# Rate of germline pathogenic sequence variants in cancer susceptibility genes in an Israeli pediatric and adolescent cancer cohort: a single institute experience

## TL;DR

This study found that 15.7% of Israeli pediatric and adolescent cancer patients had germline pathogenic gene variants, with the highest rates in retinoblastoma and brain tumor cases.

## Contribution

The study reports germline pathogenic variant rates in an Israeli pediatric cancer cohort, emphasizing retinoblastoma and CNS tumor associations.

## Key findings

- Germline pathogenic sequence variants were detected in 15.7% of 108 tested pediatric cancer patients.
- The highest PSV rates were observed in retinoblastoma (58.3%) and central nervous system tumors (13.3%).
- Younger age at diagnosis was significantly associated with PSV carrier status.

## Abstract

Multi-cancer predisposition gene panel testing (MCPGT) enables simultaneous deep-coverage genotyping of multiple CPGs (cancer predisposing genes) and detects germline pathogenic sequence variants (PSVs). Reported PSV carrier rates among pediatric and adolescent cancer patients range from 8 to 17.6%, with variability attributed to ethnic background, the number of genes tested, cancer phenotypes, and patient selection criteria. This study aimed to assess the rate and spectrum of germline PSVs in consecutive pediatric and adolescent cancer patients treated at the Sheba Medical Center, a tertiary medical center. All cancer patients aged 0–18 years treated between 01.2021 and 12.2022 were offered MCPGT. Overall, 257 eligible cancer patients were treated during the study period, of whom 116 Israeli patients underwent MCGPT (Invitae, San Francisco, CA), with complete data available for 108. The range of malignancies included central nervous system (CNS) tumors (n = 45), solid tumors (n = 37), hematological malignancies (n = 14), and retinoblastoma (RB) (n = 12). PSVs were detected in 17/108—15.7% of patients, with the highest rates in patients with RB (7/12, 58.3%) and CNS tumors (6/45, 13.3%). A significant association was found between younger age at diagnosis and PSV carrier status (4.7 years in carriers vs. 9.3 years in non-carriers, p = 0.003). Fulfilling Jongmans' criteria was correlated with PSV detection. The study highlights the importance of genetic testing in children meeting specific clinical criteria, particularly those diagnosed with RB and CNS tumors. Further studies with larger, ethnically diverse cohorts are needed to validate these findings to expand the scientific basis for personalized care strategies.

The online version contains supplementary material available at 10.1007/s10689-025-00489-1.