Genetic testing for germline variants in susceptibility genes for breast and other cancers frequently identifies variants of uncertain clinical significance, including missense, small in-frame insertion/deletion, splice and regulatory region variants. Unclassified variants are a major clinical challenge as they complicate test reporting and genetic counselling, and prevent guided clinical management of patients and their relatives.
The ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) international consortium undertakes research to improve methods for classifying variants in breast cancer predisposition genes. To promote standardised classification, ENIGMA has established detailed criteria to classify germline variants in BRCA1 and BRCA2 using a 5 tier system that reflects probability of pathogenicity. ENIGMA is a ClinGen-designated expert panel for BRCA1/2 variant classifications, and ENIGMA classification criteria are currently being applied to variants identified by research and clinical testing sites internationally.
ENIGMA expert panel and research activities to date have:
These findings demonstrate the value of large-scale international collaborations with gene- and disease-specific expertise to improve variant classification methods and processes, and deliver clinically meaningful standardised disease gene variant classification.