Classification and Clinical Management of Variants of Uncertain Significance in High Penetrance Cancer Predisposition Genes

Hum Mutat. 2016 Apr;37(4):331-6. doi: 10.1002/humu.22956. Epub 2016 Feb 5.


In 2008, the International Agency for Research on Cancer (IARC) proposed a system for classifying sequence variants in highly penetrant breast and colon cancer susceptibility genes, linked to clinical actions. This system uses a multifactorial likelihood model to calculate the posterior probability that an altered DNA sequence is pathogenic. Variants between 5%-94.9% (class 3) are categorized as variants of uncertain significance (VUS). This interval is wide and might include variants with a substantial difference in pathogenicity at either end of the spectrum. We think that carriers of class 3 variants would benefit from a fine-tuning of this classification. Classification of VUS to a category with a defined clinical significance is very important because for carriers of a pathogenic mutation full surveillance and risk-reducing surgery can reduce cancer incidence. Counselees who are not carriers of a pathogenic mutation can be discharged from intensive follow-up and avoid unnecessary risk-reducing surgery. By means of examples, we show how, in selected cases, additional data can lead to reclassification of some variants to a different class with different recommendations for surveillance and therapy. To improve the clinical utility of this classification system, we suggest a pragmatic adaptation to clinical practice.

Keywords: cancer predisposition genes; clinical management; multifactorial likelihood model (MLM); variants of uncertain significance (VUS).

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Disease Management
  • Genetic Counseling
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Genetic Variation*
  • Humans
  • Models, Statistical
  • Mutation
  • Neoplasms / diagnosis*
  • Neoplasms / genetics*
  • Penetrance*
  • Practice Guidelines as Topic
  • Uncertainty*