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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 21445056). 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. This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 258 of the TP53 protein (p.Glu258Val).
ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.773A>T (p.Glu258Val)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(1)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance
1
criteria provided, single submitter
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000546.6(TP53):c.773A>T (p.Glu258Val)
Variation ID: 2808296 Accession: VCV002808296.1
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7674190 (GRCh38) [ NCBI UCSC ] 17: 7577508 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 20, 2024 Feb 20, 2024 Oct 12, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.773A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Glu258Val missense NM_001126112.3:c.773A>T NP_001119584.1:p.Glu258Val missense NM_001126113.3:c.773A>T NP_001119585.1:p.Glu258Val missense NM_001126114.3:c.773A>T NP_001119586.1:p.Glu258Val missense NM_001126115.2:c.377A>T NP_001119587.1:p.Glu126Val missense NM_001126116.2:c.377A>T NP_001119588.1:p.Glu126Val missense NM_001126117.2:c.377A>T NP_001119589.1:p.Glu126Val missense NM_001126118.2:c.656A>T NP_001119590.1:p.Glu219Val missense NM_001276695.3:c.656A>T NP_001263624.1:p.Glu219Val missense NM_001276696.3:c.656A>T NP_001263625.1:p.Glu219Val missense NM_001276697.3:c.296A>T NP_001263626.1:p.Glu99Val missense NM_001276698.3:c.296A>T NP_001263627.1:p.Glu99Val missense NM_001276699.3:c.296A>T NP_001263628.1:p.Glu99Val missense NM_001276760.3:c.656A>T NP_001263689.1:p.Glu219Val missense NM_001276761.3:c.656A>T NP_001263690.1:p.Glu219Val missense NM_001407262.1:c.773A>T NP_001394191.1:p.Glu258Val missense NM_001407263.1:c.656A>T NP_001394192.1:p.Glu219Val missense NM_001407264.1:c.773A>T NP_001394193.1:p.Glu258Val missense NM_001407265.1:c.656A>T NP_001394194.1:p.Glu219Val missense NM_001407266.1:c.773A>T NP_001394195.1:p.Glu258Val missense NM_001407267.1:c.656A>T NP_001394196.1:p.Glu219Val missense NM_001407268.1:c.773A>T NP_001394197.1:p.Glu258Val missense NM_001407269.1:c.656A>T NP_001394198.1:p.Glu219Val missense NM_001407270.1:c.773A>T NP_001394199.1:p.Glu258Val missense NM_001407271.1:c.656A>T NP_001394200.1:p.Glu219Val missense NR_176326.1:n.802A>T non-coding transcript variant NC_000017.11:g.7674190T>A NC_000017.10:g.7577508T>A NG_017013.2:g.18361A>T LRG_321:g.18361A>T LRG_321t1:c.773A>T LRG_321p1:p.Glu258Val LRG_321t2:c.773A>T LRG_321:p.Glu258Val LRG_321t3:c.773A>T LRG_321p3:p.Glu258Val LRG_321t4:c.773A>T LRG_321p4:p.Glu258Val LRG_321t5:c.377A>T LRG_321p5:p.Glu126Val LRG_321t6:c.377A>T LRG_321p6:p.Glu126Val LRG_321t7:c.377A>T LRG_321p7:p.Glu126Val LRG_321t8:c.656A>T LRG_321p8:p.Glu219Val - Protein change
- E258V, E219V, E126V, E99V
- Other names
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- Canonical SPDI
- NC_000017.11:7674189:T:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| TP53 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3367 | 3466 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 12, 2022 | RCV003622548.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Oct 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004405042.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 21445056). 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. This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 258 of the TP53 protein (p.Glu258Val). (less)
|
Comment:
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 21445056). 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. This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 258 of the TP53 protein (p.Glu258Val).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
| A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. | Kotler E | Molecular cell | 2018 | PMID: 29979965 |
| Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. | Xu J | Nature chemical biology | 2011 | PMID: 21445056 |
| Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. | Kato S | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12826609 |
Text-mined citations for this variant ...
HelpRecord last updated Sep 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.