ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.466C>T (p.Arg156Cys)
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.
Uncertain significance(9); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000546.6(TP53):c.466C>T (p.Arg156Cys)
Variation ID: 127810 Accession: VCV000127810.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7675146 (GRCh38) [ NCBI UCSC ] 17: 7578464 (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 Jun 1, 2016 Feb 14, 2024 Jan 7, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.466C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg156Cys missense NM_001126112.3:c.466C>T NP_001119584.1:p.Arg156Cys missense NM_001126113.3:c.466C>T NP_001119585.1:p.Arg156Cys missense NM_001126114.3:c.466C>T NP_001119586.1:p.Arg156Cys missense NM_001126115.2:c.70C>T NP_001119587.1:p.Arg24Cys missense NM_001126116.2:c.70C>T NP_001119588.1:p.Arg24Cys missense NM_001126117.2:c.70C>T NP_001119589.1:p.Arg24Cys missense NM_001126118.2:c.349C>T NP_001119590.1:p.Arg117Cys missense NM_001276695.3:c.349C>T NP_001263624.1:p.Arg117Cys missense NM_001276696.3:c.349C>T NP_001263625.1:p.Arg117Cys missense NM_001276697.3:c.-12C>T 5 prime UTR NM_001276698.3:c.-12C>T 5 prime UTR NM_001276699.3:c.-12C>T 5 prime UTR NM_001276760.3:c.349C>T NP_001263689.1:p.Arg117Cys missense NM_001276761.3:c.349C>T NP_001263690.1:p.Arg117Cys missense NC_000017.11:g.7675146G>A NC_000017.10:g.7578464G>A NG_017013.2:g.17405C>T LRG_321:g.17405C>T LRG_321t1:c.466C>T LRG_321p1:p.Arg156Cys P04637:p.Arg156Cys - Protein change
- R117C, R156C, R24C
- Other names
- p.R156C:CGC>TGC
- Canonical SPDI
- NC_000017.11:7675145:G: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
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 |
3211 | 3306 |
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. |
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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Aug 18, 2022 | RCV000115721.16 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 24, 2021 | RCV000213051.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 7, 2024 | RCV000232885.13 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 12, 2023 | RCV000409094.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000764146.5 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV002465516.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 5, 2023 | RCV003467058.1 |
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 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Colorectal cancer Hepatocellular carcinoma Glioma susceptibility 1 Li-Fraumeni syndrome 1 Adrenocortical carcinoma, hereditary Bone osteosarcoma Carcinoma of pancreas Choroid plexus papilloma Nasopharyngeal carcinoma Basal cell carcinoma, susceptibility to, 7
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000895131.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely benign
(Jan 27, 2017)
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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: SCV000911117.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Likely benign
(Sep 18, 2020)
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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: SCV000149630.14
First in ClinVar: May 17, 2014 Last updated: Jun 01, 2016 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate retention of growth suppression and apoptotic activities, and partial or wildtype-like transcriptional activation (Kato 2003, Kakudo 2005, Kotler 2018); Observed in individuals with HER2-negative breast cancer (Sun 2017, Sheng 2019); This variant is associated with the following publications: (PMID: 12826609, 15781620, 23200980, 26068095, 28477877, 14559903, 28724667, 29979965, 25348012, 22983585, 28861920, 30871527, 30352134, 30840781, 28251968, 31119730) (less)
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Likely benign
(Aug 18, 2022)
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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: SCV000185652.8
First in ClinVar: Aug 06, 2014 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Jan 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003800821.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
Variant summary: TP53 c.466C>T (p.Arg156Cys) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Three … (more)
Variant summary: TP53 c.466C>T (p.Arg156Cys) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251282 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.466C>T has been reported in the literature in individuals affected with breast cancer (Sun_2017, Sheng_2020, PMID 33471991), but it has also been reported in unaffected controls (PMID 33471991). These report(s) do not provide unequivocal conclusions about association of the variant with disease. The IARC database reports the variant as being partially-functional based on overall transcription activity (TA) on eight different promoters as measured in yeast assays by Kato et al (2003). However, multiple other studies using an array of different assays determined the variant to be functional (Kakudo_2005, Giacomelli_2018, Kotler_2018, Doffe_2021). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and three ClinVar submitters (evaluation after 2014) cite it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002760886.3
First in ClinVar: Dec 17, 2022 Last updated: Aug 18, 2023 |
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Uncertain significance
(Oct 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Adrenocortical carcinoma, hereditary
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004206224.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Feb 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003827834.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Jan 07, 2024)
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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: SCV000285198.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 156 of the TP53 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 156 of the TP53 protein (p.Arg156Cys). This variant is present in population databases (rs563378859, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 127810). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). 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. (less)
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Uncertain significance
(May 03, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002530460.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Uncertain significance
(Feb 25, 2016)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000488318.2
First in ClinVar: Jan 07, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Apr 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004017916.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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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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Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Identification and functional characterization of new missense SNPs in the coding region of the TP53 gene. | Doffe F | Cell death and differentiation | 2021 | PMID: 33257846 |
Prevalence and clinical impact of TP53 germline mutations in Chinese women with breast cancer. | Sheng S | International journal of cancer | 2020 | PMID: 31119730 |
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 |
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. | Sun J | Clinical cancer research : an official journal of the American Association for Cancer Research | 2017 | PMID: 28724667 |
GESPA: classifying nsSNPs to predict disease association. | Khurana JK | BMC bioinformatics | 2015 | PMID: 26206375 |
Benchmarking mutation effect prediction algorithms using functionally validated cancer-related missense mutations. | Martelotto LG | Genome biology | 2014 | PMID: 25348012 |
Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. | Petitjean A | Human mutation | 2007 | PMID: 17311302 |
Lack of correlation between p53-dependent transcriptional activity and the ability to induce apoptosis among 179 mutant p53s. | Kakudo Y | Cancer research | 2005 | PMID: 15781620 |
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 |
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Text-mined citations for rs563378859 ...
HelpRecord last updated Mar 17, 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.