TP53 c.818G>A, p.Arg273His
NM_000546.5:c.818G>A
COSMIC ID: COSM10660, COSM3356963
Pathogenic
Strong functional evidence (PS3) combined with hotspot location (PM1), rarity (PM2), additional moderate evidence from PM5, and computational support (PP3) yields a Likely Pathogenic classification.
ACMG/AMP Criteria Applied
PS3
PM1
PM2
PM5
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.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
Genome Browser
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HGVS InputNM_000546:c.818G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00159%
Rare
Highest in Population
Ashkenazi Jewish
0.00993%
Rare
Global: 0.00159%
Ashkenazi Jewish: 0.00993%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251054Alt: 4Homozygotes: 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 33 submitter reviews in ClinVar
Submitter Breakdown
30 Path
3 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (17)
Variant summary: TP53 c.818G>A (p.Arg273His) results in a non-conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251054 control chromosomes. c.818G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (Bougeard_2015, Varley_1997, Wasserman_2015). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.817C>T, p.Arg273Cys), supporting the critical relevance of codon 273 to TP53 protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in abolishing TP53 binding (Wasserman_2015) and functional inactiviation (Lang_2004). The following publications have been ascertained in the context of this evaluation (PMID: 25584008, 26014290, 9242456, 15607981). ClinVar contains an entry for this variant (Variation ID: 12366). Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (3 clinical laboratories) and as Pathogenic (30 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
COSMIC ID
COSM10660, COSM3356963
Recurrence
1331 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
COSMIC Database Preview
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Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
3654
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (3654 mutations).
PM1 criterion applied.
Related Variants in This Domain
No evidence of other pathogenic variants at position 273 in gene TP53
Functional Summary
The TP53 R273H variant has been functionally characterized and demonstrated to have a damaging effect. It is located in the DNA binding domain of the TP53 protein and is known to be oncogenic. Functional studies have shown that this mutation results in decreased transactivation of p53 target genes, increased cell proliferation, and failure to suppress colony growth compared to the wildtype. Additionally, it activates AKT signaling and suppresses the expression of BCL-modifying factor (BMF), contributing to cell survival.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.868
0.868
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:
metasvm: Dmetalr: D
Benign:
CADD: 4.43primateai: 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 to predicted null variants (e.g., nonsense, frameshift) resulting in NMD. The variant is a missense change (R273H), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when a variant results in the same amino acid change as a known pathogenic variant via a different nucleotide change. No such alternate nucleotide change for R273H is documented. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 requires confirmed de novo occurrence with parental testing. No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, PS3 at Strong strength is: "Non-functional on Kato et al. data AND loss of function (LOF) on another assay". The evidence for R273H shows multiple functional assays demonstrating loss of transactivation, increased proliferation, and failure to suppress colony growth. Therefore, this criterion is applied at Strong strength because the variant is non-functional in Kato data and shows LOF in additional assays.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires case–control or proband counting points. No proband case counts are provided. Therefore, this criterion is not applied.
PM1
PM1 (Moderate)
According to VCEP guidelines, PM1 at Moderate strength is: "Missense variants within codons 175, 245, 248, 249, 273, 282". R273H lies within codon 273, a TP53 DNA-binding hotspot. Therefore, this criterion is applied at Moderate strength.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 at Supporting strength is: "Allele frequency <0.00003 in gnomAD or another large database". The variant’s MAF is 0.00159%, which is <0.003% (0.00003). Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to variants in trans with a pathogenic variant in recessive disorders. TP53-associated Li–Fraumeni syndrome is dominant and no trans data are relevant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes due to in-frame indels or stop-loss. This is a missense variant. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, PM5 at Moderate strength is: "Missense variant at a residue where one different missense variant has been determined pathogenic". R273C is a known pathogenic change at the same residue. Therefore, this criterion is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo without confirmation. No de novo assumption is documented. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires segregation in multiple meioses. No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies when the gene has low benign missense variation and missense is a common mechanism. TP53 has many missense variants and this specific criterion was not invoked. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, PP3 Supporting is: "Multiple lines of computational evidence support a deleterious effect". REVEL score is 0.87 (>0.75) and other in silico tools predict damaging. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 applies with highly specific phenotype observations. No phenotype data specific to TP53/LFS are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines and ClinGen recommendations, PP5 (reputable source) is no longer recommended. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies with MAF ≥0.1%. The variant’s MAF is 0.00159%, below thresholds. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies with filtering allele frequency ≥0.0003 but <0.001. The variant’s MAF is 0.00159%, above BS1 but below BA1; however, population data do not support benign classification. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies when ≥8 unaffected older adults are observed. No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 applies when functional data demonstrate no loss of function. All functional data for R273H demonstrate LOF. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies for lack of segregation. No such data are provided. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies when a missense variant in a gene where only truncating variants cause disease. TP53 disease mechanism is missense LOF/gain-of-function. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when variant is observed in trans with a pathogenic variant in a dominant gene. Not applicable for TP53. Therefore, this criterion 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. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 Supporting applies with BayesDel <0.16 and no splice impact. We lack BayesDel data and in silico predictions support pathogenicity. Therefore, this criterion is not applied.
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 basis for disease. No alternate cause is reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source calls it benign without evidence. No such report exists. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous or non-splicing intronic variants. This is missense. Therefore, this criterion is not applied.