Table 2

Alternative terms currently in use to describe five-tier disease gene variant classification categories

IARC classification scheme6
Intended use, highly penetrant cancer susceptibility genes
ACMG/AMP5
Intended use, Mendelian diseases
Numerical classTermsProbability of being pathogenicSuggested predictive testing of at-risk relativesSuggested surveillance*TermsProbability of being pathogenic†Description of clinical relevance
5Definitely pathogenic‡>0.999YesFull high-risk surveillance guidelines (for variant carriers)Pathogenic>0.999Variant classified as pathogenic using the proposed classification scheme has met criteria informed by empirical data such that a healthcare provider can use the molecular testing information in clinical decision making.
4Likely pathogenic0.950–0.999YesFull high-risk surveillance guidelines (for variant carriers)Likely pathogenic0.900–0.999Sufficient evidence that a healthcare provider can use the molecular testing information in clinical decision making when combined with other evidence of the disease in question.
3Uncertain§0.050–0.949No
(recommend research testing of family members)
Based on family history and other risk factorsUncertain significance0.100–0.899Should not be used in clinical decision making; efforts to resolve the classification of the variant as pathogenic or benign should be undertaken.
2Likely not pathogenic or of little clinical significance¶0.001–0.049No
(recommend research testing of family members)
Treat as ‘no pathogenic variant detected’ for this disorder (ie, based on family history and other risk factors)Likely benign0.001–0.099Sufficient evidence that a healthcare provider can conclude that it is not the cause of the patient’s disorder when combined with other information.
1Not pathogenic or of no clinical significance**<0.001NoTreat as ‘no pathogenic variant detected’ for this disorder (ie, based on family history and other risk factors)Benign<0.001Sufficient evidence that a healthcare provider can conclude that it is not the cause of the patient’s disorder.
  • *Represented with minor modifications for clarity (words in parentheses) introduced by the ENIGMA consortium.

  • †ACMG/AMP guidelines do not require quantitative variant classification methods to be used, but nevertheless propose probabilities of a variant either being disease-causing or benign.5

  • ‡Represented as ‘pathogenic’ by InSiGHT, ENIGMA and on the BRCA-Exchange website (http://brcaexchange.org/).

  • §Represented as ‘uncertain significance’ on the BRCA-Exchange website (http://brcaexchange.org/).

  • ¶Represented as ‘likely benign’ on the BRCA-Exchange website (http://brcaexchange.org/).

  • **Represented as ‘benign/little clinical significance’ on the BRCA-Exchange website (http://brcaexchange.org/).

  • ACMG,  American College of Medical Genetics and Genomics; AMP, Association for Molecular Pathology; ENIGMA, Evidence-Based Network for the Interpretation of Germline Mutant Alleles; IARC, International Agency for Research on Cancer; InSiGHT, International Society for Gastrointestinal Hereditary Tumours.