RAS proto-oncogenes (KRAS, HRAS and NRAS) encode GTPases, and their role in cancer, as somatic mutations, is well known (1, 2). Germline mutations in genes within the RAS/MAPK signaling pathway are responsible for a group of phenotypically overlapping developmental disorders (RASopathies)(3), including Noonan syndrome (NS) and Noonan-related disorders: NS with multiple lentigines, cardio-facio-cutaneous syndrome and Costello syndrome (CS)(4). Tumor risk in RASopathies is not yet fully established, and more studies are needed (5, 6). NS patients harboring PTPN11 germline mutations have a 3.5-fold increased risk compared to the general population (6). CS patients carrying HRAS mutations have a higher incidence (approximately 15%) of certain solid tumors, especially rhabdomyosarcomas, and a screening surveillance protocol has been proposed (7, 8). Here, we describe the presence of multiple diffuse schwannomas in a patient harboring a germline KRAS mutation (p. K5E), previously reported on (9). The proband is a 23-year-old female with clinical features compatible with a RASopathy phenotype (Fig. 1a). She was initially evaluated in our service at 8 years old. At the age of 22, she started to experience difficulty in relaxation of the hand muscles, fatigue, abdominal pain and nausea. Six months later, a superficial nodule in her forth right intercostal space was palpable. An exploratory magnetic resonance imaging (MRI) scan of her cranium, thorax and abdomen showed diffuse enlargement of all nerve roots of the spine, brachial plexus, radial, ulnar and median nerves, as well as masses on the retroperitoneum (Fig. 1b), suggesting an overgrowth of peripheral nerve sheaths, compatible with a schwannoma or neurofibroma. No brain abnormalities were found by MRI scanning. Histopathological and immunohistochemical analysis of an excised thoracic nodule were compatible with the diagnosis of schwannoma (Fig. 1c). Combining histological and MRI findings, our final diagnosis was multiple diffuse schwannomas. In otherwise healthy patients, benign tumors of the peripheral nerve sheath typically occur singly. In rare cases malignant transformation occurs. The presence of multiple schwannomas in an individual suggests an underlying tumor predisposition syndrome, more particularly neurofibromatosis type II (NF2) or schwannomatosis (SMARCB1)(10). Comprehensive NF2 and SMARCB1 mutation analysis was performed on DNA extracted from blood and tumor. Analysis included sequencing of the entire coding region, dosage analysis by Multiplex Ligation Probe Assay and Loss of Heterozygosity analysis using 15 microsatellite markers along chromosome 22q. No pathogenic NF2/SMARCB1 mutations were identified. A novel NF2 benign intronic variant was identified in blood and tumor: c. 886-15C> T. This alteration replaces a non-evolutionary conserved pyrimidine by another pyrimidine at the splice acceptor of exon 10 and was proven not to affect splicing through RNA analysis in blood, in agreement with results from in silico splice predictions. Thus, the co-occurrence of a KRAS-associated phenotype and NF2/schwannomatosis caused by mutations in NF2 or SMARCB1 genes is highly unlikely. Therefore, KRAS could be in itself the tumor predisposing gene leading to diffuse schwannomas in our patient. As it is known that SMARCB1 mutations are only found in a minority of the NF2-negative schwannomatosis patients (11, 12), we further performed sequence analysis of all KRAS exons in eight NF2/SMARCB1-negative schwannomatosis patients, but no mutations were found, indicating that KRAS might not be a …