Evidence-based Network for the
Interpretation of Germline Mutant Alleles

ENIGMA is an international consortium of investigators focused on

  • determining the clinical significance of sequence variants in BRCA1, BRCA2 and other known or suspected breast and/or ovarian predisposition genes,
  • to provide this expert opinion to global database and classification initiatives, and
  • to explore optimal avenues of communication of such information at the provider and patient level.

An ENIGMA member is currently defined as a researcher or research group (consortium) who is willing to work collaboratively towards classification of variants and contribute data from families with unclassified sequence variants, as required to aid in the variant classification projects of ENIGMA and/or conduct statistical analysis or laboratory-based assays aimed at classification of variants within a working group framework.

NEWS

  • Vocabulary Translation Project 

    Genetic testing for cancer predisposition informs precision cancer prevention and care. Clear understanding and communication of the cancer risk associated with each identified gene variant underlies responsible decision-making. We describe an initiative promoted by the ENIGMA consortium that involved 70 scientists from 25 countries worldwide to harmonize reporting of germline genetic test results for breast cancer. We provide up-to-date recommendations in 21 languages, benefitting a potentially broad audience. Consistent communication of test-derived information will empower informed decisions and more coherent risk management, fostering prevention, early detection, improved outcomes, and greater equity in the use of genetic testing in oncology. (De Nicolo et al., J. Med. Genet. 2026)

  • Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel

    The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants. (Parsons et al.,  Am J Hum Genet 2024)

  • Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup

    The ClinGen SVI Splicing Subgroup provides recommendations for the application of existing splicing-related ACMG/AMP codes and re-purposing of other codes to capture splicing-related evidence. This study outlines a process for developing a gene-specific PVS1 decision tree, and provides methodology to calibrate bioinformatic splice prediction tools. The effort was led by multiple ENIGMA members using expertise gained from years of collaborative research evaluating variants in BRCA1/2 and other cancer susceptibility genes. (Walker et al., Am J Hum Genet 2023)

Co-ordination of ENIGMA has received funding from: The Cancer Council Queensland of Australia [2015-present], an NCI sponsored Breast Cancer Specialized Program of Research Excellence (SPORE) at the Mayo Clinic (P50 CA116201) [2009-Present], NIH grants R01 CA192393 and R01 CA116167, and the Breast Cancer Research Foundation.

Disclaimer: Use of the ENIGMA website, and associated interpretation relating to gene variant pathogenicity, is subject to User discretion and responsibility. The information provided is not intended to be a substitute for professional risk assessment, and is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Gene variant classifications and classification methods are subject to change as further information becomes available.