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): Incomplete (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)
Assertion Pending
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Gene Disease Pairs: TP530007903
Li Fraumeni syndrome-associated cancers / Cancer surveillance
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
LFS is a rare cancer syndrome, with an estimated prevalence of 1-9 in 100,000.
Clinical Features
(Signs / symptoms)
LFS is a 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, and leukemia. To date, male breast cancer has rarely been reported in families with LFS.
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Natural History
(Important subgroups & survival / recovery)
LFS-related cancers often occur in childhood or young adulthood. Women have a higher risk of developing cancer and a younger average age of onset (29 years) compared to men (40 years). Roughly 50% of tumors develop by age 30 and 90% by age 60. Individuals with LFS often develop additional malignancies, with an estimated 57% developing a second cancer, and 38% developing a third. 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.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
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)
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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. Risk reduction for breast cancer after bilateral mastectomy and oophorectomy is roughly 90% and 50-75%, respectively, among populations considered high-risk due to a family history or BRCA1/2 variants. One observational study found that risk-reducing mastectomy was associated with an 81-94% reduction in breast cancer mortality in women identified as high-risk. (Tier 2)
Patients should be educated regarding the signs and symptoms of cancer. (Tier 2)
Patients should contact their physician for any lingering symptoms and illnesses, such as headaches, bone pain, or abdominal discomfort. (Tier 3)
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. Evidence on the effectiveness of MRI breast surveillance in TP53 carriers is not available. However, one study reported that women aged less than 50 years with a family history who were diagnosed with breast cancer during mammographic surveillance were less likely to die from breast cancer compared to a control group of unscreened women of similar age who developed breast cancer (HR=0.24; 95% CI: 0.09-0.66). A second study reported that women with a BRCA1/2 variant aged 28 to 77 years diagnosed with breast cancer during an intensive mammographic surveillance program were less likely to die from any cause compared to a control group diagnosed outside this program (HR=0.44 (95% CI: 0.25-0.77). Although MRI has been shown to be more sensitivity at early detection of breast cancer in women at high-risk, there is no evidence that this modality confers a survival benefit. (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 every 6-12 months with a high index for suspicion for rare cancers and second malignancies, colonoscopy and upper endoscopy every 2-5 years starting at age 25 or 5 years before the earliest known colon cancer in the family, annual dermatological examination starting at age 18, annual full blood count, annual whole body MRI, and annual brain MRI. 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)
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Circumstances to Avoid
Therapeutic radiotherapy for cancer treatment should be avoided when possible and diagnostic radiation should be minimized to the extent feasible without sacrificing accuracy. Radiation-induced malignancies have been reported among individuals with TP53 pathogenic variants, including 12 case studies of individuals who developed subsequent malignancies in the radiation field following treatment. (Tier 2)
Carriers of TP53 pathogenic variants are counseled to avoid sun exposure, tobacco use, and other known or suspected carcinogens. TP53 mutation carriers who smoke have been found to have a 3.16-fold (95% confidence interval =1.48-6.78) higher risk for lung cancer than the mutation carriers who do not smoke. (Tier 3)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
Prevalence of Genetic Mutations
Germline mutations in the TP53 gene have been observed in 50-80% of families with features of LFS. (Tier 3)
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The frequency of germline TP53 pathogenic variants in the general population is estimated between 1/5000 and 1/20,000 in the US and 1/10,000 and 1/25,000 in the UK. (Tier 3)
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(Include any high risk racial or ethnic subgroups)
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)
Pathogenic variants in TP53 are associated with estimated cancer risks of approximately 60% by age 45 and 95% by age 70. (Tier 3)
For lifetime risk of developing cancer, women have a nearly 100% risk while men have a 73% risk. (Tier 3)
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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)
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LFS patients display high variability in age at onset, tumor locations, and number of types of tumors. (Tier 3)
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
Patients should undergo intensive surveillance protocols not typical of routine clinical monitoring or annual exams. (Tier 2)
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
Primary MONDO Identifier
Additional MONDO Identifiers
OMIM Identifier
Reference List
1. Li-Fraumeni syndrome. Orphanet encyclopedia,
2. 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:
3. 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:
4. 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:
5. 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.
6. 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:
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