Navigating the nuances of clinical sequence variant interpretation in Mendelian disease

Genet Med. 2018 Sep;20(9):918-926. doi: 10.1038/s41436-018-0100-y. Epub 2018 Jul 10.


Understanding clinical genetic test results in the era of next-generation sequencing has become increasingly complex, necessitating clear and thorough guidelines for sequence variant interpretation. To meet this need the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for a systematic approach for sequence variant interpretation in 2015. This framework is intended to be adaptable to any Mendelian condition, promoting transparency and consistency in variant interpretation, yet its comprehensive nature yields important challenges and caveats that end users must understand. In this review, we address some of these nuances and discuss the evolving efforts to refine and adapt this framework. We also consider the added complexity of distinguishing between variant-level interpretations and case-level conclusions, particularly in the context of the large gene panel approach to clinical diagnostics.

Keywords: ACMG laboratory guideline; Clinical genetic testing; Clinical interpretation; Variant classification; Variant interpretation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Genetic Testing / methods*
  • Genetic Variation / genetics*
  • Genome, Human
  • Genomics / methods
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Mendelian Randomization Analysis / methods
  • Sequence Analysis, DNA / methods
  • Sequence Analysis, DNA / standards*
  • Software