A novel germline p53 splicing mutation was identified in a pediatric p
atient with two metachronous primary cancers that are constituent tumo
rs of the Li-Fraumeni syndrome. Genomic DNA from the second tumor show
ed the same mutation and loss of heterozygosity at the p53 locus. The
mutant mRNA and protein were present in the tumor tissue. In contrast,
in the normal tissues bearing the germline mutation in the heterozygo
us state, predominantly normal mRNA was expressed and the mutant p53 p
rotein was not detectable. The functional silence and relative lack of
mutant p53 mRNA expression in the normal tissues of this patient may
be caused by decreased stability or decreased production. If this prov
es a more general pattern of expression of mutant p53 in individuals w
ith germline mutations, these findings may explain the paucity of tumo
rs in individuals affected with the Li-Fraumeni syndrome.