Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released Status (Pediatric): Passed (Consensus scoring is Incomplete) P

Condition: Li-Fraumeni Syndrome
Mode(s) of Inheritance: Autosomal Dominant
Actionability Assertion
Gene Disease Pairs(s)
Final Assertion
TP530007903 (li-fraumeni syndrome; lfs)
Strong Actionability
Actionability Rationale
The preliminary assertion was Moderate, but there was consensus agreement to change the assertion to a Strong given the high tumor risk and effectiveness of surveillance. The assertion is based on genetic variants presumed to be germline.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Gene Disease Pairs: TP53 0007903 (OMIM:151623)
Morbidity and mortality from Li Fraumeni syndrome-associated cancers / Cancer surveillance
Morbidity and mortality from Li Fraumeni syndrome-associated cancers / Avoidance of radiotherapy

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Li-Fraumeni syndrome (LFS) is a rare cancer syndrome, with 300 to 400 families reported in the literature.
1 2
Clinical Features
(Signs / symptoms)
LFS is an aggressive cancer predisposition syndrome associated with early onset of neoplasms and multiple primary neoplasms within an individual. The most common cancers are soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, brain tumors, and adrenocortical carcinoma, which account for about 70% of LFS-related cancers. Other cancers include colon cancer, gastric cancer, leukemia, lymphoma, cancers of the head and neck, kidney, larynx lung, skin (e.g., melanoma), ovary, pancreas, prostate, testis, and thyroid. To date, male breast cancer has rarely been reported in families with LFS.
1 3 4 5 6 2 7 8
Natural History
(Important subgroups & survival / recovery)
LFS-related cancers often occur in childhood or young adulthood. Individuals with LFS often develop additional malignancies, with an estimated 40-49% developing a second cancer, or a median 10 years after the first cancer diagnosis. The probability of additional cancers is inversely correlated with younger age at diagnosis of first malignancy. Besides an earlier age of onset, the characteristics of LFS-associated tumors compared to non-LFS are unclear, though there is some evidence that breast cancers in LFS are more likely to be HER2-positive compared to other cases. They are also predominantly estrogen and/or progesterone hormone receptor-positive. The overall prognosis is unknown for LFS and depends on the type and severity of cancers developed.
1 3 4 5 6 2 7 8
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Individuals found to have low-level (e.g, <20%) mosaicism for a TP53 pathogenic variant in leukocytes may require additional follow-up to distinguish between germline variants and postzygotic (acquired) pathogenic variant due to clonal hematopoiesis of indeterminate potential. This is important as the clinical interventions described below are only warranted for those with a diagnosis of LFS. (Tier 3)
3 5
Women should be ‘breast aware’, in line with Department of Health advice for all women, and promptly report any changes to their healthcare provider. Guidelines are conflicting for recommendations for clinical breast exams. One guideline recommends that women should undergo clinical breast exams every 6-12 months starting at age 20. However, another guideline notes that there is a lack of evidence for a high-risk population that either clinical breast examination or self-examination is useful as the sole surveillance modality. (Tier 2)
5 2
For chemoprevention, tamoxifen should be offered for 5 years to premenopausal women (unless they have a past history of or may be at increased risk for thromboembolic disease or endometrial cancer) and anastrozole should be offered for 5 years to postmenopausal women. Tamoxifen and raloxifene could be considered in postmenopausal women who have severe osteoporosis or do not wish to take anastrozole. No direct evidence for the effectiveness of chemoprevention specific to women with TP53 pathogenic variants was identified. Data are available among high-risk populations (defined by family history of breast, ovarian or related cancer or genetic predisposition). Four studies (3 RCTs and one prospective cohort study) compared tamoxifen with placebo (n=488 to 13,207) in women aged 30 to 70. Treatment duration ranged from 5 to 8 years. Low quality evidence from a meta-analysis of the 3 RCTs (n=19,687) indicated tamoxifen is associated with a lower incidence of invasive breast cancer when compared to placebo (RR=0.70, 95% CI: 0.61-0.80). Moderate quality evidence from a meta-analysis of the 3 RCTs indicated tamoxifen was associated with a lower incidence of ductal carcinoma in situ compared to placebo (RR=0.59, 95% CI: 0.44-0.78). A long-term follow-up from one of these trials has subsequently been published which found that over a median of 16 years, there was a significant reduction in the occurrence of all breast cancers in the tamoxifen group (HR=0.71; 95% CI: 0.60 to 0.83). However, no significant difference was found in breast-cancer specific mortality (OR=1.19; 95% CI: 0.68-2.10). One randomized trial of moderate quality reported a reduction in incidence of invasive breast cancer for anastrozole versus placebo (RR=0.51; 95% CI: 0.33-0.77). Evidence from a single randomized trial of low quality suggests the incidence of breast cancer is lower in patients given exemestane compared with those given a placebo (HR=0.35, 95% CI: 0.18-0.70). (Tier 1)
