Segregation of the rare TP53 germline missense variant c.314G>T, p.Gly105Val in Algerian family with Li-Fraumeni Syndrome: First report.
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BACKGROUND: Li-Fraumeni syndrome (LFS) is an autosomal dominant disease caused by heterozygous germline pathogenic variant in TP53 gene and frequently predisposes to a broad spectrum of cancers including early-onset cancers. To date, clinical and genetic features of LFS are largely unknown in Algerian population. In this study, we performed germline variants screening in TP53 gene in an Algerian LFS family and we have reclassified the TP53 germline missense variant c.314G>T/ (p.Gly105Val). PATIENTS AND METHODS: We selected an LFS family with strong history of cancer along three generations that meets updated Chompret clinical criteria. Four family members were affected with various tumors. The proband in this family, a 4-year-old girl has been diagnosed with rhabdomyosarcoma at age 3 years old and she developed a secondary cancer in the right lung after radiotherapy. Her mother developed an early-onset breast cancer at age 30 years old, her maternal grandmother and her maternal aunt have also been diagnosed with breast cancer at age 33 and 27 years, respectively. We screened TP53 exons 3-11 using PCR-Sanger sequencing in 4 members of this LFS family: the proband, her mother and her father (trio) and her kid brother aged of 2 years old, respectively. RESULTS: The analysis identified the rare germline missense variant TP53 c.314G>T/ (p.Gly105Val) in heterozygous status in three members of the LFS family: the proband, her mother and her kid brother, respectively. The father has been tested negative for the variant. As the TP53 missense germline variant c.314G>T co-segregates within cancer in our LFS family along two generations, we can classify it for the first time as Class 4 variant with the status "Likely Pathogenic" according to ACMG nomenclature. CONCLUSIONS: Our study highlights the importance of the identification, the interpretation and the reclassification of TP53 missense variants detected in carriers in order to improve prognosis, treatment strategies, and LFS patients monitoring and identifying high risk family members.