A germ line mutation in exon 5 of the p53 gene in an extended cancer family.

Germ line p53 point mutations have been reported for some families with Li-Fraumeni syndrome, a syndrome characterized by a dominantly inherited increased susceptibility for the development of early age of onset neoplasms of diverse origin in multiple family members. All of the initially reported p53 germ line mutations have been found exclusively within a single conserved, nonpolymorphic region of the gene between condons 245 and 258. The restricted distribution of these inherited mutations has led to speculation that germ line p53 mutations have unique properties [B. Vogelstein, Nature (Lond.), 348: 681-682, 1990]. We report here on the identification of a p53 germ line mutation at codon 133 (ATG----ACG) in nine members of an extended Li-Fraumeni syndrome family. This mutation leads to an amino acid substitution in the protein and is shown to completely cosegregate with Li-Fraumeni syndrome associated cancer in this family. Its location extends the region of the p53 gene where inherited mutations predisposing to cancer are observed and suggests that their distribution may be diverse.