Prophylactic bilateral mastectomy and oophorectomy should be offered as a risk-reducing strategy. No direct evidence for the effectiveness of risk-reducing surgery among women with TP53 pathogenic variants was identified. Findings from 2 observational studies and 3 decision analysis studies suggest that risk-reducing subcutaneous/total mastectomy has a beneficial effect in terms of significantly reducing the risk of breast cancer in women with a family history of breast cancer, or with BRCA1/2 pathogenic variants. One of the observational studies found that risk-reducing mastectomy was also associated with a reduction in breast cancer mortality in women with a family history of breast cancer. Among the two observational studies, one found no cases of invasive breast cancer among women who had undergone bilateral total mastectomy over 3 years (compared to 8/63 patients undergoing surveillance only). The second study showed a reduction in the risk of breast cancer of 89.5% in moderate-risk women who had undergone mastectomy and a reduction of 90-94% among high-risk women. The risk reduction for death among women undergoing mastectomy was 100% among moderate-risk women, and 81-94% among high-risk women. (Tier 2)
5 2
Patients should be educated regarding the signs and symptoms of cancer. (Tier 2)
Pregnant women should bring any potential symptoms of cancer to the attention of their physicians. (Tier 4)
The screening and management of LFS is complex. It is preferred that individuals with LFS be followed at centers with expertise in the management of this syndrome. (Tier 4)
Annual surveillance with breast MRI should be offered to women aged 20-49 years, and should be considered for women aged 50-69. Ultrasound and mammogram breast surveillance should not be offered, unless MRI is not suitable or when results of MRI are difficult to interpret. No direct evidence on the effectiveness of breast cancer surveillance in patients with TP53 pathogenic variants was identified. Evidence cited in guidelines was based on patients with a BRCA1/2 pathogenic variant or a family history of breast cancer. One guideline summarizes that low quality evidence suggests a disease-specific survival benefit with mammographic surveillance in women aged less than 50 years with a family history of breast cancer. First, an observational study found that death from breast cancer was less likely in women aged less than 50 years with family history whose breast cancer was diagnosed during mammographic surveillance compared to a control group of unscreened women of similar age who developed breast cancer (lead time adjusted HR=0.24; 95% CI: 0.09-0.66]). Second, a study modelled death from breast cancer in a mammographic surveillance study in women with a family history aged less than 50 years and a control group from another study, using prognostic features at diagnosis and underlying risk. Projected ten-year death from breast cancer was lower in the mammographic surveillance group than in the control group of unscreened women of similar age (RR=0.80; 95% CI: 0.66-0.96). Third, a retrospective study found that death from any cause was less likely in BRCA1/2 pathogenic variant carriers aged between 28 and 77 years diagnosed with breast cancer during an intensive mammographic surveillance program than in those diagnosed outside this program (HR=0.44; 95% CI: 0.25-0.77]). (Tier 1)
Many of the other cancers associated with germline mutations in TP53 do not lend themselves to early detection. Thus, additional recommendations are general and include:
• Comprehensive physical exams including neurological examination with a high index for suspicion for rare cancers and second malignancies every 3-6 months in children (birth to age 18) and 6-12 months in adults
• Colonoscopy and upper endoscopy every 2-5 years starting at age 18-25 or 5 years before the earliest known colon cancer in the family
• Annual dermatological examination starting at age 18 for melanoma
• Annual full blood count
• Abdominal ultrasound for adrenocortical carcinoma every 3-6 months in children (birth to age 18) and annually for adults
• Annual whole body MRI from birth for soft tissue and osteosarcomas
• Annual brain MRI from birth for brain tumors.
Additional surveillance may be recommended based on family history. One 11-year prospective observational study reported outcomes among 40 TP53 carriers who chose to undergo a surveillance protocol and 49 who declined surveillance (19 crossed over to the surveillance group for a total of 59 undergoing surveillance). Surveillance included biochemical methods and imaging techniques, such as annual mammography, annual brain MRI, annual rapid total-body MRI, ultrasound of the abdomen and pelvis, and colonoscopy. Over a median period of 32 months (IQR: 12-87), surveillance identified 40 asymptomatic neoplasms in 19 of 59 (32%) patients, including both malignant tumors and low-grade or premalignant lesions. Among the 49 individuals who initially declined surveillance, 61 symptomatic tumors were diagnosed in 43 (88%). Of the patients who chose surveillance and were diagnosed with cancer, 84% (16 out of 19) were alive at follow-up (median 38 months, IQR: 12-86) compared to 49% (21 out of 43; median follow-up of 46 months, IQR: 22-72) patients diagnosed with cancer who had not chosen surveillance (p=0.012). All patients who died in the non-surveillance group died of cancer. The 5-year overall survival was greater for the surveillance group (88.8%) compared to the non-surveillance group (59.6%) (p=0.0132). A separate meta-analysis evaluated whole-body MRI among 578 individuals across 13 prospective cohorts where a whole-body MRI was administered as part of a baseline assessment with all participants asymptomatic at the time of the baseline scan and not required to be newly diagnosed. Cancer was identified in 7% of the sample, with 83% of cancers being localized and able to treat with curative intent. (Tier 2)
