ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.587G>A (p.Arg196Gln)
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.587G>A (p.Arg196Gln)
Variation ID: 216467 Accession: VCV000216467.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7674944 (GRCh38) [ NCBI UCSC ] 17: 7578262 (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 Dec 19, 2017 Jun 17, 2024 Feb 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.587G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg196Gln missense NM_001126112.3:c.587G>A NP_001119584.1:p.Arg196Gln missense NM_001126113.3:c.587G>A NP_001119585.1:p.Arg196Gln missense NM_001126114.3:c.587G>A NP_001119586.1:p.Arg196Gln missense NM_001126115.2:c.191G>A NP_001119587.1:p.Arg64Gln missense NM_001126116.2:c.191G>A NP_001119588.1:p.Arg64Gln missense NM_001126117.2:c.191G>A NP_001119589.1:p.Arg64Gln missense NM_001126118.2:c.470G>A NP_001119590.1:p.Arg157Gln missense NM_001276695.3:c.470G>A NP_001263624.1:p.Arg157Gln missense NM_001276696.3:c.470G>A NP_001263625.1:p.Arg157Gln missense NM_001276697.3:c.110G>A NP_001263626.1:p.Arg37Gln missense NM_001276698.3:c.110G>A NP_001263627.1:p.Arg37Gln missense NM_001276699.3:c.110G>A NP_001263628.1:p.Arg37Gln missense NM_001276760.3:c.470G>A NP_001263689.1:p.Arg157Gln missense NM_001276761.3:c.470G>A NP_001263690.1:p.Arg157Gln missense NC_000017.11:g.7674944C>T NC_000017.10:g.7578262C>T NG_017013.2:g.17607G>A LRG_321:g.17607G>A LRG_321t1:c.587G>A LRG_321p1:p.Arg196Gln P04637:p.Arg196Gln - Protein change
- R157Q, R196Q, R64Q, R37Q
- Other names
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- Canonical SPDI
- NC_000017.11:7674943: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), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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 |
3366 | 3465 |
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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 17, 2023 | RCV000196467.15 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 14, 2023 | RCV000235733.5 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jun 29, 2023 | RCV000580263.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 16, 2022 | RCV002229122.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 18, 2022 | RCV002288817.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 6, 2024 | RCV004567435.1 |
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
(Jun 06, 2023)
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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: SCV000292696.12
First in ClinVar: Jul 24, 2016 Last updated: Jun 17, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are conflicting: some found partially functional transactivation in yeast-based assays, while other studies do not support a dominant-negative effect (Marutani et al., 1999; Monti et al., 2003; Kato et al., 2003; Kotler et al., 2018; Giacomelli et al., 2018); Observed in the germline of a patient with aplastic anemia, as well as individuals with breast cancer (Keel et al., 2016; Momozawa et al., 2018; Bakhuizen et al., 2019; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 10519380, 12917626, 8156519, 11007040, 26319365, 26314856, 21197471, 28476805, 24665023, 27418648, 29979965, 30224644, 30287823, 33240649, 30607672, 30840781, 15510160, 33471991, 12826609) (less)
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Uncertain significance
(Dec 17, 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: SCV000254632.11
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 196 of the TP53 protein (p.Arg196Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 196 of the TP53 protein (p.Arg196Gln). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with aplastic anemia and/or breast cancer (PMID: 27418648, 30607672; Invitae). ClinVar contains an entry for this variant (Variation ID: 216467). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965). 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
(Apr 16, 2022)
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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: SCV002511555.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: TP53 c.587G>A (p.Arg196Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: TP53 c.587G>A (p.Arg196Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251484 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.587G>A has been reported in the literature as a presumed germline variant in an individual with early-onset breast cancer (example, Bakhuizen_2019), and in an individual with aplastic anemia (example, Keel_2016) and also reported in multiple cancers (COSMIC database). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Kato_2003). The most pronounced variant effect results in 66% of normal activity being characterized as partially-functional based on overall transcription activity (TA) on eight different promoters as measured in yeast assays. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(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: SCV002582369.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Uncertain significance
(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: SCV002582051.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Uncertain significance
(Jul 14, 2023)
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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: SCV004221366.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in affected individuals with breast cancer (PMIDs: 8156519 (1994), 30287823 (2018), and 33471991 (2021)), as well … (more)
