TP53 c.824G>T, p.Cys275Phe
NM_000546.5:c.824G>T
COSMIC ID: COSM10701, COSM99932
Pathogenic
The TP53 p.C275F variant demonstrates strong functional evidence of loss of function (PS3_Strong), is absent from population databases (PM2_Supporting), and is reported as pathogenic by reputable sources (PP5_Supporting). No benign or other conflicting evidence applies. The combination of one Strong and two Supporting criteria supports a Likely Pathogenic classification.
ACMG/AMP Criteria Applied
PS3
PM2
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_000546.5 | 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.824G>T
Protein Change
C275F
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 275 in gene TP53
Alternate Identifiers
COSM10701, COSM99932
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.824G>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
2 publications
Pathogenic
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 275 of the TP53 protein (p.Cys275Phe). 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: 17567834, 18937320). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 376582). 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: 12826609, 18937320, 29979965, 30224644). This variant disrupts the p.Cys275 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7887414, 12826609, 14584079, 17606709, 21343334; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
The p.C275F pathogenic mutation (also known as c.824G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 824. The cysteine at codon 275 is replaced by phenylalanine, an amino acid with highly dissimilar properties. 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 variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). This alteration was identified in an individual diagnosed with breast cancer at 30 (Trkova M et al. Cancer, 2007 Aug;110:694-702). In addition, this alteration was identified in a family that met classic Li-Fraumeni criteria (Capra V et al. Pediatr Blood Cancer, 2009 Feb;52:303-4). This alteration was also identified in an individual diagnosed with gastric cancer at 35 (Masciari S et al. Genet Med, 2011 Jul;13:651-7). 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). Another variant at the same codon, p.C275Y (c.824G>A), has been identified in multiple families that were diagnosed with Li-Fraumeni syndrome (Frebourg T et al. Am. J. Hum. Genet. 1995 Mar; 56(3):608-15; Lynch HT et al. Cancer. 2003 Nov 1;98(9):1947-57). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories).
COSMIC ID
COSM10701, COSM99932
Recurrence
102 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
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Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
490
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (490 mutations).
PM1 criterion applied.
Related Variants in This Domain
No evidence of other pathogenic variants at position 275 in gene TP53
Functional Summary
The TP53 C275F variant has been functionally characterized and demonstrated to be inactivating. In vivo studies in yeast and in vitro studies in human cancer cell lines have shown that this mutation results in a loss of transactivational activity and reduced growth suppression activity compared to the wildtype TP53. These findings support a damaging effect of the TP53 C275F variant.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.981
0.981
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: 5.87primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines for TP53 (PVS1 decision tree), the rule for PVS1 is: "PVS1 applies to predicted loss-of-function variants including nonsense, frameshift, canonical ±1,2 splice sites, initiation codon variants etc." The evidence for this variant shows: NM_000546.5:c.824G>T (p.C275F) is a missense change and not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines for TP53 (PS1 specifications), the rule for PS1 is: "Applied to variants asserting the same amino acid change as a known pathogenic variant via a different nucleotide change." The evidence for this variant shows: p.C275F has no alternate nucleotide change previously classified as pathogenic at this residue. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo occurrence in a patient with the disease and no family history, confirmed by parental testing." The evidence for this variant shows: no parental or de novo data available. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines for TP53 (PS3 functional rule codes), the rule for PS3_Strong is: "Non-functional on Kato et al. data AND loss of function (LOF) on another assay." The evidence for this variant shows: in vivo yeast (Kato-like) assays and in vitro human cancer cell line studies demonstrate loss of transactivation and growth suppression activity for C275F. Therefore, this criterion is applied at Strong strength because the variant is non-functional on Kato data and shows LOF on additional assays.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to controls." The evidence for this variant shows: no case-control or proband point data available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines for TP53 (PM1 specifications), the rule for PM1_Moderate is: "Missense variants at codons 175, 245, 248, 249, 273, or 282." The evidence for this variant shows: p.C275F affects codon 275, which is not listed. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for TP53 (PM2), the rule for PM2_Supporting is: "Variant should have an allele frequency of less than 0.00003 in gnomAD." The evidence for this variant shows: p.C275F is absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the allele frequency is below the threshold.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: no recessive or trans data applicable. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss variants." The evidence for this variant shows: p.C275F is a missense variant with no protein length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for TP53 (PM5 specifications), the rule for PM5_Moderate is: "Missense variant at a residue where ≥1 different missense variant has been classified pathogenic per TP53 VCEP." The evidence for this variant shows: no other pathogenic missense variants reported at codon 275 in TP53 VCEP specifications. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines for TP53 (PP1 specifications), the rule for PP1_Supporting is: "Cosegregation in 3-4 meioses in ≥1 families." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism." The evidence for this variant shows: insufficient evidence on overall missense constraint metrics for TP53 to apply PP2. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines for TP53 (PP3 specifications), the rule for PP3_Moderate is: "Missense variants with aGVGD Class C65 AND BayesDel ≥0.16." The evidence for this variant shows: only REVEL data (0.98) provided, no aGVGD or BayesDel scores as required. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines for TP53 (PP4 specifications), the rule for PP4_Supporting is: "Observation of variant in tumor with VAF 5–35%." The evidence for this variant shows: no somatic VAF data provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic without accessible evidence for independent evaluation." The evidence for this variant shows: ClinVar lists p.C275F as Pathogenic by two clinical laboratories. Therefore, this criterion is applied at Supporting strength because a reputable source reports pathogenicity.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for TP53 (BA1 specifications), the rule for BA1 is: "Filtering allele frequency ≥0.001 in gnomAD continental subpopulations." The evidence for this variant shows: absent from gnomAD; frequency below threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for TP53 (BS1 specifications), the rule for BS1_Strong is: "Filtering allele frequency ≥0.0003 but <0.001 in gnomAD." The evidence for this variant shows: absent from gnomAD; frequency below threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for TP53 (BS2 specifications), the rule for BS2_Strong is: "≥8 unaffected unrelated females ≥60 years old without cancer." The evidence for this variant shows: no such cohort data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for TP53 (BS3 specifications), the rule for BS3_Strong is: "Functional on Kato et al. data AND no LOF on other assays." The evidence for this variant shows: functional studies demonstrate LOF, not preserved function. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines for TP53 (BS4 specifications), the rule for BS4_Strong is: "Lack of segregation in affected family members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in gene for which only truncating variants cause disease." The evidence for this variant shows: TP53 disease mechanism is gain-of-function and dominant-negative missense, so BP1 not applicable. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant." The evidence for this variant shows: no such allelic configuration data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in repetitive regions without known function." The evidence for this variant shows: this is not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines for TP53 (BP4 specifications), the rule for BP4_Supporting is: "Missense variants with BayesDel <0.16 AND no predicted splicing impact (SpliceAI <0.2)." The evidence for this variant shows: no BayesDel or SpliceAI data provided. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no such alternate finding. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without accessible evidence." The evidence for this variant shows: no reputable source reporting benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines for TP53 (BP7 specifications), the rule for BP7_Supporting is: "Synonymous variant with no splicing impact (SpliceAI ≤0.1)." The evidence for this variant shows: p.C275F is missense, not synonymous. Therefore, this criterion is not applied.