The American College of Medical Genetics and Genomics’ (ACMG’s) April recommendations for the reporting of incidental findings uncovered in the course of clinical whole-exome and -genome sequencing kicked off a firestorm of debate pitting laboratories’ duty to report versus a desire to preserve patient autonomy. While heralded as a starting point for establishing a common foundation for reporting clinical sequencing findings, the recommendations were also criticized as being premature given a lack of evidence on the frequency of incidental findings and patient preferences. In an investigation of how laboratories are addressing the recommendations, DTTR found that most laboratories are still allowing for patients to opt out of reporting but that all laboratories have provisions for reporting incidental findings. Experts are viewing these recommendations as a first attempt to address the ethical and practical issues of reporting incidental findings but expect standardization of sequencing analysis and reporting practices to evolve over the coming years as penetrance of variants is better understood, nongeneticist clinicians are more comfortable with incorporating genomics into medical practice, and practical considerations such as reimbursement, genomic data storage, and consent issues are worked out. The recommendations call for mandatory reporting of a minimal set of incidental findings, where early intervention is likely to reduce or prevent serious morbidity or early mortality, in all patients, regardless of age or reason for the initial investigation. The initial set of variants to be added to examinations covers 57 genes for 24 conditions, including mutations known to increase risk of breast cancer, ovarian cancer, Lynch syndrome, and colorectal adenomas. While ACMG estimates that only 1 percent of patients who undergo genomic sequencing will have one of those mutations, concerns over mandatory reporting center on two key issues: the true pathological significance of the incidental findings and patient autonomy. Variant Penetrance Curation of the list of variants to be subjected to mandatory interrogations is based on the premise that early intervention improves outcomes. “The rationale for our recommendations was that not reporting a laboratory test result that conveys a near certainty of an adverse yet potentially preventable medical outcome would be unethical,” writes the ACMG in its May clarification of its original recommendation. “We agree that variants of unknown significance, variants associated with low or unknown penetrance, and variants associated with disorders not currently amenable to intervention should not be reported.” Objections to the preliminary variant list arise from the uncertainty concerning the penetrance and pathogenicity of the selected variants in the general population. “Until well-curated human mutation databases are available, patients may be told about many mutations that, because of incomplete penetrance and misclassification of benign variants as mutations, are likely neither to cause disease nor confer substantial risk when ascertained in the general population,” writes Robert Klitzman, M.D., from Columbia University in New York, in a July 24 Journal of the American Medical Association (JAMA) viewpoint opposing ACMG’s recommendations. Given the risk of significant false positives, ACMG calls for “a very high bar [to] be set with return of only those variants with a very high probability of being deleterious” and guides sequencing laboratories to be cognizant of whether their tests have adequate coverage in all of the 57 genes to be screened. In their guidance for laboratories, ACMG says they recognize that some sequencing-based tests may not be optimized for coverage of these variants and that they “do not recommend that laboratories modify these tests if they are otherwise suitable to achieve their clinical objectives.” Rather ACMG suggests laboratories report to the clinician that “the test was not optimized to detect incidental findings.” Patient Preferences The best way to report incidental findings to clinicians and how they are in turn conveyed to patients are subject to ongoing refinement. Researchers continue to examine best practices and implications of returned results in both clinicians and patients. Such research was included in the July awards of $27 million in grants from the National Human Genome Research Institute’s Clinical Sequencing Exploratory Research program. While ACMG’s recommendations do not allow for patients to opt out of the laboratory’s reporting of incidental findings to the ordering clinician, the group’s subsequent clarification did call for “the provider and patient [to] participate in a shared decision-making process regarding the return of results” with the clinician contextualizing these findings “to the clinical circumstances (e.g., the nature of ongoing clinical problems, knowledge of personal and family history, patient preferences, etc.).” This perceived softening, however, did not appease outcries that mandatory reporting was violating patients’ rights, causing questioning of whether or not these variants even fit the definition of incidental. “To date, the traditions of genetic testing and reporting have exceptionalized all genetic risk information as potentially dangerous to the well-being of patients. This tradition, in the era of genome sequencing, must be reconsidered,” writes Robert C. Green, M.D., from Brigham and Womens Hospital in Boston, in a JAMA viewpoint supporting ACMG’s recommendations. “Incidental findings in clinical medicine are often mischaracterized as unintentional observations. However, a better characterization would be that such findings are potentially important observations noted during systematic examination by those with appropriate training.” Green and colleagues cite the analogy of when a radiologist uncovers abnormalities in a chest X-ray not related to the intended evaluation of a