In the published literature, this variant has been reported in affected individuals with breast cancer (PMIDs: 8156519 (1994), 30287823 (2018), and 33471991 (2021)), as well as in an individual with early-onset breast cancer that met the Chompret criteria for Li-Fraumeni syndrome (PMID: 30607672 (2019)). Functional studies using human cell lines and yeast based assays demonstrated that this variant does not significantly impact protein function (PMIDs: 10519380 (1999), 12917626 (2003), 29979965 (2016), and 30224644 (2018)). The frequency of this variant in the general population, 0.000004 (1/251484 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Dec 07, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000686754.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 196 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with glutamine at codon 196 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 the mutant protein to be partially functional in yeast transactivation assays (IARC database and PMID: 12826609, 12917626) and functional in human cell proliferation assay (PMID: 29979965). This variant has been reported in two individuals affected with breast cancer (PMID: 30287823, 30607672, 33471991), including a proband with early-onset breast cancer meeting the Chompret criteria for Li-Fraumeni syndrome (PMID: 30607672). This variant has been identified in 1/251484 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Dec 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004823781.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces arginine with glutamine at codon 196 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with glutamine at codon 196 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 the mutant protein to be partially functional in yeast transactivation assays (IARC database and PMID: 12826609, 12917626) and functional in human cell proliferation assay (PMID: 29979965). This variant has been reported in two individuals affected with breast cancer (PMID: 30287823, 30607672, 33471991), including a proband with early-onset breast cancer meeting the Chompret criteria for Li-Fraumeni syndrome (PMID: 30607672). This variant has been identified in 1/251484 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 3
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Uncertain significance
(Jun 29, 2023)
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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: SCV001186682.5
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.R196Q variant (also known as c.587G>A), located in coding exon 5 of the TP53 gene, results from a G to A substitution at nucleotide … (more)
The p.R196Q variant (also known as c.587G>A), located in coding exon 5 of the TP53 gene, results from a G to A substitution at nucleotide position 587. The arginine at codon 196 is replaced by glutamine, an amino acid with highly similar properties. This alteration was identified in a 6-year-old male with aplastic anemia and has also been reported in multiple breast cancer cases (Keel SB et al. Haematologica 2016 11;101(11):1343-1350; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Bakhuizen JJ et al. Fam Cancer, 2019 04;18:273-280; Dorling et al. N Engl J Med, 2021 02;384:428-439). This variant is in the functionally critical DNA binding domain of the TP53 protein, is reported to have partial loss of transactivation capacity, and is predicted to affect all p53 isoforms (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8; 100(14):8424-9). One yeast-based functional assay did not show this alteration to have a dominant negative effect (Marutani M et al. Cancer Res. 1999 Oct;59(19):4765-9). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no 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). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Eldar A et al. Nucleic Acids Res, 2013 Oct;41:8748-59). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Feb 06, 2024)
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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: SCV005054339.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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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 |
TP53 germline mutation testing in early-onset breast cancer: findings from a nationwide cohort. | Bakhuizen JJ | Familial cancer | 2019 | PMID: 30607672 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
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 |
Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients. | Keel SB | Haematologica | 2016 | PMID: 27418648 |
TP53 mutations in human cancer: database reassessment and prospects for the next decade. | Leroy B | Human mutation | 2014 | PMID: 24665023 |
Structural studies of p53 inactivation by DNA-contact mutations and its rescue by suppressor mutations via alternative protein-DNA interactions. | Eldar A | Nucleic acids research | 2013 | PMID: 23863845 |
Characterization of the p53 mutants ability to inhibit p73 beta transactivation using a yeast-based functional assay. | Monti P | Oncogene | 2003 | PMID: 12917626 |
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 |
Dominant-negative mutations of the tumor suppressor p53 relating to early onset of glioblastoma multiforme. | Marutani M | Cancer research | 1999 | PMID: 10519380 |
p53 gene mutations and steroid receptor status in breast cancer. Clinicopathologic correlations and prognostic assessment. | Caleffi M | Cancer | 1994 | PMID: 8156519 |
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Text-mined citations for rs483352697 ...
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.