Pathogenic Neurofibromatosis type 1 gene variants in tumors of non-NF1 patients and role of R1276

Abstract

Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome associated with pathogenic variants affecting the GTPase-activating protein neurofibromin. Genetic variants affect neurofibromin through targeted protein degradation, failed aggregation of the monomers or failure of specific domains depending on the functional state. In addition to the occurrence in NF1, there is evidence of pathogenic variants occurring in various solid tumors. We collected data from 63 patients from our molecular tumor board for NF1 gene sequencing and detected 72 NF1 variants, thereby 32% of those being pathogenic. They occurred most often in lung cancer, glioma, melanoma, sarcoma, and gynecological cancer and affected women more often. Pathogenic NF1 variants appeared at low frequency except in malignant melanoma and glioma (10%). We present common pathogenic variants, their types, and association with tumor entities, their frequency, and domain localization and focus on common recurrent variants and their probable result and predictive quality in somatic mutation screening. We detected variants in different tumor entities without NF disease, covering more frequent truncating mutations than reported for germline. We question whether all NF1 variants reported in tumors without the presence of NF1 are somatic. To conclude, recognition of NF1 mosaicism requires multitissue sampling, precise sequencing technologies, and inclusion of genetic counseling.