TP53 c.751A>T, p.Ile251Phe
NM_000546.5:c.751A>T
COSMIC ID: COSM43967, COSM6950826
Pathogenic
The final classification is Variant of Uncertain Significance (VUS) because only PS3 (Strong), PM2 (Supporting), and PP3 (Supporting) are met, which is insufficient for a Likely Pathogenic or Pathogenic classification under VCEP guidelines.
ACMG/AMP Criteria Applied
PS3
PM2
PP3
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_000546.5 | RefSeq Select | 11 exons | Reverse |
| NM_000546.3 | Alternative | 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.751A>T
Protein Change
I251F
Location
Exon 7
(Exon 7 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 251: I251N
Alternate Identifiers
COSM43967, COSM6950826
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.751A>T
Active Tracks
ConservationRefSeqClinVargnomAD
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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
1 publications
Likely Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 1518844). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 251 of the TP53 protein (p.Ile251Phe).
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
75
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (75 mutations).
PM1 criterion applied.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 251: I251N
PM5 criterion applied.
Functional Summary
The TP53 I251F variant has been functionally characterized and shown to be damaging. In vivo studies in yeast and in vitro studies in human cancer cell lines indicate that this mutation is inactivating, as evidenced by a loss of transactivational activity and reduced growth suppression activity compared to the wildtype protein.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.962
0.962
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 4.77primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "PVS1 applies to null variants (nonsense, frameshift) predicted to result in nonsense-mediated decay". The evidence for this variant shows it is a missense change (I251F), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "PS1 Strong Strength: Can be applied to variants asserted as Pathogenic following the TP53 VCEP’s specifications". The evidence for this variant shows it is a novel amino acid change at codon 251 with no prior pathogenic assertion of the same change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "PS2 supporting to very strong based on de novo occurrence points". There are no de novo data available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "PS3 Strong Strength: Non-functional on Kato et al. data AND loss of function on another assay". The evidence for this variant shows: in vivo studies in yeast (Kato-like transactivation assay) demonstrated loss of function and in vitro human cancer cell line studies demonstrated reduced growth suppression activity. Therefore, this criterion is applied at Strong strength because the variant is non-functional on a Kato-style assay and shows loss of function on a second assay.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "PS4 Strong Strength: ≥4 proband points". There are no case or segregation data providing proband points for this variant. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "PM1 Moderate Strength: Missense variants within codons 175, 245, 248, 249, 273, 282". The evidence for this variant shows it affects codon 251, which is not one of the specified hotspot codons. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "PM2 Supporting Strength: Allele frequency <0.00003 in gnomAD or another large control database". The evidence for this variant shows it is absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "PM3 applies to variants in trans with a pathogenic variant in recessive disorders". TP53-related conditions are autosomal dominant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "PM4 applies to protein length changes (in-frame indels)". The evidence for this variant shows it is a missense change with no protein length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "PM5 Moderate Strength: Missense variant at a residue where ≥1 different missense variant previously determined to be pathogenic has been seen". There is no evidence of any other pathogenic missense variant at codon 251. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "PM6 Supporting Strength: Assumed de novo without confirmation". There are no de novo data at all for this variant. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "PP1 Supporting to Strong based on cosegregation in affected family members". No family segregation data are available for this variant. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "PP2 applies to genes with low rate of benign missense variation where missense is a common mechanism". TP53 has a high rate of both pathogenic and benign missense variants. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, the rule for PP3 is: "PP3 Supporting Strength: Multiple computational algorithms predict a deleterious effect". The evidence for this variant shows REVEL score 0.96, PolyPhen-2, MetaSVM, and MetaLR all predict damaging. Therefore, this criterion is applied at Supporting strength because multiple in silico tools support deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "PP4 applies when the patient’s phenotype or family history is highly specific for a disease with a single genetic etiology". No phenotype or family history information is provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is deprecated and not recommended for use. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "BA1 Stand Alone Strength: Allele frequency ≥0.01 in control databases". The variant is absent from gnomAD (frequency 0%). Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "BS1 Strong Strength: Filtering allele frequency ≥0.0003 but <0.001 in gnomAD continental subpopulations". The variant’s allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "BS2 applies when ≥2-8 unrelated older females without cancer carry the variant". No such observations exist. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "BS3 Strong or Supporting based on evidence of retained function in multiple assays". Functional studies demonstrate loss of function. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "BS4 Strong Strength: Lack of segregation in affected family members". No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "BP1 applies to missense variants in genes where only truncating variants cause disease". TP53 is characterized by pathogenic missense variants. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "BP2 applies when a variant is observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant". No such observations exist. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "BP3 applies to in-frame deletions/insertions in repetitive regions without known function". This variant is a missense change, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "BP4 Supporting Strength: BayesDel <0.16 and no predicted splicing impact". Computational evidence for this variant predicts a deleterious effect. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "BP5 applies when a variant is found in a gene of uncertain significance along with a pathogenic variant in a known disease gene". Not applicable here. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to VCEP guidelines, BP6 is not recommended for use; no evidence from a reputable source classifies this variant as benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "BP7 Supporting Strength: Synonymous variant outside splice sites with no splicing impact". This variant is missense, not synonymous. Therefore, this criterion is not applied.