Akademik Veri Yönetim Sistemi
2nd International Hereditary Cancer Congress, Antalya, Türkiye, 5 - 08 Şubat 2026, ss.74, (Özet Bildiri)
Objective: The NBN gene encodes nibrin, a critical component of the MRE11–RAD50–NBN (MRN) complex, which plays an essential role in the early stages of the DNA damage response (DDR). While biallelic pathogenic variants in NBN cause Nijmegen Breakage Syndrome, heterozygous pathogenic variants have been associated with increased susceptibility to various malignancies, particularly breast and prostate cancer. However, the cancer spectrum and genotype–phenotype correlations related to heterozygous NBN variants remain incompletely defined. This study aimed to evaluate the clinical indications, cancer types, and variant spectrum in individuals carrying pathogenic NBN variants identified through hereditary cancer panel testing. Materials-Methods: Targeted next-generation sequencing–based hereditary cancer panel testing was performed on DNA isolated from peripheral blood samples of 2,147 individuals referred to our center for oncogenetic evaluation. Variants were classified according to ACMG/AMP criteria. Clinical indications for testing, personal and family cancer history, and genotype–phenotype correlations were retrospectively analyzed. Results: Heterozygous pathogenic or likely pathogenic NBN variants were identified in 14 patients (14/2147; 0.65%). Of these individuals, 8 patients (8/14; 57.1%) had a personal history of breast cancer. Three patients (3/14; 21.4%) were referred for genetic testing due to a family history of breast cancer without a personal cancer diagnosis. In addition, one patient (1/14; 7.1%) had prostate cancer, one patient (1/14; 7.1%) was diagnosed with gastric cancer, and one patient (1/14; 7.1%) had colorectal polyps. The recurrent frameshift variant c.657_661delACAAA (p.Lys219AsnfsTer16; rs587776650; chr8:90983441) was detected in 7 patients (7/14; 50.0%), representing the most frequent pathogenic NBN variant in this cohort. The remaining patients harbored other rare pathogenic NBN variants. Genotype–phenotype correlations were evaluated by comparing these findings with previously reported cases in the literature. Conclusion: Although heterozygous pathogenic NBN variants—particularly the recurrent c.657_661delACAAA (p.Lys219AsnfsTer16) variant—have been repeatedly reported in individuals with breast and prostate cancer, the strength and clinical significance of this association remain uncertain. Current evidence suggests a possible contribution of NBN to cancer susceptibility; however, penetrance appears to be variable, and causality has not been definitively established. Conflicting results across populations and cancer types, as well as the limited size of most reported cohorts, underscore the need for cautious interpretation. Ongoing functional studies and larger, well-characterized population-based analyses are required to clarify the true cancer risk attributable to heterozygous NBN variants and to determine their relevance for clinical risk assessment and management.