LiâÂÂFraumeni syndrome (LFS) is a rare, autosomal dominant, hereditary disorder that predisposes carriers to cancer development. It was named after two American physicians, Frederick Pei Li and Joseph F. Fraumeni Jr., who first recognized the syndrome after reviewing the medical records and death certificates of childhood rhabdomyosarcoma patients. The disease is also known as SBLA, for the Sarcoma, Breast, Leukemia, and Adrenal Gland cancers that it is known to cause.
LFS is caused by germline mutations (also called genetic variants) in the TP53 tumor suppressor gene, which encodes a transcription factor (p53) that normally regulates the cell cycle and prevents genomic mutations. The variants can be inherited, or can arise from mutations early in embryogenesis, or in one of the parent's germ cells.
LFS is thought to occur in about 1 in 5,000 individuals in the general population. In Southern and Southeastern Brazil, there is a common founder mutation, p.R337H, that occurs in about 1 in every 375 people.ÃÂ LFS is inherited in an autosomal dominant fashion which means that a person with LFS has a 50% chance to pass the syndrome on in each pregnancy (and a 50% chance to not pass on the syndrome).
In 2025, a sperm donor from Copenhagen was discovered to have a germ line mutation causing LFS, having fathered at least 197 children in 14 countries. A presenter at a May 2025 genetics conference discovered that out of 67 children conceived from this donor, 23 had the mutation and 10 had developed cancer.
LiâÂÂFraumeni syndrome is characterized by early onset of cancer, a wide variety of types of cancers, and development of multiple cancers throughout one's life.
LFS: Mutations in TP53
TP53 is a tumor suppressor gene on chromosome 17 that codes for the protein p53. It normally assists in the control of cell division and growth through action on the normal cell cycle. TP53 typically becomes expressed due to cellular stressors, such as DNA damage, and can halt the cell cycle to assist with either the repair of repairable DNA damage, or can induce apoptosis of a cell with irreparable damage. The repair of "bad" DNA, or the apoptosis of a cell, prevents the proliferation of damaged cells and the development of cancer.
Pathogenic and likely pathogenic variants in the TP53 gene can inhibit its normal function and allow cells with damaged DNA to continue to divide. If these DNA mutations are left unchecked, some cells can divide uncontrollably, forming tumors (cancers). Many individuals with LiâÂÂFraumeni syndrome have been shown to be heterozygous for a TP53 variant. 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.
LFS-Like (LFS-L):
Families who do not conform to the criteria of classical LiâÂÂFraumeni syndrome have been termed "LFS-Like". LFS-L individuals generally do not have any detectable TP53 variants, and tend to meet either the Birch or Eeles criteria.
The classical LFS malignancies—sarcoma, cancers of the breast, brain, and adrenal glands—comprise about 80% of all cancers that occur in this syndrome.
The risk of developing any invasive cancer (excluding skin cancer) is about 50% by age 30 (1% in the general population) and is 90% by age 70. Early-onset breast cancer accounts for 25% of all the cancers in this syndrome. This is followed by soft-tissue sarcomas (20%), bone sarcoma (15%), and brain tumors—especially glioblastomas—(13%). Other tumours seen in this syndrome include leukemia, lymphoma, and adrenocortical carcinoma.
The table below depicts tumor site distribution of variants for families followed in the LFS Study at the National Cancer Institute's (NCI) Division of Cancer Epidemiology and Genetics (DCEG): About 95% of females with LFS develop breast cancer by age 60 years; the majority of these occur before age 45 years lending females with this syndrome to have almost a 100% lifetime risk of developing cancer.
Cancer Risks by Sex and Age
Age ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ 20 years old ÃÂ ÃÂ ÃÂ 40 years old ÃÂ ÃÂ ÃÂ 60 years old
Men ÃÂ ÃÂ ÃÂ ÃÂ 25% ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ 40% ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ 88%
WomenÃÂ 18% ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ 75% ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ ÃÂ >95%
Germline variants in the TP53 tumor suppressor gene were discovered to be the primary cause of LiâÂÂFraumeni syndrome in 1990.
LiâÂÂFraumeni syndrome is diagnosed if a person has a pathogenic or likely pathogenic TP53 variant and/or if these three Classic Criteria are met:
LFS should also be suspected in individuals who meet other published criteria.
2015 Revised Chompret Criteria:
Birch Criteria for Li Fraumeni-like syndrome:
Eeles Criteria for Li Fraumeni-like Syndrome:
If an individual has a personal or family history concerning for LFS, they should discuss the risks, benefits, and limitations of genetic testing with their healthcare provider or a genetic counselor.
Genetic counseling and genetic testing for the TP53 gene can confirm a diagnosis of LFS. People with LFS require early and regular cancer screening following the "Toronto Protocol":