TP53 c.993+1del
ClinGen expert panel — TP53 VCEP
Likely Pathogenic for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):
PVS1_Strong PM2_Supporting PS4_Supporting PP1
Curation rationale (ClinGen, verbatim)
The NM_000546.6:c.993+1del is a deletion of a single G nucleotide within the canonical donor site of exon 9 of TP53. Through exon 9 skipping, the variant is observed in an RT-PCR assay to produce multiple aberrant transcripts encoding frameshift alterations predicted to induce nonsense-mediated decay. Since the assay does not fully account for leakiness, code weight downgraded to Strong (PVS1_Strong (RNA); PMID: 10980596). This variant has been reported in 1 proband meeting Classic LFS criteria. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID: 10980596). This variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; PMID: 10980596). This variant is absent from gnomAD v4.1.0 (PM2_Supporting).. In summary, this variant meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PVS1_Strong(RNA), PS4_Supporting, PP1, PM2_Supporting (Bayesian Points: 7; VCEP specifications version 2.0; 7/24/2024).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | canonical splice-site (±1/±2) | predicted loss-of-function in a haploinsufficient gene (ClinGen) |
|---|---|---|
| Splicing | ||
| Splice region | donor +1 | canonical splice dinucleotide (donor +1) · inside the BP7-excluded zone |
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 11 | GERP 2.1, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.
Variant & gene context
- Gene
- TP53
- Coding
- c.993+1del
- MANE Select
- NM_000546
- dbSNP
- rs1131691033
- Type
- Deletion
- Location
- chr17:7673534 (GRCh38)
- Gene constraint
- LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.83 · 321 PDB
Disease context
Li-Fraumeni syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: hereditary neoplastic syndrome
For Li-Fraumeni syndrome (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- All ages
- Prevalence
- 1-9 / 100 000 (United Kingdom)
Similar variants
- TP53 p.Ala161_Tyr163delinsAsp Likely pathogenic ★★★ same condition
- TP53 p.Arg213fs Pathogenic ★★★ same condition
- TP53 p.Leu252_Ile254del Pathogenic ★★★ same condition
- TP53 p.Lys382fs Likely pathogenic ★★★ same condition
- TP53 p.Lys373fs Uncertain significance ★★★ same condition
- TP53 c.*772del Benign ★★★ same condition
- TP53 c.283_375+21del Likely pathogenic ★★ same condition
- TP53 c.560-19_560-9del Pathogenic/Likely pathogenic ★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tp53-c-993-plus-1del (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown