ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.1000G>T (p.Gly334Trp)
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.1000G>T (p.Gly334Trp)
Variation ID: 428876 Accession: VCV000428876.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7670709 (GRCh38) [ NCBI UCSC ] 17: 7574027 (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 Jul 1, 2017 Feb 14, 2024 Jun 18, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.1000G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Gly334Trp missense NM_001126112.3:c.1000G>T NP_001119584.1:p.Gly334Trp missense NM_001126113.3:c.*19G>T 3 prime UTR NM_001126114.3:c.*107G>T 3 prime UTR NM_001126115.2:c.604G>T NP_001119587.1:p.Gly202Trp missense NM_001126116.2:c.*107G>T 3 prime UTR NM_001126117.2:c.*19G>T 3 prime UTR NM_001126118.2:c.883G>T NP_001119590.1:p.Gly295Trp missense NM_001276695.3:c.*19G>T 3 prime UTR NM_001276696.3:c.*107G>T 3 prime UTR NM_001276697.3:c.523G>T NP_001263626.1:p.Gly175Trp missense NM_001276698.3:c.*107G>T 3 prime UTR NM_001276699.3:c.*19G>T 3 prime UTR NM_001276760.3:c.883G>T NP_001263689.1:p.Gly295Trp missense NM_001276761.3:c.883G>T NP_001263690.1:p.Gly295Trp missense NC_000017.11:g.7670709C>A NC_000017.10:g.7574027C>A NG_017013.2:g.21842G>T LRG_321:g.21842G>T LRG_321t1:c.1000G>T LRG_321p1:p.Gly334Trp - Protein change
- G202W, G295W, G334W, G175W
- Other names
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- Canonical SPDI
- NC_000017.11:7670708:C: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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
3196 | 3291 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2022 | RCV000492343.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2022 | RCV002289665.2 |
Submissions - Germline
Classification
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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
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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
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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
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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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Likely pathogenic
(Aug 13, 2013)
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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: SCV000581109.4
First in ClinVar: Jul 01, 2017 Last updated: Jun 22, 2020 |
Comment:
​The p.G334W variant (also known as c.1000G>T) is located in coding exon 9 of the TP53 gene. This alteration results from a G to T … (more)
​The p.G334W variant (also known as c.1000G>T) is located in coding exon 9 of the TP53 gene. This alteration results from a G to T substitution at nucleotide position 1000. The glycine at codon 334 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant was detected in one Korean individual's non-small cell lung cancer tumor sample along with another TP53 mutation (Lee et al. J Korean Med Sci. 2010. 25:698-705). The p.G334W alteration is located in the tetramerization domain of the protein which is critical in tumor suppressor activity. Another alteration at codon 334 (p.G334V) showed lower DNA binding activity and transactivation ability in thermal stability studies (Kamada et al. J Biological Chem. 2011 Jan; 286(1):252-258). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. Based on protein sequence alignment, 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 majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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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: SCV002582337.1
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: SCV002582998.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Likely pathogenic
(Oct 05, 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: SCV000912009.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with tryptophan at codon 334 in the tetramerization domain of the TP53 protein and is located 7 nucleotides from the … (more)
This missense variant replaces glycine with tryptophan at codon 334 in the tetramerization domain of the TP53 protein and is located 7 nucleotides from the intron 9 splice acceptor site. This variant alters the conserved glycine residue that connects a short beta-strand (Glu326-Arg333) and an alpha-helix (Arg335-Gly356) of each subunit of the tetramer by facilitating a sharp turn (PMID: 20516128, 26572807). 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 performed in yeast assays and ex vivo cultured cells have shown that this variant has largely neutral effect on the tetramer formation and transactivation function of the TP53 protein (PMID: 12826609, 16007150, 19454241) and does not exhibit dominant negative effect or loss of TP53 function in a human cell growth suppression assay (PMID: 30224644). This variant has been observed to segregate with breast cancer, glioblastoma brain cancer, esophageal and rectal cancer in a family affected with Li-Fraumeni syndrome (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Gly334Arg, has been observed in multiple families affected with Li-Fraumeni syndrome meeting Chompret criteria (PMID: 23580068, 25503501, 25584008, 32675277; ClinVar variation ID: 182969) with reported incomplete penetrance (PMID: 25584008, 32675277), indicating that glycine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic. (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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A Rare TP53 Mutation Predominant in Ashkenazi Jews Confers Risk of Multiple Cancers. | Powers J | Cancer research | 2020 | PMID: 32675277 |
Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
Tetramer formation of tumor suppressor protein p53: Structure, function, and applications. | Kamada R | Biopolymers | 2016 | PMID: 26572807 |
Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children's oncology group study. | Wasserman JD | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25584008 |
Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. | Maxwell KN | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25503501 |
Prevalence of germline TP53 mutations in HER2+ breast cancer patients. | Rath MG | Breast cancer research and treatment | 2013 | PMID: 23580068 |
The tumor suppressor p53: from structures to drug discovery. | Joerger AC | Cold Spring Harbor perspectives in biology | 2010 | PMID: 20516128 |
Evaluation of transcriptional activity of p53 in individual living mammalian cells. | Imagawa T | Analytical biochemistry | 2009 | PMID: 19454241 |
The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library. | Kawaguchi T | Oncogene | 2005 | PMID: 16007150 |
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 |
The effect of polarizing currents on unitary Ia excitatory post-synaptic potentials evoked in spinal motoneurones. | Edwards FR | The Journal of physiology | 1976 | PMID: 182969 |
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Text-mined citations for rs730882028 ...
HelpRecord last updated Feb 14, 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.