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Clinical features

  • In the classic form of Li-Fraumeni syndrome, the lifetime cancer risk of affected females and males is approximately 90% and 70% respectively.
  • Typical cancers occurring within the context of Li-Fraumeni syndrome include:
    • early-onset breast cancer (often diagnosed before age 30; more commonly over-expresses HER2 than in general population);
    • sarcomas (predominantly rhabdomyosarcoma and osteosarcoma, among others);
    • adrenocortical cancer;
    • brain tumours; and
    • haematological malignancies (including hypodiploid ALL).
  • A wide variety of other cancer types have been reported in affected individuals, with age of onset usually significantly younger than expected.
  • The exact risks associated with constitutional TP53 variants depend on the specific genotype and may be modified by other factors, including environmental/lifestyle modifiers, other genetic modifiers and the family history.
  • Some families in which a constitutional (germline) pathogenic TP53 variant is identified do not fulfil clinical criteria for Li-Fraumeni syndrome, which has prompted introduction of the broader descriptive term ‘heritable TP53-related cancer syndromes’ to include atypical phenotypes associated with constitutional (germline) variants in this gene.


  • TP53 is the most commonly mutated gene in human cancer cells.
  • Constitutional (germline) pathogenic variants in TP53 are rare, with a population frequency ranging from 1/20,000 to 1/5,000 depending on ethnicity.

Inheritance and genomic counselling

  • Li-Fraumeni syndrome is an autosomal dominant condition, such that each child and each sibling of an individual with an inherited TP53 variant has a 50% (1-in-2) chance of inheriting the condition.
  • A significant proportion (7%–20%) of constitutional TP53 variants arise de novo, and constitutional (germline) mosaicism is not infrequent; such that family history may not be informative.


A number of clinical diagnostic criteria have been developed to identify those patients in whom Li-Fraumeni syndrome should be suspected. 60%–80% of patients fulfilling classic criteria and approximately 30% of those fulfilling Chompret criteria will be found to carry a constitutional pathogenic TP53 variant.

Classic criteria Chompret criteria

Proband with a sarcoma at under 45 years; and

a first-degree relative with any cancer at under 45 years; and

a first- or second-degree relative with any cancer at under 45 years or a sarcoma diagnosed at any age.

Proband with Li-Fraumeni syndrome tumour* at under 46 years and one or more first- or second-degree relative(s) with an Li-Fraumeni syndrome tumour at under 56 years*; or

Proband with two or more Li-Fraumeni syndrome tumours**, where one or more diagnosed at under 46 years; or

patient with ACC or choroid plexus tumour irrespective of family history; or

breast cancer under 31 years.

*Li-Fraumeni syndrome tumours: soft tissue sarcoma/osteosarcoma; brain tumour; premenopausal breast cancer; adrenocortical cancer; leukaemia; broncho-alveolar cancer.

**not multiple breast cancers

  • Certain cancer types are strongly associated with constitutional TP53 variants and should prompt testing in affected individuals irrespective of family history.
  • Constitutional TP53 testing (R216 – Li-Fraumeni syndrome) should be considered in the following scenarios:
    • Rhabdomyosarcoma (five years or under).
    • Rhabdomyosarcoma of embryonal anaplastic subtype (any age).
    • Adrenocortical cancer (any age).
    • Choroid plexus cancer (any age).
    • Breast cancer (30 years or under).
    • Triple positive breast cancer (35 years or under).
    • Hypodiploid acute lymphoblastic leukaemia (at under 18 years).
    • SHH medulloblastoma (at under 18 years).
    • Jaw osteosarcoma (at under 18 years).
    • Two or more Li Fraumeni syndrome-related cancers (both occurring at 46 years or under; two breast cancers not eligible).
    • One or more Li Fraumeni syndrome-related cancer with one or more first- or second-degree relative(s) with one or more Li Fraumeni syndrome-related cancer (one case at 46 years or under, the other case at 56 years or under; two breast cancers not eligible).
    • Cancer with two or more first- or second-degree relatives(s) with cancer; across the family there is:
      • one individual with sarcoma at 45 years or under; and
      • one individual with any cancer at 45 years or under; and
      • one individual with either a sarcoma or any cancer occurring at 45 years or under.

Mangement implications of genomic testing

There is evidence to suggest that radiation increases the risk of second primary cancers in affected carriers of constitutional (germline) TP53. 

  • Radiation should therefore be avoided if there is an alternative that is, at least, non-inferior – for example, for female TP53 carriers affected by breast cancer, mastectomy is usually recommended rather than wide local excision and radiotherapy.
  • Where radiotherapy is required for optimum treatment of cancer and no non-inferior alternative exists, however, the TP53 status should not be considered an absolute contraindication to treatment.
  • Radiation exposure during screening should also be avoided where possible.

The cancer risk associated with constitutional pathogenic variants in TP53 starts from early childhood. Cancer risk management is therefore indicated from birth as shown by the table below:

Tumour Screening
  • Abdominal USS 3–4 monthly, birth–18 years.
  • Biochemistry (17 OH-progesterone, total testosterone, DHEAS, androstenedione) should only be performed where there is an unsatisfactory USS.
  • Annual dedicated MRI from age 20–70.
  • Consider risk-reducing mastectomy from age 20.
  • Annual dedicated brain MRI from birth (first MRI with contrast).
  • Annual WB-MRI from birth.
  • Not indicated due to lack of evidence.
  • Colonoscopy only indicated when family history of colorectal cancer or polyposis.
  • Consider other, possibly co-inherited, causes as appropriate.
  • Recommend H. pylori testing and eradication if required.
  • Endoscopy not indicated due to lack of evidence.
  • Annual dermatology review from 18yrs (GP or dermatology).
Physical exam
  • Full physical examination 3–4 monthly in children (including blood pressure, anthropometric measurements, signs of virilisation and neurological exam).
  • Routine physical examination not recommended in adults – advise detailed discussion of ‘red flag’ symptoms and low threshold for fast track referral of persistent or unusual symptoms.
  • Recommend detailed discussion of ‘red flag’ symptoms in both children and adults.
  • Discuss importance of making positive lifestyle choices (avoid radiation/avoid smoking).
  • Encourage participation in national cancer screening programs (colorectal/cervical).
  • At present, funding for the recommended screening is not uniformly provided across the NHS.
  • Refer to clinical genetics to discuss onward management and cascade screening of relatives at risk.

Family planning implications

The Human Fertilisation and Embryology Authority have approved the use of pre-implantation genomic testing for monogenic disorders (PGT-M) (previously known as pre-implantation genetic diagnosis, or PGD) for couples where one of the intended parents is a carrier of a likely pathogenic/pathogenic variant in TP53. It is best practice that discussions regarding PGT-M and other family planning options be undertaken by a specialist genetic counsellor or clinical geneticist.

Other options may include prenatal testing (invasive, or non-invasive if the intended father is the carrier) with termination of affected embryos, adoption, gamete donation, or natural conception and pregnancy with testing of children after birth.


For clinicians


Tagged: Constitutional mutations, Breast cancer

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  • Last reviewed: 09/05/2022
  • Next review due: 09/05/2024
  • Authors: Dr Terri McVeigh
  • Reviewers: Dr Ellen Copson