TP53 c.469G>T, p.Val157Phe
NM_000546.5:c.469G>T
COSMIC ID: COSM10670, COSM3388217
Likely Pathogenic
This legacy system is being phased out as Project HERA V3 is rolled out.
ACMG/AMP Criteria Applied
PS3
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
TP53
Transcript
NM_000546.6
MANE Select
Total Exons
11
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000546.3 | Alternative | 11 exons | Reverse |
| NM_000546.5 | RefSeq Select | 11 exons | Reverse |
| NM_000546.4 | Alternative | 11 exons | Reverse |
| NM_000546.2 | Alternative | 11 exons | Reverse |
Variant Details
HGVS Notation
NM_000546.5:c.469G>T
Protein Change
V157F
Location
Exon 5
(Exon 5 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 157 in gene TP53
Alternate Identifiers
COSM10670, COSM3388217
Variant interpretation based on transcript NM_000546.6
Genome Browser
Loading genome browser...
HGVS InputNM_000546:c.469G>T
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
COSMIC ID
COSM10670, COSM3388217
Recurrence
355 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
COSMIC Database Preview
Accessing full COSMIC database details requires institutional login or subscription. External links may prompt for authentication.
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 157 in gene TP53
Functional Summary
The TP53 V157F variant has been functionally characterized and is likely damaging. It is located in the DNA-binding domain of the TP53 protein. In vitro and structural studies have shown that this mutation results in decreased DNA-binding activity and impaired transcriptional activity. The mutant protein exhibits a rearranged DNA-binding surface, reduced expression of pro-apoptotic proteins, and a diminished apoptotic response. Additionally, the variant confers a gain of function, leading to aberrant gene regulation in cell culture.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 2.39primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, PVS1 applies only to null variants resulting in loss of function via nonsense, frameshift, canonical splice, or initiation codon disruptions. The variant NM_000546.5:c.469G>T (p.V157F) is a missense change. Therefore, PVS1 is not applied because this is not a null variant.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when the variant results in an amino acid change previously established as pathogenic at the same residue. There is no report of a different nucleotide change causing p.V157F or any other pathogenic variant at codon 157. Therefore, PS1 is not applied because there is no identical amino acid change asserted as pathogenic.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 applies to confirmed de novo occurrences with specific point thresholds. No de novo data are available for this variant. Therefore, PS2 is not applied due to lack of de novo evidence.
PS3
PS3 (Strong)
According to VCEP guidelines, PS3_Strong: "Non-functional on Kato et al. data AND loss of function (LOF) on another assay." The evidence for p.V157F shows well-established in vitro and structural studies demonstrating decreased DNA-binding activity, impaired transcriptional function, reduced pro-apoptotic protein expression, and a gain-of-function oncogenic phenotype. Therefore, PS3 is applied at Strong strength because multiple functional assays indicate non-function and LOF consistent with the VCEP PS3_Strong rule.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 applies based on proband counting and case–control data with point thresholds. No case or proband data meeting VCEP thresholds were provided. Therefore, PS4 is not applied due to absence of qualifying clinical case evidence.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to missense variants within TP53 hotspot codons (175, 245, 248, 249, 273, 282). Codon 157 is outside these specified hotspots. Therefore, PM1 is not applied because the variant is not located in a VCEP-defined hotspot codon.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2_Supporting: "Allele frequency <0.00003 in gnomAD or large population databases." The variant p.V157F is absent from gnomAD and other population databases. Therefore, PM2 is applied at Supporting strength because the allele frequency meets the VCEP PM2_Supporting threshold.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to variants observed in trans with a pathogenic variant in recessive disorders. TP53 disorders are dominant and no trans observations are relevant. Therefore, PM3 is not applied because the variant is not in a recessive context.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length–altering variants such as in-frame indels or stop‐loss variants. The variant p.V157F is a missense change without alteration of protein length. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies when ≥1 different missense variant at the same residue has been classified as (Likely) Pathogenic. There are no other reported pathogenic or likely pathogenic missense variants at codon 157. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo occurrences without confirmation of paternity/maternity. No such data are available for this variant. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies for co-segregation with disease in families meeting specific meiosis thresholds. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies when a gene has low rate of benign missense variation and missense is common mechanism. TP53 has both benign and pathogenic missense, and no VCEP specification uses PP2. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3_Moderate requires BayesDel ≥0.16 and no predicted splicing impact. BayesDel data are not provided and in silico results are mixed. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies for LFS-associated tumor types with specific VAF criteria. No tumor VAF or phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies for reputable source assertions without available data. No reputable source assertions (e.g., ClinVar) are present. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 requires allele frequency ≥0.001 in gnomAD subpopulations. The variant is absent from population databases. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 requires filtering allele frequency ≥0.0003 but <0.001. The variant is absent from gnomAD. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 requires observation in ≥2 unrelated older unaffected females. No such data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 applies when functional assays show no loss of function. The functional data for p.V157F demonstrate damaging effects. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies when there is lack of co-segregation in affected family members. No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only truncating variants cause disease. TP53 has pathogenic missense variants, so BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when observed in cis with a pathogenic variant in dominant disorders. No such observations are reported. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in‐frame indels in repetitive regions. This is a missense variant, so BP3 is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, BP4: "Multiple lines of computational evidence suggest no impact on gene or gene product." SpliceAI predicts no splicing impact and CADD score is low (2.39), though other in silico tools are mixed. Therefore, BP4 is applied at Supporting strength because overall computational evidence leans benign for splicing and functional impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when a variant is found in a case with an alternate molecular cause. No alternate cause is reported. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies to unpublished reputable source assertions without data. No such assertions exist. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous/intronic variants with no splicing impact. This is a missense variant. Therefore, BP7 is not applied.