ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.772G>A (p.Glu258Lys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000546.6(TP53):c.772G>A (p.Glu258Lys)
Variation ID: 12348 Accession: VCV000012348.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7674191 (GRCh38) [ NCBI UCSC ] 17: 7577509 (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 Apr 4, 2013 May 1, 2024 Oct 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.772G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Glu258Lys missense NM_001126112.3:c.772G>A NP_001119584.1:p.Glu258Lys missense NM_001126113.3:c.772G>A NP_001119585.1:p.Glu258Lys missense NM_001126114.3:c.772G>A NP_001119586.1:p.Glu258Lys missense NM_001126115.2:c.376G>A NP_001119587.1:p.Glu126Lys missense NM_001126116.2:c.376G>A NP_001119588.1:p.Glu126Lys missense NM_001126117.2:c.376G>A NP_001119589.1:p.Glu126Lys missense NM_001126118.2:c.655G>A NP_001119590.1:p.Glu219Lys missense NM_001276695.3:c.655G>A NP_001263624.1:p.Glu219Lys missense NM_001276696.3:c.655G>A NP_001263625.1:p.Glu219Lys missense NM_001276697.3:c.295G>A NP_001263626.1:p.Glu99Lys missense NM_001276698.3:c.295G>A NP_001263627.1:p.Glu99Lys missense NM_001276699.3:c.295G>A NP_001263628.1:p.Glu99Lys missense NM_001276760.3:c.655G>A NP_001263689.1:p.Glu219Lys missense NM_001276761.3:c.655G>A NP_001263690.1:p.Glu219Lys missense NC_000017.11:g.7674191C>T NC_000017.10:g.7577509C>T NG_017013.2:g.18360G>A LRG_321:g.18360G>A LRG_321t1:c.772G>A LRG_321p1:p.Glu258Lys P04637:p.Glu258Lys - Protein change
- E258K, E126K, E219K, E99K
- Other names
- p.E258K:GAA>AAA
- Canonical SPDI
- NC_000017.11:7674190:C:T
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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.
Exome Aggregation Consortium (ExAC) 0.00001
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 | ||
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HI score
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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. |
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TP53 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3365 | 3464 |
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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (2) |
criteria provided, single submitter
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Jun 18, 2022 | RCV000013141.28 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 30, 2021 | RCV000161071.9 | |
Likely pathogenic (1) |
no assertion criteria provided
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Dec 1, 2018 | RCV000785291.4 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2022 | RCV000772122.10 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV000582699.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 13, 2023 | RCV000792895.9 |
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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Pathogenic
(Jan 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000905196.3
First in ClinVar: May 20, 2019 Last updated: Jun 19, 2021 |
Comment:
This missense variant replaces glutamic acid with lysine at codon 258 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this … (more)
This missense variant replaces glutamic acid with lysine at codon 258 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein to be non-functional and exhibit dominant negative effect in transactivation assays (PMID: 12826609, 16492679, 20128691, 21343334) and in cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with Li-Fraumeni syndrome (PMID: 9667734, 10922393, 1978757, 21552135). This variant has been identified in 1/246228 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Likely pathogenic
(Jun 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002582357.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Likely pathogenic
(Jun 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome 1
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002583018.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Pathogenic
(Nov 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000211805.12
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Frebourg 1992, Flaman 1998, Waddell 2001, Kato 2003, Malcikova 2010, Monti … (more)
Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Frebourg 1992, Flaman 1998, Waddell 2001, Kato 2003, Malcikova 2010, Monti 2011, Kotler 2018); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15722483, 11593407, 30720243, 21343334, 17606709, 9364015, 7829527, 1458490, 10719737, 21121188, 7732013, 8252037, 10753186, 11429705, 16492679, 9546439, 9635858, 1631137, 21232794, 8570655, 14559903, 12909720, 8313374, 29625052, 29979965, 21552135, 30840781, 30577483, 33309985, 15510160, 1978757, 20128691) (less)
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Pathogenic
(Oct 13, 2023)
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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: SCV000932221.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 258 of the TP53 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 258 of the TP53 protein (p.Glu258Lys). This variant is present in population databases (rs121912652, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 1978757, 9667734, 10922393, 17606709, 21552135, 29625052, 34529667; Invitae). ClinVar contains an entry for this variant (Variation ID: 12348). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20128691, 21343334, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000602278.3
