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.
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)
ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk
The functional analysis of 430 germline missense VUS in the CHEK2 gene categorized 340 of them as functionally impaired, intermediate, or wild-type-like. The categorization was applied to the case-control analysis, which included 161,706 breast cancer patients and population-matched controls provided by the ENIGMA consortium members from 12 countries. The results show that carriers of functionally impaired missense variants include 0.5% of all breast cancer patients with a moderate breast cancer risk similar to that of carriers of the known truncating variant c.1100delC (OR = 2.83 and 2.73, respectively). (Stolarova et al., Clin Cancer Res 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.