Accurate classification of genetic variants as pathogenic (disease-causing) or benign (no clinically actionable disease risk) is key to implementation of genetic testing for personalised patient management. BRCA1 and BRCA2 pathogenic variant status is used to effectively predict lifetime breast cancer risk, and variants with uncertain or conflicting classification can lead to mismanagement of patients and clinical uncertainty with potential stress for the patient and their family.
ClinGen Variant Curation Expert Panels (VCEPs) develop gene-specific variant classification guidelines, modelled on the widely used generic ACMG/AMP guidelines, specifying how to apply evidence types such as population frequency, bioinformatic prediction, and functional, splicing or clinical data.
The ClinGen ENIGMA BRCA1 and BRCA2 VCEP has developed specifications for these genes on the assumption that a pathogenic variant is associated with a high (>4-fold) lifetime risk of breast cancer. The VCEP is currently applying these specifications to variants that are high priority for expert curation due to having a conflicting classification on ClinVar (n=223) or clinical queries direct to VCEP co-ordinators (n=217). These specifications were also applied to seven variants proven through comprehensive penetrance studies to demonstrate atypical penetrance for breast and/or ovarian cancer, to assess if such variants may be misclassified using specifications developed to assign pathogenicity for the standard high-risk pathogenic variant, and inform extension of the specifications.
Application of the VCEP specifications has already resolved classification for 142 variants currently conflicting or uncertain in ClinVar, with review of the remainder ongoing. Analysis of curation evidence for known atypical penetrance variants has provided initial guidance for flagging variants as suspected atypical penetrance in future VCEP curations. It has also provided justification for acceptance, rejection or modified application of different evidence types, to inform extension of the VCEP specifications to evaluate both high-risk and atypical risk variants alongside one another in a single framework.