Clinical impact of ENIGMA-based variant reclassification on genotype-phenotype analyses in BRCA1- and BRCA2-associated hereditary breast and ovarian cancer.

BACKGROUND

Accurate interpretation of BRCA1 and BRCA2 variants is essential for meaningful genotype-phenotype correlations and informed clinical decision-making. However, general frameworks such as the ACMG 2015 criteria frequently result in high rates of variants of uncertain significance (VUS), which may generate misleading clinicopathological associations and complicate genetic counseling.

METHODS

We conducted a retrospective analysis of 3,706 individuals tested for BRCA1/2 variants due to BRCA-related malignancies in a large Turkish cohort. Variants were initially classified according to ACMG 2015 criteria and subsequently re-evaluated using ENIGMA consensus recommendations. Clinicopathological data were compared between variant categories before and after reclassification.

RESULTS

Pathogenic or likely pathogenic variants were detected in 6.7% of patients, while 3.8% were initially classified as VUS. Following ENIGMA-guided reclassification, a substantial proportion of VUS, particularly missense variants lacking functional impact, were reclassified as benign or likely benign. Clinicopathological differences observed between ACMG-defined pathogenic and VUS groups-including age at onset, tumor distribution, receptor status, and progression-free survival-were eliminated after ENIGMA-based reassessment, revealing biological heterogeneity within the VUS category. Post-reclassification analyses allowed more precise distinction of benign variant profiles, refining genotype-phenotype interpretations.

CONCLUSIONS

ENIGMA-guided variant interpretation enhances analytical precision, reduces false-positive associations, and improves clinical utility in hereditary breast and ovarian cancer genetics, offering a more reliable framework for genetic counseling and risk assessment in populations with diverse variant spectra.