Table 2.

Overview of rare pathogenic variants in known cancer predisposition genes among 128 children with CNS tumors

#	Chromosomal location (hg19)	Gene	Ontology	HGVS p. [HGVS c.]	Clinical significance	Pathway/function	VAF [alt/ total]	Associated CPS (CNS tumors with increased risk)	Clinical impact of finding (in childhood)	Pathology in current cohort	Parent-of-origin
1*	chr16:2134364	TSC2	Frameshift	p.Leu1382Profs*32 [NM_000548: c.4144dupC]	LP	Tumor suppressor	0.40 [8/20]	Tuberous sclerosis (subependymal giant cell astrocytoma14)	Yes. Tumor surveillance [MRI and US]	Subependymal giant cell astrocytoma	De novo pat: neg mat:neg
2	chr20:57415711	GNAS	Frameshift	p.Glu190Alafs [NM_016592.3: c.559_566dup AGCCCCAG]	LP	G protein-coupled receptor signaling	0.42 [13/31]	Novel CPS (medulloblastoma15)	None	Optic pathway glioma	Not tested pat: not tested mat: not tested
3	chr9:98268824	PTCH1	Frameshift	p.Leu87Ilefs*2 [NM_000264.3: c.258_259delCT]	P	Sonic hedgehog signaling	0.50 [14/28]	Gorlin syndrome (medulloblastoma16)	Yes. Avoid radiotherapy when possible	Medulloblastoma, SHH	Maternal pat: not tested mat: verified
4	chr12:133249842	POLE	Missense	p.Ser461Thr [NM_006231.3: c.1381T>A]	LP	DNA repair and replication	0.60 [24/40]	Polymerase Proofreading- associated Syndrome (high-grade glioma17,18)	Yes. Consider CMMRD protocol; tumor surveillance [MRI, US and ENDO]	Medulloblastoma, SHH (subsequentdiffuse high-grade glioma, H3/IDH1 wt)	De novo pat: neg mat:neg
5	chr17:7577120	TP53	Missense	p.Arg273His [NM_000546.5: c.818G>A]	P	Tumor suppressor	0.45 [15/33]	Li–Fraumeni (astrocytoma, medulloblastoma, choroid plexus tumors19)	Yes. Tumor surveillance [MRI and US], avoid radiotherapy when possible	Medulloblastoma, SHH, (subsequent hemispheric anaplastic astrocytoma,IDH1wt)	Paternal | de novo pat: not tested mat: neg
6	chr5:112174947	APC	Frameshift	p.Thr1220Profs*46 [NM_000038.5: c.3656_3657dupCC]	LP	Tumor suppressor	0.52 [14/29]	Turcot Syndrome (medulloblastoma, astrocytoma, ependymoma20)	Yes. Tumor surveillance [US and ENDO], risk-reduction surgeries	Medulloblastoma, WNT	Paternal pat: verified mat: not tested
7	chr3:52439149	BAP1	Frameshift	p.His364Glnfs*33 [NM_004656.3: c.1092_1093delCA]	P	Deubiquitination, regulation of cell cycle, DNA damage response	0.51 [35/68]	BAP1 tumor disposition syndrome (meningioma21)	Yes. Tumor surveillance [OPHTAL]	Anaplastic meningioma	Maternal pat: not tested mat: verified
8	chr17:29541542	NF1	Missense	p.Tyr489Cys [NM_001042492.2: c.1466A>G]	P	Ras-MAPK signaling	0.66 [39/59]	Neurofibromatosis 1 (optic pathway glioma, other low-grade gliomas22)	Yes. Tumor surveillance [OPHTAL]	Optic pathway glioma	De novo pat: neg mat:neg
9*	chr17:29553478	NF1	Frameshift	p.Ile679Aspfs*21 [NM_000267.3: c.2033dupC]	P	Ras-MAPK signaling	0.27 [8/30]	As described for case 8	Yes. Tumor surveillance [OPHTAL]	Pilocytic astrocytoma	De novo**
10	chr17:29654857	NF1	Missense	p.Arg1870Gln [NM_001042492.2: c.5609G>A]	P	Ras-MAPK signaling	0.52 [26/50]	As described for case 8	Yes. Tumor surveillance [OPHTAL]	Unknown tumor type: likely low- grade glioma	Maternal pat: not tested mat: verified
11	chr17:29533319	NF1	Frameshift	p.Met442Valfs*3 [NM_000267.3: c.1324_1325delAT]	P	Ras-MAPK signaling	0.83 [45/54]	As described for case 8	Yes. Tumor surveillance [OPHTAL]	Optic pathway glioma	Maternal pat: not tested mat: verified
12	chr10:104267919- 104284310	SUFU	Microdeletion	c.183-1007_ 317 + 15230del [NM_016169.3: 16,352bp del]	LP	Sonic hedgehog signaling	~ 0.47 [~ 27/~ 57]	Gorlin syndrome (medulloblastoma16)	Yes. Tumor surveillance [MRI], avoid radiotherapy when possible.	Medulloblastoma, SHH	De novo pat: neg mat:neg
13	chr17:29660179- 29751689	NF1	Microdeletion	exon 41-58del [NM_001042492.2: 91510bp del]	P	Ras-MAPK signaling	~ 0.49 [~ 20/~ 41]	As described for case 8	Yes. Tumor surveillance [OPHTAL]	Pilocytic astrocytoma	Maternal mat: verified pat: not tested

SNV, single nucleotide variant; SV, structural variant; HGVS, Human Genome Variation Society; LP, likely pathogenic; P, pathogenic; VAF, variant allele frequency; CPS, cancer predisposition syndrome; wt, wild-type; CNS, central nervous system; SHH, sonic hedgehog activated; WNT, wingless activated; MRI, magnetic resonance imaging; US, ultrasound; ENDO, endoscopy; OPTHAL, ophthalmological examination.

^*reported in Byrjalsen et al⁹,

^**presumed de novo based on lack of phenotype in parents.