The TP53 c.469G>T (p.Val157Phe) variant has been observed in somatic cancers in COSMIC (COSV52667015; n=366) and has not been reported in ClinVar.1 This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1 (0/1614132 alleles; AF 0.00000%), which is below the TP53 PM2_Supporting threshold of less than 0.00003.2 TP53 expert panel functional data classify p.Val157Phe as PS3 because the variant is non-functional in Kato, shows loss of function in Funk and Kotler, and is loss-of-function by the majority of eligible assays.3 Cancer Hotspots shows p.Val157Phe in 67 tumors at the significant TP53 V157 hotspot residue (77 tumors at the residue overall), supporting PM1, while the TP53 bioinformatic worksheet assigns no PP3/BP4 evidence and SpliceAI predicts no splice impact (max delta score 0.00).4
Final classification
Likely Pathogenic
PS3PM1PM2
TP53
c.469G>T
p.Val157Phe
This variant
The TP53 c.469G>T (p.Val157Phe) variant has been observed in somatic cancers in COSMIC (COSV52667015; n=366) and has not been reported in ClinVar.
TP53 VCEP v2.4.0 CSPEC point-based final-classification framework (Tavtigian et al., 2020 Bayesian adaptation): PS3_Strong (4) + PM1_Moderate (2) + PM2_Supporting (1) = 7 points, which falls in the 6-9 point range for Likely Pathogenic.
Classification rationale
PS3PM1PM2
Likely Pathogenic
TP53 c.469G>T
PS3 + PM1 + PM2
→
Likely Pathogenic
1
COSMICClinVar
2
gnomAD v2.1gnomAD v4.1TP53 VCEP
3
Functional-worksheet.xlsx
4
Cancer HotspotsPP3-BP4-codes.xlsxSpliceAI
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_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 13 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PS3
Strong
review
Pathogenic
TP53 expert panel functional data classify p.Val157Phe as PS3. The variant is non-functional in Kato, shows loss of function in Funk and Kotler, and is loss-of-function by the majority of eligible assays, which supports damaging protein function.
Functional-worksheet.xlsx: V157F | NA | Non-functional | LOF | noLOF | LOF | NA | PS3OncoKB: Likely Loss-of-function
PM1
Moderate
review
Pathogenic
This missense variant affects TP53 codon 157, a statistically significant hotspot residue in Cancer Hotspots. The exact amino acid change p.Val157Phe is reported 67 times, which is above the TP53 PM1 threshold of at least 10 somatic occurrences for the same amino acid change.
Cancer Hotspots residue V157: tumorCount 77, qValue 1.04043861763858e-43Cancer Hotspots exact variant V157F: 67 tumors
PM2
Supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1 (0/1614132 alleles; AF 0.00000%), which is below the TP53 PM2_Supporting threshold of less than 0.00003.
gnomAD v2.1: absentgnomAD v4.1: 0/1614132 alleles, AF 0.0
Assessed · not applied
· 5 not met · 8 not assessed
Pathogenic
PS1
No evidence was identified that a different nucleotide change causing the same p.Val157Phe amino acid substitution has already been classified as pathogenic or likely pathogenic under TP53 VCEP specifications.
PS2
No confirmed de novo observations with validated maternity and paternity were identified, so PS2 cannot be assessed.
PS4
No germline proband data meeting TP53 PS4 point-based criteria were identified.
PM5
No evidence was identified that another missense change at codon 157 has already been classified as pathogenic or likely pathogenic under TP53 VCEP specifications in a way that supports PM5.
PP1
No segregation data were identified, so PP1 cannot be assessed.
PP3
TP53 bioinformatic pre-assignment does not support PP3 for this missense change.
PP4
No blood variant allele fraction data or constitutional mosaicism evidence were identified, so the TP53-specific PP4 criteria cannot be assessed.
Benign
BA1
Population frequency does not meet BA1.
BS1
Population frequency does not meet BS1.
BS2
No dataset of unrelated females aged 60 years or older without cancer who carry this variant was identified, so BS2 cannot be assessed.
BS3
Available functional evidence does not support BS3.
BS4
No lack-of-segregation data in relatives with Li-Fraumeni syndrome-associated cancers were identified, so BS4 cannot be assessed.
BP4
TP53 bioinformatic pre-assignment does not support BP4 for this missense change.
N/A · 12
PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
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.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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 = 366 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
A global suppressor motif for p53 cancer mutants.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
Strong
Mutant p53 induces the GEF-H1 oncogene, a guanine nucleotide exchange factor-H1
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
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
Strong
Sources & reference links