5 6 7 8
Circumstances to Avoid
Therapeutic radiotherapy and conventional chemotherapies for cancer treatment should be avoided when possible and diagnostic radiation should be minimized to the extent feasible without sacrificing accuracy. Subsequent primary tumors often develop after the exposure of patients with LFS to radio and/or chemotherapy treatments. (Tier 2)
5 7
Carriers of TP53 pathogenic variants are counseled to avoid sun exposure, tobacco use, and other known or suspected carcinogens. (Tier 3)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
Prevalence of Genetic Mutations
Germline pathogenic variants in the TP53 gene have been observed in 50-92% of families with features of LFS. (Tier 3)
3 5 6
The frequency of germline TP53 pathogenic variants in the general population is not well established but has been estimated to be as common as 1/3500 to 1/55. (Tier 3)
1 3 5 7
(Include any high risk racial or ethnic subgroups)
Estimations of cancer risks associated with LFS are limited to at least some degree by selection bias since dramatically affected kindreds are more likely to be identified and become the subject of further study. (Tier 4)
LFS is highly penetrance with a high lifetime risk for cancer. An analysis from the National Cancer Institute’s LFS study (N=286) showed a cumulative lifetime cancer incidence of nearly 100%. This study also estimated cumulative incidence rates by 70 years:
• Women: breast cancer=54%, soft tissue sarcoma=15%, brain cancer=6%, and osteosarcoma=5%
• Men: soft tissue sarcoma=22%, brain cancer=19%, osteosarcoma=11%. (Tier 3)
5 8
Pathogenic variants in TP53 are associated with estimated cancer risks of approximately 22% by age 5, 41% by age 18, 60% by age 45, and 95% by age 70. (Tier 3)
5 8
For lifetime risk of developing cancer, women have a 90-100% risk while men have a 73% risk. (Tier 3)
1 3 6 7
Relative Risk
(Include any high risk racial or ethnic subgroups)
The relative risk of overall tumor development was not found, however tumor-specific relative risks and 95% confidence intervals are available: bone: 107 (49-203), connective tissue: 61 (33-102), brain: 35 (19-60), pancreas: 7.3 (2-19), breast: 6.4 (4.3-9.3), colon: 2.8 (1-6), liver: 18 (2.1-64). (Tier 3)
3 6
LFS patients display high variability in age at onset, tumor locations, and number of types of tumors. (Tier 3)
Phenotypic variability is observed within the same family. (Tier 4)
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions identified in this report include prophylactic surgery to remove target organs, intense surveillance, and medications with potential side effects. Adverse events reported with chemoprevention drugs include headache, hot flushes, vaginal discharge, hypertension, musculoskeletal and vasomotor symptoms, cataracts, endometrial cancer, and thrombotic events.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
A study of 116 individuals with LFS (mean age of 37.6 years, range 3-68 years) who had not received cancer therapy at least 6 months prior to screening indicated that 7% had cancer at their baseline cancer screening. (Tier 3)
Further, testing for pathogenic TP53 variants should take place before starting cancer treatment due to the contribution of radiotherapy and conventional chemotherapy to subsequent primary tumors. (Tier 3)
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Gene Disease Associations
Disease Associations
OMIM Identifier
Primary MONDO Identifier
Additional MONDO Identifiers
Reference List
1. Li-Fraumeni syndrome. Orphanet encyclopedia,
2. Classification and care of people at risk of familial breast cancer and management of breast cancer and related risks in people with a family history of breast cancer. NICE. (2013) Website:
3. K Schneider, K Zelley, KE Nichols, J Garber. Li-Fraumeni Syndrome. 1999 Jan 19 [Updated 2013 Apr 11]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from:
4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. LI-FRAUMENI SYNDROME 1; LFS1. MIM: 151623: 2016 Jun 24. World Wide Web URL:
5. Daly MB, Pilarski R, Berry M, Buys SS, Farmer M, Friedman S, et al. Genetic/Familial High-Risk Asessment: Breast and Ovarian. National Comprehensive Cancer Network (NCCN). (2017) Website:
6. McBride KA, Ballinger ML, Killick E, Kirk J, Tattersall MH, Eeles RA, Thomas DM, Mitchell G. Li-Fraumeni syndrome: cancer risk assessment and clinical management. Nat Rev Clin Oncol. (2014) 11(5):260-71.
7. Frebourg T, Bajalica Lagercrantz S, Oliveira C, Magenheim R, Evans DG. Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes. Eur J Hum Genet. (2020) 28(1476-5438):1379-1386.
8. Kratz CP, Achatz MI, Brugières L, Frebourg T, Garber JE, Greer MC, Hansford JR, Janeway KA, Kohlmann WK, McGee R, Mullighan CG, Onel K, Pajtler KW, Pfister SM, Savage SA, Schiffman JD, Schneider KA, Strong LC, Evans DGR, Wasserman JD, Villani A, Malkin D. Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome. Clin Cancer Res. (2017) 23(1557-3265):e38-e45.
¤ Powered by BCM's Genboree.