Abstract
Li–Fraumeni syndrome (LFS; OMIM # 151623) is an autosomal dominant disorder associated with multiple early-onset cancers. Classic LFS and its variants, collectively named Li–Fraumeni-like (LFL) syndrome, are two recognized forms of the syndrome. It is estimated that carriers of a germlineTP53 mutation have, on average, a 50 % risk to develop cancer before the age of 40 years and a life risk of 90 %. Clinical management of individuals with LFS/LFL is a major challenge due to the wide tumor spectrum. Monitoring strategies have shown to reduce mortality in carriers of TP53 germline mutations. Cancer-prone families of Southeastern Brazil have been identified to carry a founder germline TP53 mutation (c.1010G>A, p.R337H) at an unusually high prevalence of about 1:300 subjects (0.3 %). Structural and functional studies have identified that p.R337H mutant proteins have an in vitro pH-dependent defect in the oligomerization domain, making them inactive only in conditions of increased intracellular pH. The TP53 p.R337H allele is a unique example of a pathogenic founder mutation persisting among a large and mixed population. Genetic counseling should integrate the clinical assessment and care of all individuals carrying TP53 germline mutations. The complexity of the diagnosis and prognostic definitions, as well as the long-term impact of being diagnosed with a germline TP53 mutation on mutation carriers and their relatives, calls for a multidisciplinary approach to counseling, involving health care professionals from multiple areas of expertise.
Keywords
- Genetic Counseling
- Mutation Carrier
- TP53 Mutation
- Preimplantation Genetic Diagnosis
- Predictive Genetic Testing
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Achatz, M.I.W., Ashton-Prolla, P. (2013). Genetic Counseling for TP53 Germline Mutations. In: Hainaut, P., Olivier, M., Wiman, K. (eds) p53 in the Clinics. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3676-8_18
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