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Access at https://isn-slidearchive.org/?col=ISN&fol=Archive&file=BPA-3743922.tif. A 58-year-old woman experienced episodes of dizziness and impaired awareness of her surroundings, preceded by an intense feeling of fear. Her history had started 5 years earlier when, after the exclusion of a vascular disorder by a brain CT scan, these episodes were interpreted as possible migraines with aura. Due to their gradual increase in frequency over time, a brain MRI was performed, which revealed a 2.5-cm blurred multinodular lesion localized in the right hippocampus and amygdala. The lesion showed mild hypointensity in T1-weighted sequences and hyperintensity in T2-FLAIR sequences, without perilesional edema, contrast enhancement or diffusion restriction on DWI. An MRI spectroscopy documented a choline peak without a myo-inositol peak association. The radiological findings overall suggested a low-grade neoplasm (Figure 1). Given the persistence of the symptoms, the patient underwent craniotomy with gross total resection of the lesion. After the surgery, the patient experienced mild receptive and expressive aphasia, which is gradually resolving. No seizures have been recorded during subsequent follow-up. Histopathological examination showed fragments of hippocampal cortex and white matter. At low power, the parenchyma appeared uneven due to the presence of pale somewhat confluent nodular areas (Figure 2A, Box 1). At medium magnification, the pale nodules displayed a mildly increased cellularity with cells featuring large, eccentric, nuclei with one or more nucleoli and abundant, finely granular and eosinophilic cytoplasm, resembling neuronal elements. The cells were embedded in a loose fibrillar matrix and showed frequent cytoplasmic or pericellular vacuolar changes (Figure 2B,C). No mitoses were observed. Ki-67 proliferative index was about 1%. By immunohistochemistry, the neoplastic cells were positive for OLIG2 (Figure 2D) and weakly positive for synaptophysin (Figure 2F), while negative for chromogranin, NeuN (Figure 2E) and neurofilaments; GFAP was positive in the matrix but not in the neoplastic cells; CD34 was restricted to vessels; NSE was negative in the cells but highlighted more clearly the nodular pattern at low magnification. The clinico-pathological features overall suggested the diagnosis of multinodular and vacuolating neuronal tumor (MVNT). A pathogenic mutation (p.Gln56_Val60del) in exon 2 of the MAP2K1 gene was found (TruSight Oncology 500, Illumina), further supporting the diagnosis. Interestingly, the lesion carried an additional pathogenic variant (p.Ile774Tyrfs*5) in exon 10 of the ATR gene. Both mutations were present at a low variant allele frequency (i.e., 2.5% and 4%, respectively) in a specimen with 30%–40% tumor cellularity. Multinodular and vacuolating neuronal tumor (MVNT), CNS WHO grade 1. MVNT is a rare neoplasm, with fewer than 60 pathology-proven cases reported in the English literature to date [1], only a minority providing molecular characterization. MVNT may arise in a wide age range, peaking in the middle age, with a slight female predominance. The clinical presentation commonly includes seizures, headache, dizziness or long-standing epilepsy, but MVNT may also be asymptomatic and be discovered incidentally on MRI study, while CT scan fails to identify the lesion in most cases. MVNT does not progress even after total or subtotal resection and is often referred to as a “leave-me-alone” lesion. Surgery can be considered depending on the absence of the pathognomonic radiological features (e.g., bubbly signal alterations) and/or on the presence of symptoms. Increasing evidence indicates that mutations in MAP2K1 encoding Mitogen-Activated Protein Kinase (MAPK) Kinase 1 (MEK1) are the oncogenic driver of MVNT, with isolated cases harboring BRAF non-V600E mutations or FGFR2 fusions [2, 3]. In our case, the tumor was located in the hippocampal region, a typical location. Although the radiological features were not specific per se, the pathological findings (i.e., the multinodular pattern and the presence of neuronal elements with vacuolar changes co-expressing OLIG2 and synaptophysin in absence of NeuN) were diagnostic of MVNT, according to the 2021 WHO Classification of the CNS tumors. Importantly, our case harbored an in-frame pathogenic deletion in MAP2K1 (p.Gln56_Val60del), further supporting the diagnosis. This variant has been previously reported in two published MVNT cases [3]. As an element of novelty, we documented the presence of an inactivating mutation in the ATR gene, encoding a serine/threonine kinase with a pivotal role in the DNA damage response. A possible interplay between MAP2K1 and ATR variants needs to be further explored. Alessandro Selvaggini: case management, wrote the manuscript; Sabrina Rossi: case management, wrote the manuscript; Marco Brollo: provided clinical and follow-up data; Sabina Barresi: performed molecular analysis; Laurino Licia: case management; Lorenzo Nicolè: case management supervision, wrote the manuscript. All authors contributed to the final review. The authors have nothing to report. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. The data are not publicly available due to privacy or ethical restrictions.