ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.853G>A (p.Glu285Lys)
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.853G>A (p.Glu285Lys)
Variation ID: 420133 Accession: VCV000420133.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7673767 (GRCh38) [ NCBI UCSC ] 17: 7577085 (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 27, 2017 May 1, 2024 Oct 13, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.853G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Glu285Lys missense NM_001126112.3:c.853G>A NP_001119584.1:p.Glu285Lys missense NM_001126113.3:c.853G>A NP_001119585.1:p.Glu285Lys missense NM_001126114.1:c.853G>A NM_001126114.3:c.853G>A NP_001119586.1:p.Glu285Lys missense NM_001126115.2:c.457G>A NP_001119587.1:p.Glu153Lys missense NM_001126116.2:c.457G>A NP_001119588.1:p.Glu153Lys missense NM_001126117.2:c.457G>A NP_001119589.1:p.Glu153Lys missense NM_001126118.2:c.736G>A NP_001119590.1:p.Glu246Lys missense NM_001276695.3:c.736G>A NP_001263624.1:p.Glu246Lys missense NM_001276696.3:c.736G>A NP_001263625.1:p.Glu246Lys missense NM_001276697.3:c.376G>A NP_001263626.1:p.Glu126Lys missense NM_001276698.3:c.376G>A NP_001263627.1:p.Glu126Lys missense NM_001276699.3:c.376G>A NP_001263628.1:p.Glu126Lys missense NM_001276760.3:c.736G>A NP_001263689.1:p.Glu246Lys missense NM_001276761.3:c.736G>A NP_001263690.1:p.Glu246Lys missense NC_000017.11:g.7673767C>T NC_000017.10:g.7577085C>T NG_017013.2:g.18784G>A LRG_321:g.18784G>A LRG_321t1:c.853G>A LRG_321p1:p.Glu285Lys - Protein change
- E153K, E246K, E285K, E126K
- Other names
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- Canonical SPDI
- NC_000017.11:7673766: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.
The Genome Aggregation Database (gnomAD) 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 |
3307 | 3402 |
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
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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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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 3, 2021 | RCV000479542.12 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2022 | RCV000492206.13 | |
drug response (1) |
no assertion criteria provided
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Nov 27, 2017 | RCV000626449.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 13, 2022 | RCV000633365.17 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2022 | RCV002289628.8 |
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
(Jul 26, 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: SCV000568756.4
First in ClinVar: Apr 27, 2017 Last updated: Sep 23, 2021 |
Comment:
Published functional studies demonstrate a damaging effect: reduced or non-functional transactivation, lack of growth suppression activity (Flaman et al., 1998; Oh et al., 2000; Kato … (more)
Published functional studies demonstrate a damaging effect: reduced or non-functional transactivation, lack of growth suppression activity (Flaman et al., 1998; Oh et al., 2000; Kato et al., 2003; Dearth et al., 2007; Kotler et al., 2018); Not observed at significant frequency in large population cohorts (Lek et al., 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: 31105275, 30840781, 29489754, 30720243, 29753700, 15510160, 29979965, 12779080, 22507745, 16337994, 20080630, 7718482, 1459726, 24700732, 17311302, 20190805, 25757734, 19671800, 18348286, 9290701, 10567903, 10987134, 17070499, 9150393, 12792784, 16000567, 9546439, 14559903, 1579447, 17724467, 10761705, 20407015, 16861262, 23624687, 26900293, 24651015, 23894400, 22768918, 1694291) (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: SCV002582343.1
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: SCV002583005.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Likely pathogenic
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002011125.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Pathogenic
(Oct 13, 2022)
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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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Invitae
Accession: SCV000754587.7
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. ClinVar contains an entry for this variant (Variation ID: 420133). This missense change has been observed in individual(s) with breast cancer and sarcoma (PMID: 11051239, 22507745, 23894400). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 285 of the TP53 protein (p.Glu285Lys). Experimental studies have shown that this missense change affects TP53 function (PMID: 9290701, 12826609, 16861262, 17724467). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu285 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 18762572, 25584008). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. (less)
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Pathogenic
(Apr 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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Ambry Genetics
Accession: SCV000581131.6
First in ClinVar: Jul 01, 2017 Last updated: May 01, 2024 |
Comment:
The p.E285K (also known as c.853G>A) pathogenic mutation, located in coding exon 7 of the TP53 gene, results from a G to A substitution at … (more)
The p.E285K (also known as c.853G>A) pathogenic mutation, located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 853. The glutamic acid at codon 285 is replaced by lysine, an amino acid with similar properties. The p.E285K variant has been identified in two Chinese families meeting Chompret critera. Both families have a proband with early onset breast cancers and family history of other TP53-related cancers (Lee DS et al. Breast Cancer Res. 2012; 14(2):R66). In addition, this alteration was identified in an individual with three primaries including breast cancer at 38, a leiomyosarcoma at 45, and thyroid cancer at 46 (Mitchell G et al. PLoS ONE. 2013 ; 8(7):e69026). The p.E285K variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Functional studies have indicated that this is a temperature sensitive alteration that has moderate activity at lower temperatures, and loses transactivation capability at 35 degrees in yeast and 37 degrees in mammalian cells (Grochova D et al. Oncogene 2008 Feb; 27(9):1243-52; Dearth LR et al. Carcinogenesis 2007 Feb; 28(2):289-98; Shiraishi K et al. J. Biol. Chem. 2004 Jan; 279(1):348-55). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). Another variant at the same position, p.E285V, was also identified as a de novo alteration in a child with both choriod plexus carcinoma and adrenocortical carcinoma by 1.5 years of age (Russell-Swetek A et al. J. Med. Genet. 2008 Sep; 45(9):603-6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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drug response
(Nov 27, 2017)
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no assertion criteria provided
Method: clinical testing
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PARP Inhibitor response
Drug used for
Cancer
Affected status: yes
Allele origin:
somatic
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Oxford Haemato-Oncology Service, Oxford University Hospitals NHS Foundation Trust
Accession: SCV000734839.1
First in ClinVar: May 06, 2018 Last updated: May 06, 2018 |
Method: PCR-Free library Preparation on germline and tumour. Data analyzed after Tumour-Normal Substraction.
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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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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 |
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 |
High frequency of germline TP53 mutations in a prospective adult-onset sarcoma cohort. | Mitchell G | PloS one | 2013 | PMID: 23894400 |
Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients. | Lee DS | Breast cancer research : BCR | 2012 | PMID: 22507745 |
Identification of a novel TP53 germline mutation E285V in a rare case of paediatric adrenocortical carcinoma and choroid plexus carcinoma. | Russell-Swetek A | Journal of medical genetics | 2008 | PMID: 18762572 |
Analysis of transactivation capability and conformation of p53 temperature-dependent mutants and their reactivation by amifostine in yeast. | Grochova D | Oncogene | 2008 | PMID: 17724467 |
Inactive full-length p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers. | Dearth LR | Carcinogenesis | 2007 | PMID: 16861262 |
Isolation of temperature-sensitive p53 mutations from a comprehensive missense mutation library. | Shiraishi K | The Journal of biological chemistry | 2004 | PMID: 14559903 |
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 |
Heterogeneity in the clinical phenotype of TP53 mutations in breast cancer patients. | Alsner J | Clinical cancer research : an official journal of the American Association for Cancer Research | 2000 | PMID: 11051239 |
Screening the p53 status of human cell lines using a yeast functional assay. | Jia LQ | Molecular carcinogenesis | 1997 | PMID: 9290701 |
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Text-mined citations for rs112431538 ...
HelpRecord last updated May 19, 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.