TP53 c.818G>A, p.Arg273His
NM_000546.5:c.818G>A
COSM10660, COSM3356963
Population Frequency
0.00159%
Low Frequency
ClinVar Classification
Likely Pathogenic
17 publications
REVEL Score
0.868
Likely Pathogenic
COSMIC Recurrence
1331 occurrences
PM1 Criterion Applied
Classification Evidence
Detailed Information
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.818G>A
Protein Change
R273H
Location
Exon 8
(Exon 8 of 11)
5'
Exon Structure (11 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 273 in gene TP53
Alternate Identifiers
COSM10660, COSM3356963
Variant interpretation based on transcript NM_000546.6
Clinical Evidence
Global Frequency
0.00159%
Rare
Highest in Population
Ashkenazi Jewish
0.00993%
Rare
Global: 0.00159%
Ashkenazi Jewish: 0.00993%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 251054
Alt: 4
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00159%, 4/251054 alleles, homozygotes = 0) and at a higher frequency in the Ashkenazi Jewish population (MAF= 0.00993%, 1/10072 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
17 publications
Likely Pathogenic
Based on 31 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
17 publications
Show publication details
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (3 clinical laboratories) and as Pathogenic (28 clinical laboratories) and as Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen expert panel.
Expert Panel Reviews
Pathogenic
ClinGen TP53 Variant Curation Expert Panel, ClinGen
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
3654
Reported mutations in this domain
0
50
100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (3654 mutations).
PM1 criterion applied: Located in a mutational hot spot and/or critical and well-established functional domain.
Related Variants in This Domain
No evidence of other pathogenic variants at position 273 in gene TP53
Functional Studies
Summary
The TP53 R273H variant has been functionally characterized and shown to have a damaging effect. It is located in the DNA binding domain of the TP53 protein and results in loss of DNA binding and decreased transactivation of TP53 target genes. This variant leads to increased cell proliferation, migration, invasion, and protein stability, as well as apoptosis resistance and failure of G1 arrest. Additionally, it confers a gain of function, resulting in aberrant transcriptional activation and increased migration. These functional alterations support its oncogenic role.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.868
0.868
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
metasvm: D
metalr: D
Benign:
CADD: 4.43
primateai: T
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Not Applied)
Strength Modified
According to VCEP guidelines for TP53, 'PVS1 applies to null variants (nonsense, frameshift, canonical splice, etc.) that are predicted to undergo nonsense-mediated decay.' The evidence for this variant shows it is a missense variant (R273H) and not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, 'PS1 is applied when the same amino acid change as a previously established pathogenic variant is produced by a different nucleotide change.' The evidence for this variant does not indicate an alternative nucleotide change creating the same amino acid substitution. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, 'PS2 is applied for de novo variants confirmed by parental testing.' The evidence for this variant does not include de novo occurrence data. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines for TP53, 'PS3 is applied when well‐established in vitro or in vivo functional studies show a damaging effect on the gene product.' The evidence for this variant shows that TP53 R273H has been functionally characterized to result in loss of DNA binding, decreased transactivation, increased cell proliferation, migration, invasion, and gain‐of‐function properties. Therefore, this criterion is applied at strong strength.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, 'PS4 is applied when there is a statistically increased prevalence of the variant in affected individuals compared to controls.' The evidence for this variant does not provide any case-control data. Therefore, this criterion is not applied.
PM1
PM1 (Moderate)
According to VCEP guidelines for TP53, 'PM1 applies at Moderate strength for missense variants within hotspot codons (e.g., 175, 245, 248, 249, 273, 282).' The evidence for this variant shows it affects codon 273, a known mutational hotspot. Therefore, this criterion is applied at moderate strength.
