The TP53 NM_000546.6:c.469G>T (p.Val157Phe, p.V157F) variant has been reported in ClinVar with Likely pathogenic and Pathogenic clinical submissions.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, including 0 of 1,614,132 alleles in gnomAD v4.1, which supports PM2_Supporting under the TP53 VCEP threshold of less than 0.00003.2 In the TP53 VCEP functional framework, p.Val157Phe is assigned PS3 because Kato-based transactivation results are non-functional and the majority of other eligible assays show loss of function; additional published studies describe abnormal mutant behavior and structural destabilization consistent with impaired normal p53 activity.3 SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and although REVEL is 0.708 and BayesDel is 0.314073, the TP53 VCEP precomputed in silico table assigns c.469G>T as 'No evidence', so neither PP3 nor BP4 was applied.4
Final classification
VUS
PS3PM2
TP53
c.469G>T
p.Val157Phe
This variant
The TP53 NM_000546.6:c.469G>T (p.Val157Phe, p.V157F) variant has been reported in ClinVar with Likely pathogenic and Pathogenic clinical submissions.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM2 supporting (+1) = 5 points, which maps to VUS.
Classification rationale
PS3PM2
VUS
TP53 c.469G>T
PS3 + PM2
→
VUS
3
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:16778209 ↗PMID:21561095 ↗
4
spliceai ↗revelbayesdelvcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000546.6 · variants mapped to exon structure
TP53
NM_000546.6
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 14 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
Pathogenic
In the TP53 VCEP functional worksheet, p.(Val157Phe) is assigned PS3. The worksheet records non-functional Kato transactivation results and loss-of-function findings across the majority of other eligible assays, which supports a damaging effect on normal p53 function.
TP53 VCEP functional worksheet row: V157F -> PS3worksheet values include Non-functional and majority LOF callspublished exact-variant studies describe abnormal mutant behavior and structural destabilization
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0/1,614,132 alleles observed in gnomAD v4.1 (AF 0.0). This is below the TP53 VCEP PM2 threshold of less than 0.00003, so PM2_Supporting is met.
gnomAD v2.1 absentgnomAD v4.1 total AC 0 / AN 1614132AF 0.0
Assessed · not applied
· 5 not met · 9 not assessed
Pathogenic
PS1
No previously classified TP53 variant producing the same amino acid change through a different nucleotide substitution was confirmed, so PS1 was not applied.
PS2
No confirmed de novo occurrence of this exact variant with interpretable TP53 VCEP point scoring was identified, so PS2 was not applied.
PS4
This variant has been reported in ClinVar, but no proband-level Li-Fraumeni syndrome point total meeting TP53 VCEP PS4 thresholds was established from the available evidence.
PM1
Codon 157 is not one of the TP53 codons that automatically qualify for PM1, and the available Cancer Hotspots review did not verify an exact hotspot count for this amino acid change.
PM5
No validated same-residue TP53 comparator variant meeting the TP53 VCEP PM5 requirements was confirmed, so PM5 was not applied.
PP1
No segregation data with enough informative meioses to meet TP53 VCEP thresholds were identified, so PP1 was not applied.
PP3
Computational results show REVEL 0.708, BayesDel 0.314073, and no predicted splice effect by SpliceAI (max delta score 0.00).
PP4
No low-variant-allele-fraction constitutional mosaic observation meeting the TP53 VCEP PP4 requirements was identified, so PP4 was not applied.
Benign
BA1
This variant is absent from gnomAD v4.1 (0/1,614,132 alleles; AF 0.0), which is below the TP53 VCEP BA1 threshold of at least 0.001.
BS1
This variant is absent from gnomAD v4.1 (0/1,614,132 alleles; AF 0.0), which is below the TP53 VCEP BS1 threshold of at least 0.0003.
BS2
No source documenting unaffected older female carriers in numbers sufficient for TP53 VCEP BS2 was identified, so BS2 was not applied.
BS3
Available functional evidence does not show retained or near-normal p53 activity.
BS4
No family data showing lack of segregation with Li-Fraumeni syndrome-associated cancers were identified, so BS4 was not applied.
BP4
SpliceAI predicts no splice effect (max delta score 0.00), but BayesDel is 0.314073 rather than below the benign thresholds, and the TP53 VCEP precomputed PP3/BP4 table assigns NM_000546.6:c.469G>T as 'No evidence'.
N/A · 12
PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1614132 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/75036 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,614,132
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories) and as Pathogenic (2 clinical laboratories). (ClinVarID = 12353)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.708. BayesDel score = 0.314073.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52667015, n = 375 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 5 further PMIDs triaged but not cited — see Sources & references.
Mutant p53 induces the GEF-H1 oncogene, a guanine nucleotide exchange factor-H1 for RhoA, resulting in accelerated cell proliferation in tumor cells.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Structural effects of the L145Q, V157F, and R282W cancer-associated mutations in the p53 DNA-binding core domain.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links
Triaged references · 5 PMIDs not cited in assessment
10713666 ↗
Quantitative analysis of residual folding and DNA binding in mutant p53 core domain: definition of mutant states for rescue in cancer therapy.
CLINVAR
10754498 ↗
Clinical significance of p53 functional loss in squamous cell carcinoma of the oropharynx.
CLINVAR
27993330 ↗
Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR