Determining actionability of genetic findings in clinical practice

Just as radiology screenings can return results of incidentalomas, genetic scans can also return inadvertent findings. But some guidance can be taken from criteria developed in 1968 for adopting any screening test.

It has happened to all of us. A diagnostic or screening test is ordered for a specific indication and yields an entirely unexpected result. Sometimes the result is related to the initial reason for the test, but commonly, and often without welcome, it isn't.

The classic example is the chest X-ray ordered for fever, dyspnea and cough that radiology describes as “a vague 1-cm opacity in a single view, cannot rule out malignancy. Clinical correlation suggested. Additional views or chest CT may be of value in characterizing the finding further.” Occasionally, incidental findings are lifesaving, although they often lead to medical misadventures that incur cost, morbidity and mortality.


How to handle inadvertent findings is a major subject of discussion in the genomics community. Right now, the “return of results” issue is a critical point of debate for investigators conducting clinical research studies involving genome scale sequencing. The medical, ethical and legal challenges of incidental findings in routine clinical care, especially with the advent of very low-cost exome or whole-genome sequencing, are daunting and just beginning to be grappled with.

We are approaching a phase of exponential growth in use of sequencing technologies in clinical care. Yet, targeted panels of clinically useful, patent-protected genetic tests will soon be more expensive than sequencing the patient's full genome.

Already there are examples in the research community in which patients have been sequenced for one clinical purpose, only to find other potentially important abnormalities. In fact, in each of our genomes there are variations that could be considered clinically significant at some point in our lives. Some of the variations might predict response to medications and others the risk of passing on a serious condition to offspring, while still others may provide insights into future health risks.

Additionally, there is a lot of variation that amounts to “noise” in our genomes, including variations that confer low or uncertain risk for a wide variety of traits and diseases. And even with the best sequencing and interpretive technologies, the size of the human genome ensures that errors in the sequence data will be admixed with the significant findings.

The National Human Genome Research Institute has recently funded a number of Mendelian Disorders Sequencing Centers and a Clinical Sequencing Exploratory Research Program to better understand the issues surrounding the clinical application of inexpensive sequencing technologies.

Investigators from these groups have formulated a “Return of Results Consortium “ to explore the particular issue of incidental findings. The first meeting was held in late April 2012. Many diverse opinions on the topic were expressed at this meeting; clearly best practices have yet to emerge.

One approach being considered is to “bin” variants into categories of clinical importance, then present patients with incidental genomic variations that meet “actionability” criteria according in part to personal preference.

However, “actionability” is rather difficult to define. For example, is a variable “actionable” simply because patients are interested in knowing about their genotype at that location? Or is the threshold of “actionability” only met when the presence or absence of a variation indicates an immediate clinical intervention to avert an immediate health risk?

Additionally, “actionability” is often highly context-specific (e.g., a high-risk BRCA1 gene mutation is less actionable in an 80-year-old male without children than in a 25-year-old female with three children). How complex will the binning need to be to account for patient characteristics?

One way to assess the “actionability” of incidental results would be to consider them as several billion individual screening tests performed in unselected individuals. Uniquely, in the case of exome or whole-genome sequencing, one could argue that the screening test is not the biochemical act of measuring and calling the sequence, but the choice to actively look for and interpret the result at a given spot in the genome.

In 1968, Wilson and Jungner of the World Health Organization published what have become classic criteria for adopting a screening test for a given condition:

With minor adaptations, most of these criteria seem remarkably sensible as a general guide for deciding whether to actively interpret and return incidental variants that are discoverable on an exome or whole-genome sequence.

Clearly, in a time when patients are increasingly invested in their health care, individual patient preference will play an important role in any real-world solution to this issue. However, some degree of paternalism/maternalism may be necessary when the science does not support a conclusion that any genomic finding is more than noise.

The American College of Medical Genetics has already established a committee to consider strategies for binning variants to guide return of results. Very likely other health professional groups will be interested in contributing to this complicated and contentious issue. Many of us will eventually have to live with the decisions that are made, either as clinicians or as patients.