Figure 4.

Family tree of patient number 15. Despite not fulfilling the Jongmans MC criteria nor the revised criteria by Ripperger, the patient’s family history of cancer was still suggestive for genetic cancer predisposition and the genetic counseling was advised based on this information. The adolescent was diagnosed with extraosseous Ewing sarcoma. A CHEK2 variant was detected by the NGS OncoNano V2 panel. The variant was described in the general population (gnomAD reports three total heterozygotes). However, it was described six times in ClinVar and three times in cancer patients (uncertain clinical significance (ID 233261)). It was not found in other databases. In addition, it is a variant studied functionally on one occasion. It was reported in the literature in a patient with hereditary breast cancer, with functional in vitro study that demonstrated a 50% reduction in kinase activity [45], although the location of the variant was outside of a functional domain. The variant was found to be of maternal origin and family history of melanoma was identified in the grandfather and great-uncle in this branch of the family. In addition, the grandfather had had a second tumor at an older age. Based on the ACGM criteria and family information, the variant was classified as likely pathogenic.