TP53 c.832C>T, p.Pro278Ser
NM_000546.6:c.832C>T
COSMIC ID: COSM1646810, COSM3773297
Pathogenic
Under TP53-specific VCEP guidelines, only PM2 (Supporting) is met for absence from population databases, and no other criteria can be applied given available data. Therefore, the variant is classified as a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
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_000546.6:c.832C>T
Protein Change
P278S
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 278 in gene TP53
Alternate Identifiers
COSM1646810, COSM3773297
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.832C>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
5 publications
Likely Pathogenic
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
2 Path
3 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (5)
The p.P278S pathogenic mutation (also known as c.832C>T), located in coding exon 7 of the TP53 gene, results from a C to T substitution at nucleotide position 832. The proline at codon 278 is replaced by serine, an amino acid with similar properties. This variant has been identified in individuals meeting Chompret criteria for Li Fraumeni syndrome (Bougeard G et al. J. Med. Genet., 2001 Apr;38:253-7; Evans DG et al. J Med Genet, 2022 02;59:115-121). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and dominant negative effect in yeast and mammalian based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Epstein CB et al. Oncogene, 1998 Apr;16:2115-22; Campomenosi P et al. Oncogene, 2001 Jun;20:3573-9; Dearth LR et al. Carcinogenesis, 2007 Feb;28:289-98; Monti P et al. Mol. Cancer Res., 2011 Mar;9:271-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (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). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). Internal structural analysis indicate that this variant may destabilize the structure in the DNA binding domain (Kitayner M et al. Mol. Cell, 2006 Jun;22:741-53; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 alteration is interpreted as a disease-causing mutation.
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 278 of the TP53 protein (p.Pro278Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 11370630, 15993273, 16258005, 33758026). ClinVar contains an entry for this variant (Variation ID: 376642). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 8633021, 11370630, 12826609, 21343334, 23264849, 29979965, 30224644). 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.
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 11867759]. This variant is expected to disrupt protein structure [Myriad internal data].
The p.Pro278Ser variant in TP53 has been reported in 2 individuals with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome (Bougeard 2001, Guran 2005, Monti 2007). It was absent from large population studies. In vitro functional studies provide some evidence that this variant impacts protein function by disrupting its transactivation activity (Brachmann 1996, Epstein 1998, Bougeard 2001, Kato 2003, Dearth 2007, Monti 2011). It has also been reported as a common somatic mutation across multiple tumor types (COSMIC Database, https://cancer.sanger.ac.uk/cosmic/). Computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominan Li-Fraumeni syndrome. ACMG/AMP criteria applied: PM2, PS3_Moderate, PP3, PS4_Supporting.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as Likely Pathogenic (1 clinical laboratories).
COSMIC ID
COSM1646810, COSM3773297
Recurrence
221 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
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 P278S 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 results in the loss of transactivation of the p21 promoter, indicating an inactivating effect. In vitro and in vivo studies show that this variant promotes tumor growth and reduces the activation of TP53 target genes, as well as the apoptotic response following DNA damage.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.963
0.963
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: 5.58primateai: 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 causing NMD or affecting canonical splice sites. The evidence for this variant shows it is a missense change (P278S), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 requires a variant resulting in the same amino acid change as a previously established pathogenic variant. There is no evidence of another pathogenic missense change at codon 278. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 applies based on de novo occurrence with validated maternity/paternity. No de novo data are provided. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 strength levels require specific functional assays (e.g., Kato, Giacomelli, Kotler). The available functional evidence is general in vitro/in vivo data and does not specify these assays. Therefore, this criterion is not applied under VCEP.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires case-control or proband counting data. No case data or proband points are provided. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 Moderate applies only to missense variants at codons 175, 245, 248, 249, 273, or 282. Codon 278 is outside these hotspots. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 Supporting applies to variants with allele frequency <0.00003 in gnomAD. The evidence shows P278S is absent from population databases. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to recessive disorders with trans observations. No such data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes (in-frame indels). P278S is a missense substitution. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 requires other pathogenic missense variants at the same residue. There is no evidence of such at codon 278. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to presumed de novo variants. No de novo evidence is provided. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires cosegregation in affected family members. No segregation data are provided. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low rate of benign missense variation. TP53 has many reported benign missense variants. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 Supporting or Moderate requires specific in silico scores (BayesDel, aGVGD) and SpliceAI thresholds. These data are not available. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 applies to phenotype specificity. No clinical phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to ACMG guidelines, PP5 is deprecated and not recognized by VCEP. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies to allele frequency ≥0.001. P278S is absent in gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 Strong applies to allele frequency ≥0.0003. P278S is absent in gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies to observations in healthy older females. No such data are provided. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires functional evidence of preserved function. The evidence indicates damaging effect, not preserved function. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation. No segregation data are provided. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where truncating variants are pathogenic and missense are benign. TP53 has pathogenic missense variants. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies to observed in trans with a pathogenic variant in recessive disorders. Not applicable here. 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. P278S is a missense substitution. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 requires BayesDel <0.16 and SpliceAI <0.2. These data are not available. 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 gene with an alternate molecular basis. Not applicable. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to ACMG guidelines, BP6 is deprecated. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to silent or intronic variants with no splicing impact. P278S is missense. Therefore, this criterion is not applied.