When is a medical finding “incidental”?

James P. Evans MD, PhD

Genetics in Medicine

doi:10.1038/gim.2013.74

Received: 22 April 2013
Accepted: 22 April 2013
Published online: $dateTool.format('dd MMMMMMMMM yyyy', $thisDate)

Not surprisingly, the recent guidelines from the American College of Medical Genetics and Genomics (ACMG) regarding the return of incidental findings¹ continue to generate controversy. At the heart of much of the controversy lies a single question: what makes a medical finding truly “incidental”?
Implicit in the new recommendations is a mandate to laboratories that when genome-scale sequencing is performed, the resultant data be actively and systematically queried for specific types of mutations in a selected set of genes. How can such a call for an active search be reconciled with the designation of those results as “incidental”? And why is this not tantamount to a call for overt screening for mutations in those genes? The details of how genome-scale sequencing is carried out, as well as long-established norms of clinical medical practice, are critical to resolving these questions.
Genome-scale sequencing involves two phases, both of which are vital to the overall process. The first phase consists of the actual generation of sequence data; the second consists of complex informatic analysis of those data. Let us examine how the ACMG’s new recommendations would play out in the context of a typical patient who might undergo whole-exome sequencing or whole-genome sequencing for unexplained, progressive neurological deterioration and examine the ACMG’s call to look for mutations in, among other selected genes, MSH2 (which, when mutated, is responsible for Lynch syndrome).
In the first phase of this patient’s whole-exome sequencing testing, physical capture of all exons in the patient’s genome is carried out, libraries are prepared, and the captured and processed DNA is subjected to sequencing. If whole-genome sequencing is pursued, essentially all of the patient’s genomic DNA is processed and directly sequenced. At this point, testing is incomplete. No matter the indication for testing, no matter the use to which the results will be put, an extensive series of complex informatics filters must now be applied to the data in order to render it suitable for interpretation by the laboratorian and clinician. Informatic algorithms will determine quality scores of each nucleotide, and predetermined decisions will be made regarding mapping fidelity and the threshold required for calling of nucleotides. Sequence data will be compared with external databases to weed out innocuous variants, and methodical parsing of the data by informatic filters will pluck out those few variants most likely to be relevant to the patient at hand. In other words, an exhaustive series of preordained analyses will necessarily be carried out by whatever informatic system is employed by the laboratory to ultimately determine which of the many thousands of genomic variants present in the raw data deserve human inspection and interpretation.
The point of my summarizing the testing process is to highlight the fact that in any genome-scale sequencing test, if a deleterious, life-threatening mutation in MSH2 exists, it has already been sequenced and now resides in the data that will soon be subjected to a whole series of obligatory and methodical informatics analyses. We must therefore make a conscious decision as we formulate the analytic algorithms by which the data will be analyzed—do we ignore the possible presence of this MSH2 mutation or, while we are already implementing extensive informatics algorithms, do we also ask those algorithms to pluck it out of the patient’s already generated sequence data and reveal it to the clinician along with the diagnostic information that is being primarily sought in the context of the patient’s neurological disorder?
This decision must be driven, in part, by how burdensome it is to query the patient’s data for the presence of the possible MSH2 mutation and whether detecting it necessitates departing in a qualitative manner from the normal analytic process. If such a query were to rely on the application of different technology or a new test, or necessitate a “work flow” unrelated to how such data are normally analyzed, then it would indeed seem a stretch to classify the elucidation of the patient’s MSH2 mutation as “incidental.” But this is not the case. Any genome-scale sequencing process necessarily involves the application of myriad informatics filters. Complying with the ACMG’s recommendations asks laboratories only to apply one more straightforward filter to check whether a recognizable MSH2 mutation is present in the patient’s data files that have already been generated. The burden to the laboratory is minor and does not introduce qualitatively new demands.