TP53 c.734G>A, p.Gly245Asp

NM_000546.6:c.734G>A

COSM43606

Classification Summary

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.

Population Frequency

0.000398%

Rare

ClinVar Classification

Likely Pathogenic

3 publications

REVEL Score

0.974

Likely Pathogenic

COSMIC Recurrence

260 occurrences

PM1 Criterion Applied

Classification Evidence

Very Strong (PVS)

None applied

Strong (PS/BS)

PM5

Moderate (PM/BA)

PM1 PP3 PP5

Supporting (PP/BP)

PM2

ClinVar COSMIC gnomAD OncoKB JAX-CKB SpliceAI

Created: 2025-04-06T23:11:32.570666

Detailed Information

Genetic Information Clinical Evidence Functional Studies Computational Evidence VCEP Guidelines

Genetic Information

Gene & Transcript Details

Gene

TP53

Transcript

                                        
                                            NM_000546.6
                                        
                                                    MANE Select

Total Exons

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

Clinical Evidence

Population Frequency

Global Frequency

0.000398%

Extremely Rare

Highest in Population

South Asian

0.00327%

Rare

Global: 0.000398%

South Asian: 0.00327%

0.0005%

0.001%

0.01%

0.05%

1%+

Allele Information

Total: 251464 Alt: 1 Homozygotes: 0

ACMG Criteria Applied

PM2

This variant is rare in the population (0.000398% MAF).

ClinVar 2025-04-06T23:10:23.111384

Classification

3 publications

Likely Pathogenic

Based on 9 submitter reviews in ClinVar

Submitter Breakdown

5 Path

4 LP

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Publications

3 publications

Show publication details

PMID: 17606709

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.

PMID: 17606709

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.

PMID: 2259385

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.

Publication Summary:

- **17606709**: This variant is predicted to have a damaging effect on the protein and has been found in at least one symptomatic patient. It is associated with abnormal protein function and inconclusive segregation with disease. - **20128691**: Functional studies indicate that this variant results in a non-functional protein, affecting DNA binding and transactivation. - **25119136**: The variant is associated with a damaging effect on the protein, supported by functional studies. - **21232794**: The variant has been observed in individuals with Li-Fraumeni syndrome and is associated with a non-functional protein in DNA binding assays. - **22052707**: This variant has been observed in individuals with Li-Fraumeni syndrome and is associated with a non-functional protein in DNA binding assays. - **2259385**: The variant was initially described in a family with Li-Fraumeni syndrome, where it segregated with the disease. It is located in the DNA binding domain of the TP53 protein and is associated with loss of transactivation capacity and decreased DNA binding activity. - **21343334**: The variant is associated with a non-functional protein in transactivation assays and has been observed in individuals with Li-Fraumeni syndrome. - **12826609**: Experimental studies show that this variant affects TP53 function, with a high predictive value for pathogenicity. - **29979965**: The variant is associated with a non-functional protein in human cell proliferation assays and has been observed in individuals with Li-Fraumeni syndrome. - **30224644**: The variant is associated with a non-functional protein in human cell proliferation assays and has been observed in individuals with Li-Fraumeni syndrome. - **1565143**: Other variants affecting the same amino acid residue have been determined to be pathogenic, suggesting clinical significance. - **1591732**: Other variants affecting the same amino acid residue have been determined to be pathogenic, suggesting clinical significance. - **7783166**: Other variants affecting the same amino acid residue have been determined to be pathogenic, suggesting clinical significance. - **12885464**: Other variants affecting the same amino acid residue have been determined to be pathogenic, suggesting clinical significance. - **23538418**: Other variants affecting the same amino acid residue have been determined to be pathogenic, suggesting clinical significance.

Clinical Statement

This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories) and as Pathogenic (5 clinical laboratories).

COSMIC

COSMIC ID

COSM43606

Recurrence

260 occurrences

PM1 Criteria

Applied

Criterion PM1 is applied based on the high recurrence in COSMIC database.

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Functional Domain

Cancer Hotspots

Hotspot Status

Hotspot

PM1

Mutation Count

1694

Reported mutations in this domain

0 50 100+

Domain Summary

This variant is located in a mutational hotspot or critical domain (1694 mutations).

PM1 criterion applied: Located in a mutational hot spot and/or critical and well-established functional domain.

Related Variants in This Domain

ClinVar reports other pathogenic variants at position 245: G245S, G245C

PM5 criterion applied: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Functional Studies

Functional Impact

OncoKB JAX-CKB

Summary

The variant has not been functionally characterized in the provided sources.

Computational Evidence

Pathogenicity Predictions

REVEL Score

0.974

Likely Benign 0.0

Uncertain (Low) 0.2

Uncertain (Med) 0.5

Likely Pathogenic 0.75

REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)

Predictor Consensus

Unknown

PP3 Applied

Yes

SpliceAI Scores Window: ±500bp

Effect Type	Score	Position
- Acceptor Loss	0.0	-416 bp
- Donor Loss	0.0	22 bp
+ Acceptor Gain	0.0	14 bp
+ Donor Gain	0.0	-48 bp

High impact (≥0.5)

Medium impact (0.2-0.49)

Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria 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.

LYFE SCIENCES

TP53 c.734G>A, p.Gly245Asp

Classification Summary

Genetic Information

Clinical Evidence

Functional Studies

Computational Evidence

VCEP Guidelines