NEW YORK (GenomeWeb) – The American College of Medical Genetics and Genomics, along with the Association for Molecular Pathology, and College of American Pathologists, have developed a variant classification system and standard terminology as a resource for labs and clinical geneticists who want to determine if a genetic variant identified in a patient is associated with disease.
The new system is published online in Genetics in Medicine. "These updated guidelines provide a systematic and sound way to classify genomic variants so that when Lab A on the east coast and Lab B on the west coast are reporting results, they are using the same method to classify that variant," Sue Richards, medical director of the Knight Diagnostic Laboratories and the chair of the workgroup that issued the guidelines, said in a statement.
According to the published guidelines, the recommendations are intended to be applied when interpreting results from genetic tests performed in clinical labs, such as genotyping and single-gene tests, as well as diagnostics employing panels of markers, and when assessing exomes or genomes.
The report also lays out standard terminology — "pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign" — for characterizing variants gauged by tests for Mendelian disorders. Users of the framework can employ the process described in the paper to classify variants into these five categories based on evidence, such as population, computational, functional, and segregation data.
The workgroup said in a statement that doctors should interpret genomic test results with other available evidence for a patient. For example, a variant deemed to be "likely pathogenic" according to the guidelines may be actionable in the context of information gleaned from prenatal ultrasounds and imaging studies.
Due to limited evidence, the standards may classify more variants as having uncertain significance. The workgroup recommends against using variants of uncertain significance, or VUS, to make clinical decisions.
In order to develop the guidelines, the workgroup garnered feedback from the clinical genetics community using surveys and workshops convened at professional society meetings.
"In the past, standard terms such as 'pathogenic' and a consistent strategy for classifying variants have been lacking," Richards, who also is a professor of molecular and medical genetics at Oregon Health & Science University, said, "leading to wide variation in how laboratories classify individual differences in DNA sequence.”
Although these guidelines were developed for clinical labs, Heidi Rehm, workgroup co-chair and chief laboratory director at Partners Laboratory for Molecular Medicine, added that the developers of the guidelines hope researchers will also use the recommendations "to improve the quality of published literature and the genetic claims being made."
Rehm two years ago received an NIH grant to collect variant data from labs and clinics for the ClinGen project, and to develop standard formats for submitting the data to a centralized repository called ClinVar. Within ClinGen, "laboratories are employing the ACMG guidelines as a best standard in resolving any differences in variant interpretation," she said in a statement.
The ACMG/AMP/CAP workgroup also "strongly" recommends that clinical molecular genetic testing be performed in labs certified by the Clinical Laboratory Improvement Amendments and the results be interpreted by a board-certified molecular geneticist, genetic pathologist, or a professional with similar expertise.
The new guidelines should only be used for inherited genetic variants and aren't meant for somatic variations or for use in the context of complex diseases, such as heart disease, the ACMG said.