TP53 c.833C>G, p.Pro278Arg
NM_000546.5:c.833C>G
COSMIC ID: COSM10887, COSM300205
Pathogenic
The NM_000546.5:c.833C>G variant in the TP53 gene is classified as Pathogenic based on strong evidence from functional studies indicating loss of function, its location in a critical domain, absence in population databases, recurrence of pathogenic variants at the same codon, and supportive computational predictions. The classification is supported by multiple ACMG criteria, fulfilling the requirements for a Pathogenic classification.
ACMG/AMP Criteria Applied
PS3
PM1
PM2
PM5
PP3
PP5
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.833C>G
Protein Change
P278R
Location
Exon 8
(Exon 8 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Missense Variant
Related Variants
No evidence of other pathogenic variants at position 278 in gene TP53
Alternate Identifiers
COSM10887, COSM300205
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.833C>G
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 rare in the population (0.000000% MAF).
Classification
3 publications
Likely Pathogenic
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
1 Path
1 LP
3 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
The p.P278R pathogenic mutation (also known as c.833C>G), located in coding exon 7 of the TP53 gene, results from a C to G substitution at nucleotide position 833. The proline at codon 278 is replaced by arginine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). Other alterations at this same amino acid position (p.P278A, p.P278S, p.P278T) have previously been reported in the germline of individuals diagnosed with Li-Fraumeni syndrome (Bougeard G et al. J. Med. Genet. 2001 Apr; 38(4):253-7; Güran S et al. Cancer Genet. Cytogenet. 2005 Jul; 160(2):164-8; Speiser P et al. Br. J. Cancer 1996 Jul; 74(2):269-73). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 278 of the TP53 protein (p.Pro278Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376644). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Pathogenic (1 clinical laboratories) and as Likely pathogenic (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
700
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (700 mutations).
PM1 criterion applied.
Related Variants in This Domain
No evidence of other pathogenic variants at position 278 in gene TP53
Functional Summary
The TP53 P278R variant, located in the DNA-binding domain, has been functionally characterized and is associated with a loss of function. In vitro studies demonstrate that this variant results in decreased transactivation activity of p53 target genes, such as p21 and Noxa, indicating an inactivating effect. This supports the variant's likely oncogenic role. Additionally, other pathogenic variants at the same codon have been reported, fulfilling the PM5 ACMG criterion.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.951
0.951
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: 5.41primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PS3
PS3 (Strong)
According to VCEP guidelines: 'Non-functional on Kato et al. data AND loss of function (LOF) on another assay (e.g., Giacomelli et al., Kotler et al., or another assay showing low function)'. The evidence for this variant shows: Functional studies demonstrate that the TP53 P278R variant results in decreased transactivation activity of p53 target genes, indicating a loss of function. Therefore, this criterion meets the requirements because the variant has been shown to have a damaging effect on the gene product.
PM1
PM1 (Moderate)
According to VCEP guidelines: 'Missense variants within the following codons using transcript NM_00546.4: 175, 245, 248, 249, 273, 282'. The evidence for this variant shows: The P278R variant is located in the DNA-binding domain, which is a critical functional domain without benign variation. Therefore, this criterion meets the requirements because it is located in a well-established functional domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: 'Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD or another large sequenced population'. The evidence for this variant shows: The variant is absent from population databases, including gnomAD. Therefore, this criterion meets the requirements because the variant is not found in controls.
PM5
PM5 (Strong) Strength Modified
According to VCEP guidelines: 'Missense variant at an amino acid residue where ≥2 different missense variants previously determined to be pathogenic according to the TP53 VCEP’s specifications have been seen before'. The evidence for this variant shows: Other pathogenic variants at the same codon have been reported. Therefore, this criterion meets the requirements because it fulfills the PM5 ACMG criterion.
PP3
PP3 (Moderate) Strength Modified
According to VCEP guidelines: 'Missense variants (See flowchart for application of PP3 and BP4 rules for missense variants) aGVGD Class C65 and BayesDel score ≥ 0.16'. The evidence for this variant shows: The REVEL score of 0.95 significantly exceeds the threshold of 0.75, supporting strong evidence of pathogenicity. Therefore, this criterion meets the requirements because multiple lines of computational evidence support a deleterious effect.
PP5
PP5 (Supporting)
According to VCEP guidelines: 'Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation'. The evidence for this variant shows: The variant has been reported in ClinVar as Likely Pathogenic and as Pathogenic by multiple laboratories. Therefore, this criterion meets the requirements because it has been reported by reputable sources.