Abstract PS3-03-05: High-prevalence of NF1 pathogenic variants in cancer patients without classic features of Neurofibromatosis type 1

Abstract Background: Neurofibromatosis type 1 (NF1), is a classic example of a complete penetrance disease with an estimated prevalence of 1 in 3000. Βroader application of multigene panel testing in candidate hereditary cancer predisposition cases, reveals pathogenic NF1 variants in Breast/ovarian/colorectal cancer patients without a clinical NF1 diagnosis. The scope of this study is to enlighten the contribution of NF1 to cancer risk in general population and the need of medical management guidelines in NF1 breast/ ovarian cancer patients lacking the relevant clinical phenotype. Methods: This retrospective observational study included patients with mutated germline NF1, referred at GENEKOR Medical SA, Athens, Greece between the period of 1st Jan 2020 to 31st Oct 2024. Ηigh risk cancer patients, with no neural crest derivant malignancies, underwent germline mutation testing, with a 52 gene panel. All the NF1 mutations were crosschecked via the ClinVar mutation database to be classified as pathogenic. Results: This retrospective observational study included 15 patients with incidentally identified mutated germline NF1, who were referred due to breast cancer (5/15, 33%), ovarian cancer (4/15,27 %), colorectal cancer (2/15,13%), multiple myeloma (1/15,7%) and glioblastoma (1/15,7%). Among the 12782 cancer patients, with no neural crest derivant malignancies, who underwent germline high-risk cancer gene susceptibility testing, 2616 (20.5%) cases had pathogenic mutations and 15 out of them (0.6%) were NF1 mutated. We identified an unexpectedly high prevalence (1 out of 852), of PVs in the NF1 gene, more than 3 times the rate expected given the reported prevalence of NF1. We identified 13 pLOF variants, 1 missense, 1 single amino acid deletion and 1 deletion involving the entire NF1 gene, all in heterozygosity, with the exception of 2 samples with blood mosaicism. Physical exam, medical and family history revealed no features consistent with NF1 diagnosis contrary to the complete penetrance of the disease. In 3 samples, additional PVs were identified, in BRCA2 (ovarian cancer), ATM and NTHL1 (2 colorectal cancer cases) genes. Conclusions: This study highlights that NF1 PVs are more frequent than previously estimated and often discovered in unaffected individuals. Incomplete penetrance and missed diagnoses probably explain this. The aforementioned data presented provides insights into the need of establishment of screening and management strategies in patients with incidental findings. Citation Format: A. Koutras, K. Papazisis, I. Boukovinas, R. Iosifidou, I. Intzidis, K. Potska, C. Dogka, A. Katseli, D. Paranou, A. Karavaggeli, A. Meintani, D. Bouzarelou, D. Lachanas, G. Rigas, M. Kanara, M. Müslümanoglu, I. Bobolaki, E. Biziota, E. Papadopoulou, G. Nasioulas. High-prevalence of NF1 pathogenic variants in cancer patients without classic features of Neurofibromatosis type 1 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-03-05.