Table 3.

Clinical information for the 13 patients identified with rare pathogenic cancer predisposition gene alterations

#	Gene	CNS tumor diagnosis, molecular subtype, WHO grade	Tumor location	Tumor methylation class (score)	Most relevant somatic alteration(s)	Age (y)	Presenting signs/ symptoms	CPS recognized before/ after tumor d iagnosis	Criteria for clinical CPS diagnosis met
1	TSC2	Subependymal giant cell astrocytoma, WHO I	Lateral ventricle	N/A	None detected. Classical histopathology and IHC	0.3	Epileptic seizures	Before	Yes
2	GNAS	Optic pathway glioma	Optic nerve, intraorbital	N/A	Not biopsied	2.8	Unilateral proptosis and vision impairment	After	N/A
3	PTCH1	Nodular/desmoplastic medulloblastoma, SHH activated, TP53 wt, WHO IV	Vermis	Medulloblastoma SHH (0.99), subclass SHH B (infant) (0.98)	SNVs of unclear clinical significance in JAK3, ERBB4, NOTCH1. No C- or NMYC amplification	1.5	Increasing head circumference	After	No
4	POLE	Anaplastic/nodular/desmoplastic medulloblastoma, SHH activated, TP53 mutated, WHO IV	Cerebellar hemisphere	Medulloblastoma SHH (0.97), subclass SHH A (children and adult) (0.82)	TP53, HNF1A and PIK3CA mutations. SNV of unclear clinical significance in VHL. No C- or NMYC amplification	4.4	Headache, affected gait, torticollis	After	N/A
		Diffuse pediatric high- grade glioma, H3 and IDH1 wt	Temporal lobe	Pediatric-type diffuse high-grade glioma (0.99)	TP53 and RB1 mutations. PTPN11 variant of unknown significance	8.0	None. Detected on routine surveillance MRI
5	TP53	Anaplastic and nodular/desmoplastic medulloblastoma, SHH activated, TP53 mutated, WHO IV	Cerebellar hemisphere	Medulloblastoma SHH (0.99), subclass SHH A (children and adult) (0.96)	TP53 mutation. Loss of 2q and 5q, partial loss of 8q and 10q. No C- or NMYC amplification	7.1	Headache, nausea, vomiting, torticollis	After	No
		Anaplastic astrocytoma, IDH wt, WHO III	Frontal lobe	No match ≥ 0.3	TP53 mutation	8.8	None. Detected on routine surveillance MRI
6	APC	Nodular/desmoplastic medulloblastoma, WNT activated, TP53 wt, WHO IV	Fourth ventricle	Medulloblastoma WNT (N/A)	TERT promoter and PIK3CA mutation	5.4	Affected gait and balance	After	No
7	BAP1	Anaplastic meningioma, WHO III	Petrous and mastoid bones, jugular vein	Meningioma (0.91), meningiomas intermediate (0.61), meningiomas intermediate A (0.58)	BAP1 mutation. Partial loss 3p	15.1	Focal neck swelling, fatigue, unilateral tinnitus	After	N/A
8	NF1	Optic pathway glioma	Optic nerve and optic chiasm	N/A	Not biopsied	3.2	Strabismus	After	Yes
9	NF1	Pilocytic astrocytoma, BRAF wt, WHO I	Suprasellar/hypothalamus	N/A (insufficient tumor tissue)	Inconclusive KIAA1549- BRAF fusion analysis	13.3	Vision impairment	After	Yes
10	NF1	Well-circumscribed tumor of unknown type (tentative diagnosis based on radiological findings: low-grade glioma)	Mesencephalon	N/A	Not biopsied	10.7	Headache and affected fine motor skills	Before	Yes
11	NF1	Optic pathway glioma (later also diagnosed with JMML)	Bilateral optic nerves, prechiasmal	N/A	Not biopsied	4.1	Weight loss, recurrent episodes with fever	After	Yes
12	SUFU	Nodular medulloblastoma, SHH activated, TP53 wt, WHO IV	Fourth ventricle	Medulloblastoma SHH (N/A), subclass SHH B (infant) (N/A)	No C- or NMYC amplification	1.1	Early motor delay	After	No
13	NF1	Pilocytic astrocytoma, BRAF wt, WHO I	1) Brainstem 2) Cerebellar hemisphere	1) Pilocytic astrocytoma (0.85), low-grade glioma, subclass midline pilocytic astrocytoma (0.81) 2) Low-grade glioma, pilocytic astrocytoma subtype, infratentorial (0.39)	1) Gain of chromosomes 5, 6, 7 and 12, loss of chromosomes 3 and 18. Loss of 13q and 18q 2) Gain of chromosomes 4, 6, 8, 12. Gain of 15q No pathogenic mutations/fusions detected.	15.6	Affected balance	Before	Yes

IHC, immunohistochemistry; SNV, single nucleotide variant; SHH, sonic hedgehog activated; WNT, wingless activated; N/A, not available/applicable; wt, wild-type; JMML, juvenile myelomonocytic leukemia; CPS, cancer predisposition syndrome.