Medically Actionable Secondary or Incidental Results

Key Points:

  • Secondary findings are additional results that do not directly relate to the reason for testing.
  • Patients are often given the opportunity to opt in/out of receiving secondary findings when a whole exome or genome sequencing is ordered.
  • Common types of secondary findings include risk of future disease, response to medications, and carrier status results.
  • Many laboratories only report secondary findings that are medically actionable.

whole genome imageGenomic sequencing is used to aid in the diagnosis of a patient who, because of symptoms or family history, is suspected to have an underlying genetic disorder. The term “secondary results” refers to results that do not pertain to this primary diagnostic question. Secondary findings are a diverse category. Some secondary findings are medically actionable, meaning they prompt clinical action by the patient’s medical provider. In the case where genomic sequencing is being performed to identify future disease risk in an ostensibly healthy individual, results that are traditionally thought of as secondary results may become the primary results.

The terms “secondary findings” and “incidental findings” are often used interchangeably; however, they are sometimes employed in different ways. The secondary findings label is applied to results that are unrelated to the diagnostic question, but are nonetheless systematically sought out and analyzed. Incidental findings are not sought out, but identified nonetheless. Other terms that have been used to refer to secondary findings include “additional findings,” “off-target results,” and “unanticipated findings.”

Secondary findings, if present, are typically reported for the person undergoing sequencing. When genomic sequencing is completed for relatives of that person, such as parents for trio analysis, secondary findings may also be reported in relatives.

A patient presents with a personal history of peripheral neuropathy. Genomic sequencing is performed and a pathogenic variant is identified in the MLH1 gene. Pathogenic mutations in the MLH1 gene are associated with hereditary Lynch syndrome, which increases an individual’s risk to develop a variety of cancers including colon cancer. However, it is unrelated to the neuropathy symptoms and would thus not be part of the patient’s diagnostic result. This result would be classified as a secondary finding, unrelated to symptoms and reason for testing. Patients with Lynch syndrome are advised to have a colonoscopy with removal of any polyps every 1-2 years beginning in their mid-20s. This is a highly effective way to reduce colon cancer risk in individuals with Lynch syndrome. Because the identification of a pathogenic MLH1 mutation would prompt the patient’s clinician to initiate the colonoscopy screening protocol at the appropriate age, this is a medically actionable secondary finding.

Genomic testing can identify risk factors for future disease development. Genomic testing can also provide information about an individual’s carrier status for autosomal recessive diseases. While carrier status is not expected to impact an individual’s own health or medical care and is not actionable in the same way as was the secondary finding in the example above, it may be considered medically actionable by some, particularly by patients of reproductive age and their providers. Similarly, pharmacogenomics results (results concerning how genes affect a person’s response to drugs) may be included in secondary findings. These results would be medically actionable only if the patient takes a relevant drug. For more information about these types of results, please see the section anbout pharmacogenomics results.

How likely is a medically actionable secondary finding?
Most, if not all, laboratories offering clinical genomic sequencing return medically actionable secondary findings of some sort. The likelihood of such a finding depends on how secondary findings are defined and analyzed by the laboratory. The American College of Medical Genetics and Genomics (ACMG) proposed a list of 56 genes with 24 associated phenotypes as a minimum list of secondary findings to be systematically analyzed and reported by laboratories offering exome or genome sequencing. It has been estimated that ~1% of patients undergoing exome sequencing would receive a secondary finding using this list.

Because it would be inappropriate to initiate medical intervention for an unaffected person on the basis of uncertain information, laboratories typically only report pathogenic or likely pathogenic variants as secondary findings2. The ancestral background of the patient undergoing sequencing may influence the likelihood of a secondary finding. To date, individuals of European Caucasian ancestry have been overrepresented among cohorts undergoing genetic sequencing. Thus, there may be more evidence available to assess pathogenic and likely pathogenic variants in this group. Causative variants identified in non-European Caucasian populations such as African or Asian may go unrecognized due to lack of data, may be labeled variants of uncertain significance (VUS), or may not be reported.

Depending on a specific laboratory’s policy, there is often an opportunity for patients to opt in or out of receiving such secondary findings.

What if there are no medically actionable secondary findings?
Most patients undergoing genomic sequencing will not have a medically actionable secondary finding. This means there were no genetic variants identified that suggested a high likelihood of an actionable genetic condition that was unanticipated due to clinical signs and symptoms. Laboratories set a high bar for returning secondary finding results. Therefore, a lack of medically actionable secondary findings is not a clean bill of health, and does not reduce a person’s risk for future health problems such as cancer, cardiac arrhythmia, or vascular disease, since in the general population, most cases of such health problems are not attributable to the types of rare genetic conditions revealed as secondary findings from genetic sequencing. In addition, false negative results are possible due to a number of technological and interpretive limitations. Secondary findings must be examined in the context of the individual’s medical history and family history.

Why might a lab report secondary findings that are not medically actionable?
Many laboratories only report secondary findings that are not medically actionable if the patient actively chooses to receive such information. However, some laboratories may report on secondary findings that are not medically actionable but may be highly predictive. For example, pathogenic mutations in the SOD1 gene are associated with familial amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. People with a pathogenic mutation in this gene have a 90% chance to develop ALS by the time they are in their 70s. This finding would not be considered medically actionable because there are currently no therapies to prevent or delay ALS, or slow its progress. Despite this, a result of this sort may be desired. Patients electing to learn this type of information should consider possible benefits (such as enhanced ability to plan) with possible negative consequences (such as the risk of life insurance discrimination, or increased anxiety).

Age Matters
Most laboratories that return medically actionable secondary findings routinely do so regardless of the age of the patient. Laboratories that offer non-medically actionable secondary findings generally offer this only for adults who are competent to provide informed consent to receive this category of findings.


Next Steps to Consider

  • Learn more about the condition with which the patient has been diagnosed through GeneReviews and other resources
  • Referral to appropriate medical specialist, e.g. cardiologist for cardiovsascular genetic finding
  • Referral to genetic services (medical geneticist and/or genetic counselor) for medical follow-up and discussion of recurrence risks and implications for other family members



  • Anticipate and Communicate: Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-to-Consumer Contexts, from the Presidential Commission for the Study of Bioethical Issues
  • GeneReviews ( a resource for clinicians that provide clinically relevant and medically actionable information for inherited condition. This resource includes information on diagnostic criteria, management, and information about genetic counseling for patients and their families. There are chapters available about many, but not all, genetic conditions.
  • National Society of Genetic Counselors ( the professional organization for genetic counselors, with patient and provider resources and a searchable tool to “find a genetic counselor” near you.



  1. Kalia, S.S., et al. “Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.” Genet Med. 2016. Advance online publication doi:10.1038/gim.2016.190..
  2. Amendola, L.M., et al. “Actionable exomic incidental findings in 6503 participants: challenges of variant classification.” Genome Res. 2015 Mar;25(3):305-15.