A semiquantitative metric for evaluating clinical actionability of incidental or secondary findings from genome-scale sequencing

Genet Med. 2016 May;18(5):467-75. doi: 10.1038/gim.2015.104. Epub 2015 Aug 13.


Purpose: As genome-scale sequencing is increasingly applied in clinical scenarios, a wide variety of genomic findings will be discovered as secondary or incidental findings, and there is debate about how they should be handled. The clinical actionability of such findings varies, necessitating standardized frameworks for a priori decision making about their analysis.

Methods: We established a semiquantitative metric to assess five elements of actionability: severity and likelihood of the disease outcome, efficacy and burden of intervention, and knowledge base, with a total score from 0 to 15.

Results: The semiquantitative metric was applied to a list of putative actionable conditions, the list of genes recommended by the American College of Medical Genetics and Genomics (ACMG) for return when deleterious variants are discovered as secondary/incidental findings, and a random sample of 1,000 genes. Scores from the list of putative actionable conditions (median = 12) and the ACMG list (median = 11) were both statistically different than the randomly selected genes (median = 7) (P < 0.0001, two-tailed Mann-Whitney test).

Conclusion: Gene-disease pairs having a score of 11 or higher represent the top quintile of actionability. The semiquantitative metric effectively assesses clinical actionability, promotes transparency, and may facilitate assessments of clinical actionability by various groups and in diverse contexts.Genet Med 18 5, 467-475.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Chromosome Mapping
  • Genetic Diseases, Inborn / diagnosis*
  • Genetic Diseases, Inborn / epidemiology
  • Genetic Diseases, Inborn / pathology
  • Genetic Testing*
  • Genome, Human*
  • Genomics
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Incidental Findings