Ann Lab Med.  2019 Sep;39(5):421-429. 10.3343/alm.2019.39.5.421.

Challenges and Considerations in Sequence Variant Interpretation for Mendelian Disorders

  • 1Department of Laboratory Medicine, Hanyang University College of Medicine, Seoul, Korea.
  • 2Green Cross Genome, Yongin, Korea.
  • 3Department of Laboratory Medicine and Genetics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea.


In 2015, the American College of Medical Genetics and Genomics (ACMG), together with the Association for Molecular Pathology (AMP), published the latest guidelines for the interpretation of sequence variants, which have been widely adopted into clinical practice. Despite these standardized efforts, the degrees of subjectivity and uncertainty allowed by the guidelines can lead to inconsistent variant classification across clinical laboratories, making it difficult to assess the pathogenicity of identified variants. We describe the critical elements of variant interpretation processes and potential pitfalls through practical examples and provide updated information based on a review of recent literature. The variant classification we describe is meant to be applicable to sequence variants for Mendelian disorders, whether identified by single-gene tests, multi-gene panels, exome sequencing, or genome sequencing. Continuing efforts to improve the reproducibility and objectivity of sequence variant interpretation across individuals and laboratories are needed.


American College of Medical Genetics (ACMG); Mendelian disorder; Variant interpretation
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