the discussion with a clear sense of next steps, and a follow-up appointment to check on progress with this plan.

What about the cause of Jayne’s neurologic condition?

With regard to Jayne’s neurologic symptoms, the results from exome testing were negative, meaning no pathogenic variant was identified in a gene associated with the symptoms. While exome testing is a broad test, a negative result does not completely rule out a condition. There could be a causal variant that exome testing technology is not able to detect. Additionally, Jayne’s symptoms could have a non-genetic cause or a multifactorial etiology due to both environmental and more moderate genetic risk factors not assessed by exome testing.


Exome testing is becoming more accessible as the cost of testing decreases, and the ability to screen or intervene in genetic conditions improves. With broader testing, clinicians are more likely to be seeing patients with secondary finding results such as Jayne’s. Knowing how to discuss these findings with patients and to whom to refer patients in the local community are important in supporting patients trying to understand these types of results.


To learn more

Other resources