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Genetic testing

ACMG guides on the interpretation of sequence variants

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The increased availability of sequence data in clinical settings has been accompanied by challenges in standardization, interpretation and reporting of genetic tests. Meeting the need for community guidelines, a new report from the American College of Medical Genetics and Genomics (ACMG) summarizes updated recommendations for the reporting and interpretation of sequence variants for Mendelian disorders in a clinical context.

The current guidelines are applicable to genetic testing for inherited Mendelian disorders within clinical diagnostic laboratories, and encompass single-gene, multi-gene, exome and whole-genome sequencing tests. These guidelines are not intended for the interpretation of variants associated with common complex disease, somatic variation or pharmacogenomic variants.

variants are classified as pathogenic, likely pathogenic, uncertain significance, likely benign and benign

The authors recommend the use of standard terminology for describing variants in genes causing Mendelian disorders based on a five-tier system, in which variants are classified as pathogenic, likely pathogenic, uncertain significance, likely benign and benign. This terminology has already been in use in a majority of 100 sequencing laboratories surveyed through the United States and Canada.

In addition to recommending standard terminology, the report provides detailed classification and weighting criteria for both pathogenic and benign variants. Variants in genes with a known role in a Mendelian disorder are classified after consideration of the evidence for all of the cases available, although the cause of the disease may vary between these cases. Intended to reduce the number of variants reported as causative and actionable without sufficient evidence, this classification system may be more restrictive than current practice in some clinical laboratories.

The use of additional case data from public resources such as ClinVar, Human Gene Mutation Database and locus-specific databases is encouraged and may be useful for classifying variants as well as identifying appropriate reference sequences. The authors review the use of in silico prediction programs, cautioning that multiple algorithms should be used to allow for comparison of results and that only one summary conclusion regarding pathogencity based on prediction programs should be included within the clinical report.

The authors stress the need for confirmation of results for all sequence variants classified as pathogenic or likely pathogenic using another method, including retesting the same sample, testing parents or using an alternative genotyping or sequencing technology. Continued updating of variant classification that incorporates additional data as they become available is also encouraged. Implementation of procedures to update this information within clinical reports will require clear policies on re-analysis of genetic testing data and access to updated information.


  1. Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. (2015)

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MacArthur D. G. et al. Guidelines for investigating causality of sequence variants in human disease. Nature 508, 469–476 (2014)



Human Gene Mutation Database

Human Genome Variation Society

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Bahcall, O. ACMG guides on the interpretation of sequence variants. Nat Rev Genet 16, 257 (2015).

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