Abstract Cancer remains the second leading cause of death worldwide, with 5-10% of cases attributed to hereditary syndromes. Among these, Li-Fraumeni Syndrome (LFS) is closely associated with pathogenic germline variants in the TP53 gene, a critical tumor suppressor responsible for maintaining genomic stability and regulating cell cycle and apoptosis. In Brazil, the TP53-R337H variant is highly prevalent due to a well-documented founder effect, particularly in the central and southern regions. Recent studies have revealed the co-segregation of the truncating variant XAF1-E134* with TP53-R337H, forming a functional haplotype associated with increased tumor aggressiveness and earlier onset (Jung et al., 2020; Fortes et al., 2021).This study aimed to evaluate the frequency and clinical impact of this haplotype in a cohort of Brazilian individuals with suspected hereditary cancer syndromes, recruited through the Brazilian Unified Health System (SUS). A total of 527 participants (probands and relatives) were referred to the Human Genetics Center at the Federal University of Goiás (UFG), based on NCCN 2025 criteria for Hereditary Breast and Ovarian Cancer Syndrome (HBOC) and LFS. After informed consent, venous blood samples were collected for DNA extraction. Next-generation sequencing (NGS) was used to analyze the coding region of TP53, and genotyping assays were performed to detect the R337H and XAF1-E134*variants in both probands and their family members.Among the 527 participants, 198 (37.56%) were probands and 329 (62.44%) were family members. Of the probands, 7.58% (15/198) carried pathogenic TP53 variants, with 93.33% (14/15) being R337H. Thirteen probands were tested for XAF1-E134*, and 76.92% (10/13) tested positive. Of these, 90% (9/10) had a confirmed cancer diagnosis, with a mean age at diagnosis of 40.7 years. Furthermore, 30% (3/10) presented with multiple primary tumors, including prostate, osteosarcoma, sarcoma, and adenocarcinoma. Metastasis was observed in 10% (1/10). Among family members, 14.29% (47/329) carried TP53 variants. Of the 35 relatives tested for XAF1-E134*, 91.43% (32/35) were positive.These results provide strong evidence for co-inheritance of TP53-R337H and XAF1-E134*, forming a high-risk haplotype associated with more aggressive cancer phenotypes. Notably, in families where probands were negative for TP53-R337H, relatives were also negative for both variants, supporting the hypothesis of joint transmission. The clinical manifestations observed among carriers reinforce the functional synergy between these two variants and their potential contribution to early-onset and multifocal malignancies.This study highlights the relevance of including XAF1-E134* in genetic screening panels, particularly in Brazilian regions affected by the R337H founder mutation. Incorporating haplotype-based analysis into clinical genetics can improve risk stratification, facilitate early diagnosis, and guide personalized prevention and surveillance strategies in high-risk families. Further studies are essential to clarify the molecular mechanisms underlying this haplotype and to define its role in cancer pathogenesis and clinical management. Citation Format: K. M. Veiga, P. F. Silva, W. D. Oliveira;, D. C. Maia, R. M. Rahal, E. P. Silveira-Lacerda. Co-segregation of XAF1-E134and TP53-R337H in a brazilian cohort: clinical impact of a high-risk haplotype abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-02-11.
Veiga et al. (Tue,) studied this question.