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Gene-disease assertions not curated here (add link or write note): Hereditary breast and ovarian cancer (limited by ClinGen GCEP)

Disease

Li-Fraumeni syndrome

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

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Definitive

Source: ClinGen Hereditary Cancer GCEP, accessed 07.14.20

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss-of-function OR dominant negative

ClinGen Hereditary Cancer GCEP, accessed 07.14.20

Penetrance

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(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

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

 Options

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

Clinical Features

Sources:

Gene SOPs & Notes

Clonal hematopoisis - NEED A WORKFLOW FOR THIS

Curation Summary:

 Examples

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dsiease relationship is limited

Case ID, Curator name, Date, Jira ticket link

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