This document represents an update to the proposed approach of the American College of Medical Genetics and Genomics (ACMG) to categorize laboratory-developed tests (LDTs) for inherited conditions according to risk.1 Risk classification has historically been a determinant of whether, and to what extent, the US Food and Drug Administration (FDA) has overseen and regulated clinical tests. LDTs for constitutional variants continue to proliferate without a comprehensive federal regulatory framework in place. Therefore, an ACMG-appointed workgroup of laboratory and clinical geneticists considered the analytical and health care–related risks and implications resulting from laboratory testing of constitutional genetic information in a variety of contexts to develop a proposed approach. This document is provided as a proposed framework to guide federal agencies, policymakers, and other stakeholders.

The ACMG, through this document, has categorized testing for inherited conditions by utilizing a three-tiered risk-based system (Table 1) incorporating two elements. The first element is consistent with the usual FDA determination of testing-associated risk, whereby the FDA aligns risk with medical decision making based on the test results and the clinical significance of an erroneous result. The second element considers factors that impact analytical performance and the likelihood of an erroneous result based on methodology. It is recognized that novel technologies for an otherwise lower risk clinical application could temporarily place that test in a higher risk category until additional experience with the methodology is gained. The risk model specifies criteria that define each level of risk and identifies mitigating factors that could potentially lower the chance of inappropriate or harmful clinical action based on the test result. It should be recognized that genetic testing is a process including not only the analytical phase addressed in this document, but also preanalytical and postanalytical components, which are beyond the scope of this document. Patient harm can occur in the preanalytical phase (e.g., lack of education/counseling, disregard for the informed consent process, incorrect test ordered) as well as postanalytically in the delivery of results and subsequent clinical follow-up.

Table 1 ACMG’s proposed approach to risk classification and oversight of laboratory-developed tests for inherited conditions.

Although the ACMG agrees that the elements recommended by the College of American Pathologists be included in the oversight framework for LDTs,2 we recommend additional considerations for clinical constitutional genetic testing. When initially considering risk level, there are elements that can reduce overall risk of a test, irrespective of the indication for testing (e.g., diagnostic, presymptomatic, predisposition, and pharmacogenomic genetic testing; carrier detection; preimplantation genetic diagnosis; and prenatal testing). These elements include factors such as (1) using nonproprietary methods or algorithms, (2) being amenable to interlaboratory comparisons, and (3) being evaluated by external proficiency testing. We are also proposing recommendations for laboratory director oversight of testing based upon risk (Table 1). Published data are available demonstrating that LDTs developed, validated, and performed within an experienced laboratory supervised by appropriately credentialed individuals are generally accurate.3 Finally, as risk also exists in the pre- and postanalytical phases, we recommend pre- and post-test educational content/counseling developed and/or delivered by an appropriately trained professional, particularly for higher complexity tests.