2.3. Familial Segregation of the Cancer Predisposing Variant

The studied family shows aggregation of CRC and multiple other malignancies such as prostate, female genital tract, testicular, and breast cancer. In order to define familial segregation criteria for the pathogenic variant predisposing for cancer development in this family, the hereditary line of malignant diseases was retraced, assigning to each analyzed family member a probability of being a Mendelian case and carrier of the mutation (Figure 1).

The first case sequenced in this family (III-1) developed CRC as well as colorectal polyps (CRP) at the age of 57 and 60 years, respectively, and was thus considered as a carrier of the mutation. Tracing genetic cancer predisposition back to his CRC-affected mother (II-4) and further to his cancer-affected grandparents (I-3, I-4; prostate, female genital tract cancer, respectively), the cancer predisposing mutation might have been further inherited to his first cousin once removed (IV-8; via II-6 and III-7). Since this family member (IV-8) developed CRC at the young age of 23 years, he was regarded as the second case of the family and thus carrier of the mutation. On the other hand, the CRC-unaffected family member included in this study (IV-7) was 39 years at the time of recruitment. Her first-degree relatives were affected by cancer or CRP (IV-6, and III-6, respectively), suggesting that she might show the genotype without expressing the disease phenotype yet. Thus, she was considered as a possible carrier of the mutation.

The identified variants were filtered according to the described definitions of III-1 and IV-8 as cases and IV-7 as a possible carrier of the family, respectively summarized in Supplementary Table S1.