Fig. 1

Pedigrees of 10 tumor families with at least one glioma case each carrying rare heterozygous POLE (a-h) or POLD1 (i-j) germline missense variants, and variant localization (k). (a) Co-segregation of POLE variant V1 with the glioma phenotype in patients III.1/M1 and II.2 of family Fam011. Patient I.2 was diagnosed with colorectal cancer. (b) Co-segregation of POLE variant V2 with the tumor phenotype in glioblastoma patient III.1 and small cell lung cancer patient III.2 of family WI70. (c) The POLE variant V2 was also identified in glioblastoma patient III.2 of family WI127. (d) In family WI161, glioblastoma patient II.1 carries the POLE variant V3. Patient II.2 was diagnosed with colorectal cancer. (e) In family WI207, patient III.1 with an astrocytoma CNS WHO grade 2 carries the POLE variant V4. Patient I.2 was diagnosed with meningioma. (f) In family WI140, glioblastoma patient III.1 carries the POLE variant V5. Patient II.1 was diagnosed with colorectal cancer. (g) The POLE variant V6 was identified in patient III.1 of family WI69 who was diagnosed with breast cancer at age 53 years and glioblastoma at age 57 years. (h) In family WI104, patient III.1 with an astrocytoma CNS WHO grade 3 carries the POLE variant V7. Patient II.3 was diagnosed with meningioma, and patient II.4 with oligodendroglioma. (i) In family WI27, astrocytoma patient III.1 carries the POLD1 variant V8. Patients II.1 and II.4 were diagnosed with breast cancer, and patient I.4 with uterus cancer. (j) In family WI40, patient II.1 with an oligodendroglioma CNS WHO grade 2 carries the POLD1 variant V9. Patient II.2 was diagnosed with optic nerve glioma. (k) Domain structures of the catalytic subunit of DNA polymerase ε (POLE) and the catalytic subunit of DNA polymerase δ (POLD1), and localization of the identified POLE/POLD1 variants. Exonuclease domain (IPR006133) and multifunctional domain (IPR006134) of POLE/POLD1 according to the InterPro database (https://www.ebi.ac.uk/interpro/). Aa, amino acids; Dx, age at diagnosis; CNS, central nervous system; V, variant; WHO, World Health Organization; WT, wildtype; y, years. Asterisks indicate patients of whom DNA was available for genetic testing. A question mark indicates that the tumor diagnosis is uncertain