Genomic test validation for incidental findings.

In March of 2013, the American College of Medical Genetics and Genomics (ACMG) issued recommendations for the reporting of incidental findings produced by clinical exome and genome sequencing (1, 2 ). This guideline on incidental findings has been controversial, because the recommendations are a departure from previous ethical concepts of patient autonomy and the reporting of adult-onset disease in children (3–5 ). One aspect of the incidental-findings guideline that has not been discussed is the lack of required analytical validation for the reporting of a subset of pathogenic variants known to cause severe disease. Analytical validation of any clinical test is critical before its implementation. In the case of genetic testing, clinical laboratories should neither interpret nor report sequence changes that have not been previously validated. More importantly, test results that do not meet the minimum requirements of analytical performance should not be used for clinical decision-making. The ethical concerns raised by the general clinical community in response to the incidental-findings guideline are justified. The clinical laboratory community must specifically consider the ethical and regulatory implications of returning lifechanging results from tests that have not been analytically validated or have not met the minimal quality standards established by the laboratory. The incidental-findings guideline was based on a working group appointed by the ACMG. The guideline is for clinical exome/genome laboratories to report a limited number of pathogenic DNA variants; there are 57 genes in the current guideline. The criteria on which the selection of genes was based include only “unequivocally pathogenic mutations in genes where pathogenic variants lead to disease with very high probability and where evidence strongly supports the benefits of early intervention” (2 ). The 57 genes are associated or causative of cancer, cardiovascular disease, or adverse drug reactions. Importantly, the guideline defines incidental findings as the “deliberate search for pathogenic or likely pathogenic alterations in genes that are not apparently relevant to a diagnostic indication for which the sequencing test was ordered” (1 ). Under the ACMG guideline, patients and their families do not have the ability to decline the return of results on the 57 genes. Furthermore, there is no allowance for a tiered consent. Instead, a patient may consent only to have either the test performed with the incidental findings reported or no test performed at all. For example, a pediatric patient being examined for a genetic cause of a seizure disorder cannot have an exome result restricted to genes associated with the seizure disorder. Instead, by consenting to testing the pediatric patient and their family must also agree to the return of results including those for adult-onset cancers unrelated to seizure disorders. The rationale is that the return of the pathogenic incidental finding is clinically actionable, either for the pediatric patient or for the patient’s parents. The ethical dilemmas with this type of return of results are part of an ongoing discussion (3–5 ). From the perspective of clinical laboratories, the ACMG guideline raises several issues regarding clinical test validation and quality. The guideline describes the possibility that a laboratory may be split into 2 entities. One entity could “generate the raw sequencing data,” and a second separate entity could “further evaluate and interpret the sequence.” The guideline focuses on the second separate entity— evaluating and interpreting the sequence data. Laboratories (as defined by the guideline) are instructed to “seek and report mutations” from both constitutional and “normal” samples submitted with a matched tumor sample. The ACMG guideline indicates that the reported incidental findings do not have to meet the laboratory’s established quality standard for reporting (e.g., depth of sequence coverage). Furthermore, because the clinical exome/ genome test may not be designed or validated for the 57 genes, results for the incidental-findings genes should come with a caveat in the report that distinguishes the (lower) quality of the incidental findings from the primary indication. There is no recommendation for confirming a positive pathogenic incidental finding by a secondary method, such as Sanger sequencing. Furthermore, the ACMG guideline does “not recommend that laboratories modify these [exome/genome] tests if they are otherwise suitable to achieve their clinical ob1 Department of Pathology, University of Texas Southwestern Medical Center and Children’s Medical Center, Dallas, TX; 2 Cancer Genomics Laboratory, Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Jefferson Medical College, Philadelphia, PA; 3 Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA. * Address correspondence to this author at: Department of Pathology, University of Texas Southwestern Medical Center and Children’s Medical Center, 1935 Medical District Dr., Dallas, TX 75235. E-mail [email protected]. Received May 30, 2013; accepted June 18, 2013. Previously published online at DOI: 10.1373/clinchem.2013.210609 Clinical Chemistry 60:2 292–293 (2014) Perspective