Recommended terminology and descriptors for five-tier disease gene variant classification categories, considering variant pathogenicity in the multigene panel testing arena*
| Numeric class | Consolidated five-tier description | Suggested acronym | Generic description of cancer risk determined for the variant | Generic description of relevance to clinical management for germline variants in cancer susceptibility genes | |
| High penetrant variants (>fourfold risk relative to population) | Moderate penetrant variants (twofold to fourfold relative risk) | ||||
| 5 | Pathogenic | P | Sequence variant is associated with ≥twofold cancer risk, and could be used to inform medical management. | Sequence variant may be used alone to inform clinical management. Management recommendations for an individual should be determined in accordance with absolute risk of specified cancer types, considering clinical presentation and other known genetic and environment risk factors.‡ Offer predictive testing for relatives. | Clinical management recommendations for a variant carrier should consider knowledge of personal and family history of disease, and other known genetic and environmental risk factors, that together can strongly influence absolute risk for an individual.‡ Consider predictive genetic testing for relatives only if supported by local (regional/national) guidance |
| 4 | Likely pathogenic | LP | Sequence variant is likely associated with ≥twofold cancer risk, and could be used to inform medical management.† | As above—sequence variant may be used alone to inform clinical management. Consider other factors to refine estimate of absolute risk for an individual. | As above—sequence variant should be used to inform clinical management only after consideration of other factors with influence absolute risk for an individual.‡ |
| 3 | Uncertain (significance) | VUS | Sequence variant has been assessed for association with cancer phenotype/s but risk association remains uncertain. | Clinical management recommendations should be determined on the basis of personal and/or family history of disease, and other known genetic and environmental risk factors.‡ The presence of the variant should not be used to influence management of the carrier individual or their relatives. Research testing of family members may be recommended to aid variant classification. | |
| 2 | Likely little clinical significance/likely benign§ | LB | Sequence variant is likely NOT associated with ≥twofold cancer risk. | Variant on its own is likely to be of no or little clinical significance. Clinical management recommendations should be determined on the basis of personal and/or family history of disease, and other known genetic and environmental risk factors.‡ Further research may clarify variant contribution (if any) to risk. | |
| 1 | Little clinical significance/benign§ | B | Sequence variant is NOT associated with ≥twofold cancer risk. | Variant on its own is of no or little clinical significance. Clinical management recommendations should be determined on the basis of personal and/or family history of disease and other known genetic and environmental risk factors.‡ | |
*The tier descriptions have been adapted to: allow for both high-risk and moderate-risk variants (irrespective of the gene involved) to be annotated for medical actionability in accordance with the level of risk/s they impart to individual carriers; consider that relative risks are age-specific for common diseases such as cancer where incidence in the general population increases with increasing age, so the relative risk associated with a cancer predisposition gene falls with increasing age; denote specifically that clinical management recommendations should consider personal and family history of disease, as well as environmental exposures, and other genetic risk factors (in particular polygenic risk score information). Terminology assumes that only variants associated with a relative risk of >twofold will be reported out as unique variants with directly assigned pathogenicity.
†Defined as 90% (ACMG/AMP) or 95% (IARC) certainty of being pathogenic or benign. As per IARC recommendations,6 further research, including research testing of family members, may be helpful to better determine the risk association and clinical significance of the variant.
‡Other factors may reduce or increase the risk of disease. Risk factors to be assessed may include polygenic risk scores, which themselves include information about individual variants associated with <twofold risk (low increased risk). Note: inclusion of both family history and polygenic risk score information for absolute risk estimation should account for the proportion of familial relative risk that is explained by genetic factors included in the polygenic risk score calculation.44 Further implementation research is required to understand how best to implement PRS testing to stratify cancer risks in a range of settings, including patients with cancer and general population screening.
§The combined text description was selected as preferable for initial presentation in reporting, to underscore the fact that some sequence variants falling into class 1 or class 2 may be causally associated with a defined low increased risk of cancer, eg, the BRCA2 c.9976A>T p.(Lys3326Ter) variant associated with <1.5-fold increased risk of breast or ovarian cancer.37