TP53 c.734G>A, p.Gly245Asp
NM_000546.6:c.734G>A
COSMIC ID: COSM43606
Likely Pathogenic
The variant NM_000546.6:c.734G>A (G245D) in the TP53 gene is classified as Likely Pathogenic based on multiple lines of evidence including its location in a critical domain, rarity in the population, and strong computational predictions of pathogenicity. The classification is supported by external clinical evidence from ClinVar and aligns with VCEP guidelines.
ACMG/AMP Criteria Applied
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_000546.6:c.734G>A
Protein Change
G245D
Location
Exon 7
(Exon 7 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Missense Variant
Related Variants
ClinVar reports other pathogenic variants at position 245: G245S, G245C
Alternate Identifiers
COSM43606
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.734G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000398%
Extremely Rare
Highest in Population
South Asian
0.00327%
Rare
Global: 0.000398%
South Asian: 0.00327%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251464Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is rare in the population (0.000398% MAF).
Classification
3 publications
Likely Pathogenic
Based on 9 submitter reviews in ClinVar
Submitter Breakdown
5 Path
4 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Two other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. Inconclusive segregation with disease.
The p.G245D mutation (also known as c.734G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 734. The glycine at codon 245 is replaced by aspartic acid, an amino acid with similar properties. This mutation was initially described in a classic Li-Fraumeni syndrome (LFS) family in which the mutation segregated with disease (Srivastava S et al. Nature. 348(6303):747-9). This alteration is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity, a dominant negative effect in yeast-based assays, decreased DNA binding activity to several responsive elements, and is predicted to affect several p53 isoforms (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Clin Cancer Res. 2007 Jul 1;13(13):3789-95; Malcikova J et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205; Monti P et al. Mol Cancer Res. 2011 Mar; 9(3):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). 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 available evidence, p.G245D is classified as a pathogenic mutation.
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 245 of the TP53 protein (p.Gly245Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with chronic lymphocytic leukemia and chronic-phase primary myelofibrosis and Li Fraumeni syndrome-associated cancers (PMID: 2259385, 21232794, 22052707). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12355). 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, 17606709, 20128691, 25119136, 29979965). This variant disrupts the p.Gly245 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565143, 1591732, 7783166, 12826609, 12885464, 23538418). 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.
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories) and as Pathogenic (5 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
1694
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (1694 mutations).
PM1 criterion applied.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 245: G245S, G245C
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.974
0.974
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Unknown
PP3 Applied
Yes
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
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 variant G245D is located in a critical domain of the TP53 gene, specifically in the DNA binding domain. Therefore, this criterion meets the requirements because it is located in a mutational hotspot without benign variation.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: 'This rule should be applied at supporting level. 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 MAF is 0.000398%, which is below the threshold. Therefore, this criterion meets the requirements because the variant is extremely rare.
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: The G245D change is at a residue where other pathogenic variants have been reported. Therefore, this criterion meets the requirements because it is a novel missense change at a residue with established pathogenicity.
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 0.97 supports a deleterious effect on protein function. Therefore, this criterion meets the requirements because it demonstrates strong computational evidence of pathogenicity.
PP5
PP5 (Moderate) Strength Modified
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 as Likely Pathogenic by multiple clinical laboratories in ClinVar. Therefore, this criterion meets the requirements because it is supported by external clinical evidence.