First in ClinVar: Oct 09, 2016 Last updated: Jan 06, 2024 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in affected individuals with … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in affected individuals with Li-Fraumeni Syndrome, glioblastoma, gastric, brain, and colon cancers (PMIDs: 29625052 (2018), 26425688 (2015), 21552135 (2011), 17606709 (2007), and 1978757 (1990)). Functional studies showed severe deficiencies in DNA binding and transactivation of transcriptional targets (PMIDs: 21343334 (2011) and 20128691 (2010)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Apr 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001189203.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.E258K variant (also known as c.772G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide … (more)
The p.E258K variant (also known as c.772G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 772. The glutamic acid at codon 258 is replaced by lysine, an amino acid with similar properties. The p.E258K variant was first reported in a patient diagnosed with breast cancer at 34 whose tumor demonstrated loss of heterozygosity (LOH), and whose family met classic LFS criteria with a history of early onset sarcomas, and brain tumors (Malkin D et al. Science. 1990 Nov;250:1233-8). This variant has also been reported in a family with a strong history of gastric cancers, and in an individual with glioblastoma multiforme (Masciari S et al. Genet. Med. 2011 Jul;13:651-7; Huang KL et al. Cell, 2018 04;173:355-370.e14). Yeast based functional studies showed this alteration to have loss of transactivation capacity, and dominant negative effect (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9). Studies on this variant conducted in mammalian cells showed inability to suppress growth, and a protein binding profile indicative of a mutant protein conformation (Frebourg T et al. Proc. Natl. Acad. Sci. U.S.A., 1992 Jul;89:6413-7). Additional studies conducted in human cell lines also 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 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. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000692070.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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Likely pathogenic
(Dec 01, 2018)
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no assertion criteria provided
Method: research
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Ovarian neoplasm
Affected status: yes
Allele origin:
somatic
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German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000923859.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
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Pathogenic
(Aug 27, 2020)
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no assertion criteria provided
Method: literature only
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LI-FRAUMENI SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033388.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 29, 2020 |
Comment on evidence:
In a family with the Li-Fraumeni syndrome-1 (151623), Malkin et al. (1990) identified a G-to-A mutation at the first nucleotide of codon 258, resulting in … (more)
In a family with the Li-Fraumeni syndrome-1 (151623), Malkin et al. (1990) identified a G-to-A mutation at the first nucleotide of codon 258, resulting in substitution of lysine for glutamic acid (E258K). (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical and molecular characterization of patients fulfilling Chompret criteria for Li-Fraumeni syndrome in Southern Brazil. | Matzenbacher Bittar C | PloS one | 2021 | PMID: 34529667 |
Prediction of TP53 mutations by p53 immunohistochemistry and their prognostic significance in gastric cancer. | Hwang HJ | Journal of pathology and translational medicine | 2020 | PMID: 32601264 |
A quantitative model to predict pathogenicity of missense variants in the TP53 gene. | Fortuno C | Human mutation | 2019 | PMID: 30840781 |
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 |
Pathogenic Germline Variants in 10,389 Adult Cancers. | Huang KL | Cell | 2018 | PMID: 29625052 |
TP53 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients. | Kandioler D | EBioMedicine | 2015 | PMID: 26425688 |
Gastric cancer in individuals with Li-Fraumeni syndrome. | Masciari S | Genetics in medicine : official journal of the American College of Medical Genetics | 2011 | PMID: 21552135 |
Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. | Malcikova J | Biological chemistry | 2010 | PMID: 20128691 |
Transcriptional functionality of germ line p53 mutants influences cancer phenotype. | Monti P | Clinical cancer research : an official journal of the American Association for Cancer Research | 2007 | PMID: 17606709 |
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 |
Absence of germline p16(INK4a) alterations in p53 wild type Li-Fraumeni syndrome families. | Portwine C | Journal of medical genetics | 2000 | PMID: 10922393 |
Comprehensive mutational scanning of the p53 coding region by two-dimensional gene scanning. | Rines RD | Carcinogenesis | 1998 | PMID: 9667734 |
Germ-line mutations of the p53 tumor suppressor gene in patients with high risk for cancer inactivate the p53 protein. | Frebourg T | Proceedings of the National Academy of Sciences of the United States of America | 1992 | PMID: 1631137 |
Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. | Malkin D | Science (New York, N.Y.) | 1990 | PMID: 1978757 |
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Text-mined citations for rs121912652 ...
HelpRecord last updated Sep 29, 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.