Inheritance

Autosomal dominant

Prevalence

 1-4/20,000

Source:https://medlineplus.gov/genetics/condition/li-fraumeni-syndrome/#frequency

Rapid or full curation?

• Rapid
• Full

ClinGen / GenCC / BabySeq / HGMD

ClinGen Hereditary Cancer GCEP, accessed 07.14.20

Clinical Validity Scoring Notes and points

TP53 was first reported in relation to autosomal dominant Li-Fraumeni syndrome in 1991 (Malkin et al., 1991, PMID: 1978757; Li et al., 1998, PMID: 3409256). Li Fraumeni is associated with increased risk of multiple pediatric and adult malignancies (see discussion below). Numerous variants have been reported in TP53 in relation to the development of Li-Fraumeni syndrome and include missense, small duplications, small deletions, frameshift, and nonsense mutations have been reported in humans. De novo inheritance has been noted in Li-Fraumeni syndrome in 7-20% of cases (Schneider et al., OMID: 20301488; Gene Reviews). There are several databases describing TP53 variants of interest in Li-Fraumeni Syndrome, including: (1) the TP53 database in LOVD (https://databases.lovd.nl/shared/genes/TP53) ; (2) The TP53 Website (http://p53.fr/) (Leroy et al, 2013; PMID: 23161690) which houses the IARC TP53 database (http://p53.iarc.fr/) (Olivier et al., 2002, PMID: 12007217); (3) Database of germline p53 mutations (http://stary.lf2.cuni.cz/projects/germline_mut_p53.htm); (4) The UMD TP53 website (http://www.umd.be:2072/IFAMTP53A.shtml). There is significant genetic evidence supporting this gene-disease relationship includes case-level data and segregation data and the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by expression studies and multiple animal models that get LFS associated tumors. TP53 has been associated with several disease entities and/or phenotypes through germline inheritance, including: (1) Adrenocortical carcinoma, pediatric (MIM: 202300); (2) Bone marrow failure syndrome (MIM: 5618165); (3) Choroid plexus papilloma (MIM: 260500); (4) Colorectal cancer (MIM: 114500); (5) Li-Fraumeni syndrome (MIM: 151623); (6) Osteosarcoma (MIM: 259500). Although isolated cases of cancer have been observed in individuals with TP53 variation, all are associated with the heterogeneous Li Fraumeni cancer syndrome. Classic Li-Fraumeni syndrome (LFS) is characterized by the development of a sarcoma before the age of 45 years old and one additional first- or second- degree relative in the same lineage with a cancer (Li et al., 1988 PMID: 3409256). Other definitions of Li-Fraumeni like disorder or the Chompret criteria are similar, but not all isolated individuals with a cancer diagnosis have family history information. The inheritance pattern for all the listed, asserted disease entities is autosomal dominant. The molecular mechanism of TP53 dysfunction for all the associated disease entities listed above are either loss of function or dominant negative; both of which result in reduced (or absent) transcriptional activity and loss of the tumor suppressive function of the p53 protein function. Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we have found no difference in molecular mechanism, inheritance pattern, or phenotypic expressivity, and therefore have lumped the above listed disease entities into the curation for TP53 in Li-Fraumeni Syndrome. In summary, TP53 is definitively associated with autosomal dominant Li-Fraumeni syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Validity Points Total

18

Source: ClinGen Hereditary Cancer GCEP, accessed 07.14.20

Clinical Validity Classification

Definitive

Source: ClinGen Hereditary Cancer GCEP, accessed 07.14.20

Molecular Mechanism

Loss-of-function OR dominant negative

ClinGen Hereditary Cancer GCEP, accessed 07.14.20

Penetrance

(list source/PMID)

High (age-related)

Source: PMID: 20301488

Between 70% (men) and 80-90% (women) lifetime risks, though penetrance may be overestimated in the literature.

Age of Onset

(list source/PMID)

Pediatric - adulthood

Source: PMID: 20301488

Severity

Moderate

Clinical Features

Cancer predisposition syndrome:

• Adrenocortical carcinoma

• Breast cancer (more likely to be ductal, estrogen receptor and progesterone receptor positive, and show HER2 amplification)

• Central nervous system tumors (Glioblastomas and astrocytomas are most common. Others include ependymomas, choroid plexus carcinomas, and supratentorial primitive neuroectodermal tumor, medulloblastomas).

• Osteosarcomas

• Soft-tissue sarcomas (rhabdomyosarcomas

• Additional cancers:

  • Leukemias (lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS)).

  • Lymphomas - Hodgkin and non-Hodgkin lymphomas.