possible rib fracture. “Radiologists are specifically trained neither to report every conceivable finding, nor to stop after satisfaction of search reveals an indicated finding. Rather radiologists use professional standards to assess and report a subset of unexpected findings that are likely to be medically important,” they write. But in yet a third JAMA viewpoint on the recommendations, Lainie Friedman Ross, M.D., Ph.D., from the University of Chicago, and colleagues further debate the definition of incidental. “Any positive findings from these additional analyses are hardly incidental; they are the results of a new recommendation for mandatory testing beyond the scope of the original request that will require a significant amount of time, effort, and resources,” write Ross and colleagues. “This approach is similar to requiring a laboratory to test every blood sample for human immunodeficiency virus, hemoglobin A1c level, and 54 other tests for which early treatment can reduce morbidity or mortality, even if the physician had only ordered, and the patient had only consented to, a cholesterol measurement.” While ethicists will continue to debate the definition of incidental findings, laboratories are interested in the more practical issues, including consent. Considerations for Labs Based on conversations with experts in the field, DTTR uncovered that the majority of laboratories, like Medical College of Wisconsin’s Human and Molecular Genetic Center, are maintaining some form of an opt-in, opt-out option for incidental findings. It appears as if all exome sequencing laboratories are equipped to report on, or are preparing to report on, at least the variants listed in the ACMG recommendations, with some reporting on incidental findings beyond the scope of the recommendations. “It would be unrealistic to propose to every patient undergoing a physical examination, laboratory testing, or radiological procedure that they consent in advance to the panoply of low-probability findings that might be discovered, or that the clinician, radiologist, or laboratory be required to mask or delete such findings from the report because a patient might be fearful of their discovery,” writes Green. “Categorical statements of preference such as tell me about treatable conditions, but not untreatable conditions will never be adequate to guide the management of incidental findings in genomic sequencing because the value of the incidental finding to the health of the individual patient, like any other laboratory value, cannot be accurately assessed until it is clinically contextualized for that patient.” Taking the individual patient’s circumstances into account has led some laboratories to maintain their opt-out positions when it comes to incidental findings. “After serious reflection and discussion we concluded that the patients and family are in the best position to decide what to do with their results,” says David Bick, M.D., medical director of genetics at Childrens Hospital of Wisconsin. “Our experiences with patients are divergent from the college. In our experience families do understand what they are choosing. We have seen patients from every economic and socioeconomic background and they are not all Ph.D.s and in general they do think carefully about it and understand what they are choosing.” Practically, Bick says the workload of counseling patients and families has been reduced significantly with experience. Based on initial experiences, other experts also say the incremental workload is light given current volumes, but reimbursement remains a big uncertainty for laboratories in implementing ACMG’s recommendations. Pinar Bayrak-Toydemir, M.D., Ph.D., medical director of the molecular genetics laboratory at ARUP (Salt Lake City), tellsDTTR that since adopting recommendations ARUP has not found anything incidental to report after doing “tens of exomes.” She says that following ACMG’s recommendations might add a few hours of interpretation work (and additional time for confirmatory Sanger sequencing if any incidental findings were discovered), but the turnaround time on exome sequencing is already so long that the incremental work doesn’t really impact it. As far as reimbursement, she says there is currently no method to seek compensation for the additional variants. In the long run, genome sequencing has the potential to bring down costs, as it queries the whole genome at less of a cost than many single gene tests,” says Michael Watson, Ph.D., ACMG’s executive director. “ACMG is working with government regulators as well as third-party payers on both the new CPT codes for molecular pathology and the reimbursement rates that have been proposed by the Medicare carriers. At the time those codes were submitted to the American Medical Association’s CPT panel, there was no expectation that there would be a recommendation for reporting of incidental findings. As more laboratories begin to offer the incidental findings as a part of their testing, a new genome sequencing CPT code would need to be proposed to the CPT panel that included reporting of these findings.” While clinical sequencing continues to permeate clinical practice and laboratories gain experience to draw from in informing future iterations of practice standards, ACMG has been lauded for kick-starting the dialogue. “I think the ACMG did an excellent job staring the discussion, but I strongly believe this discussion is a topic requiring wide discussion, not just among laboratory directors and physicians, but it must include the public,” says Bick. “WGS won’t be acceptable to the public if their wishes are not respected.” Takeaway: Many ethical and practical considerations remain unresolved relating to the reporting of WGS findings. Laboratories are currently inclined to not fully adopt ACMG’s recommendations and instead maintain the ability for patients to opt out of reporting of incidental variants.

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