PM2
PM2 (Supporting)
Strength Modified
According to VCEP guidelines for TP53, 'PM2 should be applied at Supporting strength when the variant allele frequency is below the specified threshold (<0.00003 in gnomAD).' The evidence for this variant shows an extremely rare frequency (MAF = 0.00159%, which equates to 0.0000159 in fraction, below the threshold). Therefore, this criterion is applied at supporting strength.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, 'PM3 is applied for recessive disorders when the variant is detected in trans with a pathogenic variant.' The evidence for this TP53 variant does not involve recessive inheritance or trans configuration context. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, 'PM4 is applied for protein length changes due to in-frame deletions/insertions in non-repeat regions.' The evidence for this variant shows it is a missense change rather than an in-frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to VCEP guidelines for TP53, 'PM5 is applied when a different missense change at the same amino acid residue previously established as pathogenic is observed.' The evidence for this variant does not include additional distinct missense variants at residue 273 aside from the one under evaluation. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, 'PM6 is applied for assumed de novo variants without confirmation of paternity and maternity.' The evidence for this variant does not include such data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, 'PP1 is applied when there is cosegregation of the variant with disease in multiple affected family members.' The evidence for this variant does not include segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, 'PP2 is applied for genes with low benign missense variation and where missense variants are a common mechanism of disease.' Although TP53 is highly constrained, the VCEP guidelines do not specifically invoke PP2 for TP53. The evidence does not support applying PP2 independently. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, 'PP3 is applied when multiple computational evidence lines predict a deleterious effect on the gene or gene product.' The evidence for this variant shows a REVEL score of 0.87, which exceeds the threshold, alongside multiple deleterious predictions. Therefore, this criterion is applied at supporting strength.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, 'PP4 is applied when the patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.' The evidence for this variant does not include detailed phenotype information that would warrant PP4. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, 'PP5 is applied when a reputable source recently reports the variant as pathogenic without available primary evidence.' The evidence for this variant includes multiple reports in ClinVar and classification by the ClinGen TP53 Variant Curation Expert Panel as pathogenic or likely pathogenic by several clinical laboratories. Therefore, this criterion is applied at supporting strength.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines for TP53, 'BA1 is applied when the filtering allele frequency in any large population database exceeds the benign threshold (≥0.001).' The evidence for this variant shows a very low allele frequency which does not meet the benign cutoff. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, 'BS1 is applied when the allele frequency is greater than expected for the disorder but below the BA1 threshold.' The allele frequency for this variant is extremely low, not meeting BS1. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines, 'BS2 is applied when there are multiple unaffected individuals beyond a defined age without the disorder.' The evidence for this variant does not include such data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, 'BS3 is applied when functional studies show no damaging effect on gene or protein function.' The evidence for this variant clearly demonstrates damaging functional effects. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, 'BS4 is applied when there is a lack of segregation in affected family members.' The evidence for this variant does not provide segregation information contradicting pathogenicity. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, 'BP1 is applied when missense variants are a common mechanism of benign impact in a gene for which truncating variants are the dominant pathogenic mechanism.' The evidence for this variant and TP53 indicates missense variants have pathogenic consequences. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, 'BP2 is applied when the variant is observed in trans with a pathogenic variant for a fully penetrant dominant disease.' The evidence for this variant does not include data on in trans occurrence. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, 'BP3 is applied for in-frame deletions or duplications in repetitive regions without a known function.' The evidence for this variant shows it is a missense, not an in-frame indel, and thus BP3 is not applicable. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, 'BP4 is applied when multiple computational tools predict no impact on the gene or gene product.' The evidence for this variant demonstrates multiple computational predictors (e.g., REVEL score) supporting a deleterious effect. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, 'BP5 is applied when an alternative molecular basis can explain the phenotype.' The evidence for this variant does not include such alternative explanations. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, 'BP6 is applied when a reputable source reports the variant as benign without providing primary data.' The evidence for this variant robustly supports pathogenicity from multiple reputable sources. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines, 'BP7 is applied for synonymous or intronic variants outside of consensus splice sites with no predicted splicing impact.' The evidence for this variant shows it is a missense change directly affecting the protein sequence. Therefore, this criterion is not applied.