Clinical impact of ENIGMA-based variant reclassification on genotype–phenotype analyses in BRCA1- and BRCA2-associated hereditary breast and ovarian cancer
Breast Cancer, cilt.33, sa.6, ss.1329-1339, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 33 Sayı: 6
- Basım Tarihi: 2026
- Doi Numarası: 10.1007/s12282-026-01913-9
- Dergi Adı: Breast Cancer
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, EMBASE, MEDLINE
- Sayfa Sayıları: ss.1329-1339
- Anahtar Kelimeler: BRCA, ENIGMA, Genotype-phenotype correlation, Reclassification, Variant spectrum
- Ankara Yıldırım Beyazıt Üniversitesi Adresli: Evet
Özet
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.