TP53 p.Val197Met
c.589G>A · rs786204041 · VCV188060
ClinGen expert panel — TP53 VCEP
Likely Pathogenic for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):
PM2_Supporting PS4_Supporting PS3_Moderate PM1_Supporting PP4
Curation rationale (ClinGen, verbatim)
The NM_000546.6:c.589G>A variant in TP53 is a missense variant predicted to cause substitution of valine by methionine at amino acid 197 (p.Val197Met). This variant has been reported in 1 family meeting Revised Chompret criteria and reported in 1 additional individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal contributors). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, ClinVar SCV001186711.5, Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and loss of growth suppression activity, indicating that this variant impacts protein function (PS3_Moderate; PMIDs: 12826609, 30224644, 29979965). This variant has three somatic occurrences for the same amino acid change in cancerhotspots.org (v2), sufficient to be defined as a mutational hotspot by the ClinGen TP53 VCEP (2–9 somatic occurrences; PMID: 30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li-Fraumeni syndrome, based on the ACMG/AMP criteria applied as specified by the ClinGen TP53 VCEP: PS4_Supporting, PP4, PM2_Supporting, PS3_Moderate, PM1_Supporting (Bayesian Points: 6; VCEP specifications version 2.3).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.8149 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.758 | pathogenic-leaning |
| SaProt | LLR -11.77 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 6 | GERP 1.3, phastCons 1 |
| Regional constraint | o/e 0.89 | unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic |
| Overall | ||
| CADD | 24.6 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
No allele count reported in gnomAD v4.1 (AN 1,614,178). 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
- Protein
- p.Val197Met
- Coding
- c.589G>A
- MANE Select
- NM_000546
- dbSNP
- rs786204041
- Type
- single nucleotide variant
- Location
- chr17:7674942 (GRCh38)
- Gene constraint
- LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.83 · 321 PDB
- Residue 197
- a DNA-binding region; the 'interaction with axin1' region; a β-strand; the 'interaction with ccar2' region; a UniProt-annotated variant site (in a familial cancer not matching lfs; germline mutation and in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in lfs; germline mutation and in sporadic cancers; somatic mutation); the 'interaction with hipk1' region; the 'required for interaction with znf385a' region; the 'required for interaction with fbxo42' region
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.Val197Leu Uncertain significance ★★ ⚠ same residue
- TP53 p.Val197Ala Uncertain significance ★ ⚠ same residue
- TP53 p.Val197Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
- TP53 p.Val197Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
- TP53 p.Val197= Likely benign ★ same residue
- TP53 c.375+5G>A Likely pathogenic ★★★ same condition
- TP53 c.919+1G>A Pathogenic ★★★ same condition
- TP53 c.97-1G>A 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-p-val197met (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown