Rare TP53 variant associated with Li-Fraumeni syndrome exhibits variable penetrance in a Saudi family

Abstract

Li-Fraumeni syndrome (LFS) is an inherited, autosomal-dominant condition that predisposes individuals to a wide-spectrum of tumors at an early age. Approximately 70% of families with classic LFS have pathogenic variants in the tumor suppressor gene TP53 that disrupt protein function or stability. While more than 70% of pathogenic variants in TP53 are missense variants, the vast majority occur very infrequently, and thus their clinical significance is uncertain or conflicting. Here, we report an extremely rare TP53 missense variant, c.799C > T (p.Arg267Trp), identified in a 2-year-old Saudi proband diagnosed with choroid plexus carcinoma (CPC) and six of his first- and second-degree relatives. CPC is frequently found in families with LFS, and this is the first detailed report of a family with this variant. Intriguingly, the proband’s father is homozygous for TP53 c.799C > T and phenotypically normal at 39 years of age. While loss of TP53 heterozygosity is often observed in tumors from individuals with LFS, homozygous germline TP53 pathogenic variants are rare. Based on our analysis of this single family, we hypothesize that TP53 c.799C > T has low or variable penetrance for LFS, with predisposition to the development of CPC. The observations from this family have furthered our understanding of the phenotypic variability that may be caused by one variant of TP53, even in the same family, and suggest that other factors (genetic and/or environmental) may play a role in mechanism of disease manifestation in LFS.

Case Report: Identification of a Novel Pathogenic Germline TP53 Variant in a Family With Li–Fraumeni Syndrome

“…At the protein level, the revealed c.645del variant causes a frameshift with the introduction of a premature stop codon within the p53 DNA binding domain (DBD) (p.Ser215Argfs * 32). The DBD domain, located in the central part of the p53 protein, contains most of the LFS-associated missense variants (Bouaoun et al, 2016 ; AlHarbi et al, 2018 ). However, also frameshift pathogenic variants in the p53 DBD, such as c.685dup (p.Cys229Leufs * 11), have been observed in a family with LFS (Ji et al, 2018 ).…”

“…Here, we describe a family carrying a novel pathogenic germline variant of the TP53 gene. This inherited frameshift variant is extremely rare because more than 70% of the pathogenic TP53 variants in LFS families were observed to be missense variants (AlHarbi et al, 2018 ). This family case report highlights the importance of offering genetic counseling and genetic testing to all family members at high risk to be carriers of TP53 inherited pathogenic variants.…”

New Insights into Melanoma Tumor Syndromes

“…More recently, germline TP53 p.I254V mutations causing p53 inactivation were found in two unrelated uveal melanoma patients (Hajkova et al 2018). Approximately 70% of TP53 pathogenic variants in LFS arise as missense mutations interspersed in six "hotspot" regions of the DNA binding domain (Leroy, Anderson, and Soussi 2014;AlHarbi et al 2018).…”

“…More recently, germline TP53 p.I254V variants causing p53 inactivation were found in two unrelated patients with UM ( Hajkova et al., 2018 ). Approximately 70% of TP53 pathogenic variants in LFS arise as missense variants interspersed in six hotspot regions of the DNA-binding domain ( AlHarbi et al., 2018 ; Leroy et al., 2014 ). For such patients, routine skin examinations should be considered alongside interdisciplinary clinical management.…”

Investigating the prevalence of pathogenic variants in Saudi Arabian patients with familial cancer using a multigene next generation sequencing panel

“…The authors also observed this variant in an additional, unrelated individual with colon, breast and ovarian cancer, indicating the potential relevance of this variant to multiple types of cancer in this population. A second study reports on a 5-year-old female, whose data is also included in this study, with glioblastoma multiforme and constitutional mismatch repair-deficiency due to an MSH6 homozygous c.1883G>A mutation, who continued to experience an exceptional and durable response, 9 months later, to the immune checkpoint inhibitor (ICPI) nivolumab [ 48 ]. To the authors’ knowledge, this was the first report in the Arab world of a durable response to ICPIs in a pediatric glioblastoma patient.…”