Li-Fraumeni syndrome: genes and variants

Genes linked to Li-Fraumeni syndrome

• TP53: Cellular tumor antigen p53

  It coordinates transcriptional responses to DNA damage and other cellular stresses, promoting cell-cycle arrest, senescence, DNA repair, or apoptosis when appropriate. Loss of this tumor-suppressive control is one of the most common events in cancer, while germline pathogenic variants cause Li-Fraumeni syndrome.

  188 disease-causing and 857 uncertain variants in TP53 are linked to Li-Fraumeni syndrome.

• CHEK2: Serine/threonine-protein kinase Chk2

  It propagates DNA-damage checkpoint signals to proteins controlling cell-cycle arrest, repair, and apoptosis. Germline loss-of-function variants confer moderate cancer susceptibility, especially for breast cancer, while risk estimates depend on the specific allele and family context.

  0 disease-causing and 7 uncertain variants in CHEK2 are linked to Li-Fraumeni syndrome.

Weakly linked (only a few uncertain records): CDKN2A.

Where Li-Fraumeni syndrome variants cluster

• TP53 DNA binding (positions 102–292): 167 of 179 disease-causing changes, 1.9× more than its size predicts.

Known disease-causing variants in Li-Fraumeni syndrome

Showing 60 of 188.

Uncertain variants in Li-Fraumeni syndrome that look disease-causing

Which prediction tools work for Li-Fraumeni syndrome

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• MutPred2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 95 out of 100
• ESM1b (LLR): 95 out of 100
• MetaLR: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaGenome (regulatory): 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 90 out of 100
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 88 out of 100
• SIFT: 86 out of 100
• phyloP: 84 out of 100
• DMS / MaveDB: 57 out of 100
• AlphaGenome (splicing): 56 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Adrenocortical carcinoma, hereditary is also caused by TP53 variants; they fall in the same places as the Li-Fraumeni syndrome variants (23 disease-causing).
• Acute myeloid leukemia is also caused by TP53 variants; they fall in the same places as the Li-Fraumeni syndrome variants (6 disease-causing).
• Familial cancer of breast is also caused by TP53 variants; they fall in the same places as the Li-Fraumeni syndrome variants (5 disease-causing).
• Glioma susceptibility 1 is also caused by TP53 variants; they fall in the same places as the Li-Fraumeni syndrome variants (5 disease-causing).
• Hereditary breast ovarian cancer syndrome is also caused by TP53 variants; they fall in the same places as the Li-Fraumeni syndrome variants (5 disease-causing).

Diseases related to Li-Fraumeni syndrome

• Familial cancer of breast, also linked to CHEK2 and TP53
• Colorectal cancer, also linked to CHEK2 and TP53
• Gastric cancer, also linked to CHEK2 and TP53
• Hereditary breast ovarian cancer syndrome, also linked to CHEK2 and TP53
• Breast and/or ovarian cancer, also linked to CHEK2 and TP53
• Bone osteosarcoma, also linked to CHEK2 and TP53
• Acute myeloid leukemia, also linked to TP53
• Adrenocortical carcinoma, hereditary, also linked to TP53
• Breast-ovarian cancer, familial, susceptibility to, 1, also linked to TP53
• Hereditary nonpolyposis colon cancer, also linked to CHEK2
• Glioma susceptibility 1, also linked to TP53
• Ovarian neoplasm, also linked to TP53

Frequently asked questions

Which genes are linked to Li-Fraumeni syndrome?

In CATVariant, Li-Fraumeni syndrome is linked to 2 analyzed proteins: TP53 (Cellular tumor antigen p53) and CHEK2 (Serine/threonine-protein kinase Chk2).

How many genetic variants are linked to Li-Fraumeni syndrome?

1,147 variants: 188 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 865 are of uncertain significance or have conflicting reports.

Which uncertain variants in Li-Fraumeni syndrome look disease-causing?

55 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example TP53 T125S, TP53 C275S, TP53 P278R, TP53 A276D and TP53 C242F. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Li-Fraumeni syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.95, based on 179 disease-causing and 156 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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