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This document represents the proposed approach of the American College of Medical Genetics and Genomics (ACMG) to classify laboratory-developed tests for inherited conditions. Risk classification has been the determinant of whether or not medical tests are overseen and regulated by the US Food and Drug Administration (FDA). Therefore, because laboratory-developed tests for germline mutations continue to proliferate without sound regulatory frameworks in place, an ACMG-appointed workgroup of laboratorians and clinicians considered the medical risks and implications resulting from germline mutation analysis in a variety of contexts to develop the proposed approach. It is expected that the expert opinion represented in this proposed classification system will be used to guide federal agencies, policymakers, and other stakeholders.
The ACMG has categorized testing for inherited conditions by utilizing the three-tiered risk-based system (Table 1), as recommended by the College of American Pathologists
and consistent with the usual FDA determination of testing-associated risk, whereby the FDA aligns risk with the medical decision made on the test results. The proposed risk categorization model of the ACMG is based on how an incorrect result might have an impact on patients and their blood relatives (including offspring). The risk model specifies determining factors for categorization and oversight recommendations for each level of risk. 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 harms can occur in the preanalytical phase (e.g., lack of education/counseling, disregard for the informed consent process, wrong test ordered) as well as postanalytically in the delivery of results and subsequent clinical follow-up.
Table 1ACMGs proposed approach to risk classification and oversight of laboratory developed tests for inherited conditions
Although the ACMG is in agreement with the features that the College of American Pathologists recommends to be included in the oversight framework for laboratory-developed tests, we recommend additional considerations for germline genetic testing. We recommend that all clinical molecular genetic tests fall into either the moderate-risk or high-risk category. Tests that (i) do not utilize proprietary methods or algorithms, (ii) are amenable to interlaboratory comparisons, and (iii) are evaluated by external proficiency testing should be categorized as moderate risk.
Due to the potentially serious implications of an incorrect result or interpretation for the patient and the patient’s blood relatives, we recommend that all clinical molecular genetic test results be reviewed and interpreted by an individual certified in either Clinical Molecular Genetics (American Board of Medical Genetics, ABMG) or Molecular Genetic Pathology (American Board of Pathology/ABMG). The professional interpretation of test results should be provided by an individual certified in clinical genetics (ABMG), clinical cytogenetics (ABMG), clinical molecular genetics (ABMG), or molecular genetic pathology (American Board of Pathology/ABMG). In addition, we recommend that an ABMG-certified clinical geneticist and/or American Board of Genetic Counseling/ABMG-certified genetic counselor provide pre- and posttest counseling to patients, as necessary.
The authors declare no conflict of interest. However, please note that all authors (except J.B. and M.S.W.) direct clinical testing laboratories.