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

• Kim YE
• Ki CS
• Jang MA

• KMID: 2450964
• DOI: http://doi.org/10.3343/alm.2019.39.5.421

Abstract

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.

Keyword

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

MeSH Terms

Classification
Exome
Genetics, Medical
Genome
Genomics
Pathology, Molecular
Uncertainty
Virulence

Figure

• 

  Fig. 1 A sample pedigree used to quantify segregation. The arrow indicates the proband. A black symbol indicates a clinically affected family member. Positive (+) and negative (−) symbols indicate carrier status at the sequence variant under assessment.

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