Clinical and surveillance outcomes of the TP53 c.1000G > C (p.Gly334Arg) variant

BACKGROUND: Germline TP53 pathogenic variants are classically associated with Li-Fraumeni syndrome, although penetrance and tumor spectrum vary substantially across specific alleles. The Ashkenazi Jewish TP53 c.1000G > C (p.Gly334Arg) variant has been reported as a lower-penetrance, later-onset cancer predisposition allele, but its clinical classification and penetrance remain subjects of ongoing discussion. Consequently, the optimal surveillance approach for carriers remains uncertain, and real-world surveillance outcome data are limited. METHODS: We performed a retrospective descriptive study of heterozygous TP53 p.Gly334Arg carriers followed at two Israeli hereditary cancer clinics between 2021 and 2025. Clinical records were reviewed for demographic data, personal and family cancer history, and surveillance outcomes. Whole-body magnetic resonance imaging (WB-MRI) findings were analyzed for carriers who underwent serial surveillance. RESULTS: Eighteen carriers from five families were identified, all of Ashkenazi Jewish ancestry. Seven of 18 carriers (39%) had a personal history of malignancy. Breast cancer was the most common malignancy, occurring in four women, all diagnosed after age 50; available pathology showed hormone receptor-positive disease. No pediatric malignancies were observed, and none of the carriers met classic or Chompret clinical criteria for Li-Fraumeni syndrome. Ten carriers underwent serial WB-MRI surveillance, totaling 36 examinations (mean 3.6 per patient). No malignancies were detected. However, surveillance generated nine abnormal findings (0.25 per scan), all false positives, including one that led to invasive procedures. CONCLUSIONS: In this clinic-based cohort, TP53 p.Gly334Arg was observed in association with a later-onset, potentially lower-penetrance cancer phenotype and low short-term surveillance yield. These findings support phenotypic heterogeneity among TP53 variants and raise questions regarding the optimal intensity of surveillance in this population; however, current data are insufficient to support modification of existing TP53 surveillance protocols. Larger multicenter studies with longer follow-up are needed to define penetrance and guide genotype-informed management.