  • Gastrointestinal cancers (colorectal cancer, gastric cancer)

  • Other (head and neck, kidney, layrnx, lung, skin, ovary, pancreas, prostate, testis, and thyroid.

  • Gestational choriocarcinoma in female partners (ie - fetus with a paternally inherited TP53 pathogenic variant).

Sources: PMID: 20301488

HPO terms

Adrenocortical carcinoma HP:0006744

Breast carcinoma HP:0003002

Neoplasm of the central nervous system HP:0100006

Osteosarcoma HP:0002669

Soft tissue sarcoma HP:0030448

Leukemia HP:0001909

Lymphoma HP:0002665

Gastrointestinal carcinoma HP:0002672

Gene SOPs & Notes

Variant Scoring Guidelines from TP53 VCEP (version 1.4.0):

Allele frequency criteria - BA1, BS1, PM2

BA1 - 0.1%

BS1 - 0.03%

PM2_Supporting - absence

PS4 (case counting): Points per proband is dependant upon whether the individual meets classic or Chompret criteria

*general note: please be mindful of the risk of clonal hematopoeisis, ensure that probands have germline and not mosaic somatic variants.

• Classic LFS (1 point for each proband). Must meet all three of the following:

  • A proband with a sarcoma diagnosed <45 years

  • A first-degree relative with any cancer diagnosed before age 45 years

  • A first- or second-degree relative with any cancer diagnosed before age 45 or a sarcoma diagnosed at any age

• Chompret 2015 criteria - 0.5 point for each proband. Must meet one of the following criteria:

  • A proband with a tumor belonging to the LFS tumor spectrum (e.g., premenopausal breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system (CNS) tumor, adrenocortical carcinoma) before age 46 years AND at least one first- or second-degree relative with an LFS tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors

  • A proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum and the first of which occurred before age 46 years; OR

  • A proband with adrenocortical carcinoma, choroid plexus tumor, or rhabdomyosarcoma of embryonal anaplastic subtype, irrespective of family history; OR

  • A female proband with breast cancer before age 31 years.

• ACMG/AMP criteria strength:

  • PS4 - 4 or more points

  • PS4_Moderate - 2-3 points

  • PS4_Supporting - 1 point

PS2/PM6 scoring (de novo):

PS3 - Functional evidence

Specific guidelines for the application of functional evidence (PMID: 33300245). You may look up the Kato and Giacomelli functional evidence in the IARC database (columns TA class and DNE/LOF class, respectively). Do not use if DNE/LOF evidence from Giacomelli is in conflict with other LOF evidence.

PM1 - Mutational Hotspot

• Applicable for missense variants occurring at amino acid positions 175, 245, 248, 249, 273, and 282

• PM1 criterion can also apply to somatically detected hotspots with ≥10 occurrences in http://cancerhotspots.org. This information is annotated in the IARC TP53 Database.

BP2 - In trans with a pathogenic TP53 variant and phase is confirmed

• or 3 or more observations with a TP53 pathogenic variant when phase is unknown. At least two different pathogenic TP53 variants must be observed.

Excluded ACMG/AMP Criteria: PM3, PM4, PP2, PP4, PP5, BP1, BP3, BP5, BP6

Clonal hematopoiesis

It is well known that pathogenic variants in TP53 can be blood limited due to clonal hematopoiesis, and pose a challenge to interpreting TP53 variants for risk of Li Fraumeni syndrome due to germline variants.

• PMID: 28279308

  • Somatic pathogenic variants accounted for 38.8% of all pathogenic variants in TP53 identified at Myraid in a cohort of >220,000 individuals who underwent clinical testing at Myriad.

  • Variants that are likely somatic are conservatively defined in this study as those with allele balance between 10% and 30%. Variants with AB <10% are below the lab’s reporting thresholds.

• PMID: 29189820

  • Ambry reviewed their TP53 variant dataset for abnormal metrics including decreased AB ratio (<25%) and >2 detected alleles. Alternate tissues and/or close relatives were teseted to discern between aberrant clonal expansions (ACE) and germline variants.

  • Abnormal metrics were observed in 20% of 353 TP53 positive results, and ACE was confirmed for 91% of cases with ancillary materials, mostly due to clonal hematopoiesis. Only 4 met Chompret criteria. ACE cases were older (50 years vs 33.7; P = 0.02) and found more frequently in cancer panels compared to TP53 only genetic tests.

• PMID: 34906512

• PMID: 35654360

• PMID: 31533767

Sources:

• PMID: 33300245, TP53 CSPEC v1.4.0

Curation Summary:

Case ID, Curator name, Date, Jira ticket link