If these DNA mutations are left unchecked, some cells can divide uncontrollably, forming tumors (cancers). Further mutations in the DNA could lead to malignant cells that can travel to, and develop cancer in, different areas of the body. Many individuals with Li–Fraumeni syndrome have been shown to be heterozygous for a TP53 mutation. Recent studies have shown that 60% to 80% of classic LFS families harbor detectable germ-line TP53 mutations, the majority of which are missense mutations in the DNA-binding domain. These missense mutations cause a decrease in the ability of p53 to bind to DNA, thus inhibiting the normal TP53 mechanism. Unique Brazilian mutation: Although other mutations leading to Li–Fraumeni syndrome have been found outside the DNA-binding domain, a mutation at codon 337 of the tetramerization domain of TP53 has shown a particularly high frequency. The tetramerization domain plays a major role in the oligomerization of the p53 protein, which exists as a tetramer. This mutation has only been found in Brazilian families, and is located in exon 10 of the TP53 gene. The mutation causes an amino acid change from arginine to histidine at codon 337. With pH in the low to normal physiological range (up to 7.5), the mutant protein forms normal oligomers and retains its suppressor function. However, at a high physiological pH, p53 is unable to assemble into a tetramer. This unique feature may contribute to why families with this particular mutation often show incomplete penetrance.
About 2-3% of osteosarcomas, 9% of rhabdomyosarcomas, and 7-20% of patients with multiple primary tumours have p53 mutations.Although most cases of this syndrome have early onset of cancer, cases have also been reported later in life. Diagnosis
Li–Fraumeni syndrome is diagnosed if these three criteria are met:

The patient has been diagnosed with a sarcoma at a young age (below 45). A first-degree relative has been diagnosed with any cancer at a young age (below 45). Another first- or a second-degree relative has been diagnosed with any cancer at a young age (below 45) or with a sarcoma at any age.Other criteria have also been proposed:
A proband with any childhood cancer or sarcoma, brain tumor or adrenal cortical carcinoma diagnosed before age 45
A first- or second-degree relative with a typical LFS malignancy (sarcoma, leukaemia, or cancers of the breast, brain or adrenal cortex) regardless of age at diagnosis
A first- or second-degree relative with any cancer diagnosed before age 60A third criterion has been proposed:
Two first- or second-degree relatives with LFS-related malignancies at any age. Management
Genetic counseling and genetic testing are used to confirm that somebody has this gene mutation. Once such a person is identified, early and regular screenings for cancer are recommended for them as people with Li–Fraumeni are likely to develop another primary malignancy at a future time (57% within 30 years of diagnosis).