IARC classification scheme6 Intended use, highly penetrant cancer susceptibility genes | ACMG/AMP5 Intended use, Mendelian diseases | ||||||
Numerical class | Terms | Probability of being pathogenic | Suggested predictive testing of at-risk relatives | Suggested surveillance* | Terms | Probability of being pathogenic† | Description of clinical relevance |
5 | Definitely pathogenic‡ | >0.999 | Yes | Full high-risk surveillance guidelines (for variant carriers) | Pathogenic | >0.999 | Variant 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. |
4 | Likely pathogenic | 0.950–0.999 | Yes | Full high-risk surveillance guidelines (for variant carriers) | Likely pathogenic | 0.900–0.999 | Sufficient 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. |
3 | Uncertain§ | 0.050–0.949 | No (recommend research testing of family members) | Based on family history and other risk factors | Uncertain significance | 0.100–0.899 | Should not be used in clinical decision making; efforts to resolve the classification of the variant as pathogenic or benign should be undertaken. |
2 | Likely not pathogenic or of little clinical significance¶ | 0.001–0.049 | No (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 benign | 0.001–0.099 | Sufficient evidence that a healthcare provider can conclude that it is not the cause of the patient’s disorder when combined with other information. |
1 | Not pathogenic or of no clinical significance** | <0.001 | No | Treat as ‘no pathogenic variant detected’ for this disorder (ie, based on family history and other risk factors) | Benign | <0.001 | Sufficient 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.