ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.188C>G (p.Ala63Gly)
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.188C>G (p.Ala63Gly)
Variation ID: 229693 Accession: VCV000229693.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7676181 (GRCh38) [ NCBI UCSC ] 17: 7579499 (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 Apr 20, 2024 Aug 5, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.188C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Ala63Gly missense NM_001126112.3:c.188C>G NP_001119584.1:p.Ala63Gly missense NM_001126113.3:c.188C>G NP_001119585.1:p.Ala63Gly missense NM_001126114.3:c.188C>G NP_001119586.1:p.Ala63Gly missense NM_001126118.2:c.71C>G NP_001119590.1:p.Ala24Gly missense NM_001276695.3:c.71C>G NP_001263624.1:p.Ala24Gly missense NM_001276696.3:c.71C>G NP_001263625.1:p.Ala24Gly missense NM_001276760.3:c.71C>G NP_001263689.1:p.Ala24Gly missense NM_001276761.3:c.71C>G NP_001263690.1:p.Ala24Gly missense NC_000017.11:g.7676181G>C NC_000017.10:g.7579499G>C NG_017013.2:g.16370C>G LRG_321:g.16370C>G LRG_321t1:c.188C>G LRG_321p1:p.Ala63Gly - Protein change
- A24G, A63G
- Other names
- NM_000546.6(TP53):c.188C>G
- Canonical SPDI
- NC_000017.11:7676180:G:C
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00003
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 |
3211 | 3306 |
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Sep 8, 2023 | RCV000216082.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2023 | RCV000465288.11 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Apr 11, 2023 | RCV000587780.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 22, 2016 | RCV000614877.7 | |
Likely benign (1) |
reviewed by expert panel
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Aug 5, 2021 | RCV001723801.3 |
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
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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
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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Likely benign
(Aug 05, 2021)
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reviewed by expert panel
Method: curation
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None
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen TP53 Variant Curation Expert Panel, ClinGen
Accession: SCV001949917.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
Transactivation assays show retained/supertransactivation function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according … (more)
Transactivation assays show retained/supertransactivation function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor). In summary, TP53 c.188C>G (p.Ala63Gly) meets criteria for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BP4, BS2_Supporting. (less)
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Uncertain significance
(Jul 03, 2017)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697433.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.188C>G (p.Ala63Gly) in TP53 gene is a missense variant involves a non-conserved nucleotide and 3/5 in silico tools predict benign outcome. The … (more)
Variant summary: The c.188C>G (p.Ala63Gly) in TP53 gene is a missense variant involves a non-conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant is located within the mSin3a binding site, which is required for stabilization of p53 protein. In the functional study A63G was able to bind to mSin3a and thus prevent p53 from degradation. The variant is absent from control population datasets of ExAC and gnomAD. To our knowledge, the variant has not been reported in affected individuals via published reports, but is cited as VUS by reputable databases/clinical laboratories. Taken together, the variant was classified as VUS, until new information becomes available. (less)
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Uncertain significance
(Nov 22, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712636.2
First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019 |
Comment:
The p.Ala63Gly variant in TP53 has not been previously reported as a germline va riant in individuals with Li-Fraumeni syndrome or in large population studies. … (more)
The p.Ala63Gly variant in TP53 has not been previously reported as a germline va riant in individuals with Li-Fraumeni syndrome or in large population studies. C omputational prediction tools and conservation analysis suggest that the variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala63Gly variant is uncertain. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Dec 13, 2019)
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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: SCV001812994.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this … (more)
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: functional transactivation, as reported by the International Agency for Research on Cancer TP53 database (Kato 2003); This variant is associated with the following publications: (PMID: 30886117, 30224644, 12826609, 15450421, 11024481, 11359905, 14559903) (less)
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Likely benign
(Oct 22, 2020)
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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: SCV000272992.6
First in ClinVar: May 29, 2016 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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Likely benign
(Apr 11, 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: SCV004221346.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
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Uncertain significance
(Oct 23, 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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Invitae
Accession: SCV000545280.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 63 of the TP53 protein (p.Ala63Gly). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 63 of the TP53 protein (p.Ala63Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acute lymphocytic leukemia (PMID: 29300620). ClinVar contains an entry for this variant (Variation ID: 229693). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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
(Sep 08, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000908801.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant is located in the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score … (more)
This variant is located in the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant behaves like wild-type in yeast transactivation studies and human cell growth suppression assays (PMID: 11359905, 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has been identified in 1/31376 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
(Oct 02, 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: SCV004823840.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This variant is located in the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score … (more)
This variant is located in the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant behaves like wild-type in yeast transactivation studies and human cell growth suppression assays (PMID: 11359905, 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has been identified in 1/31376 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: 1
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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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TP53_PROF: a machine learning model to predict impact of missense mutations in TP53. | Ben-Cohen G | Briefings in bioinformatics | 2022 | PMID: 35043155 |
Rates of Actionable Genetic Findings in Individuals with Colorectal Cancer or Polyps Ascertained from a Community Medical Setting. | Gordon AS | American journal of human genetics | 2019 | PMID: 31422818 |
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 |
TP53 Germline Variations Influence the Predisposition and Prognosis of B-Cell Acute Lymphoblastic Leukemia in Children. | Qian M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2018 | PMID: 29300620 |
iFish: predicting the pathogenicity of human nonsynonymous variants using gene-specific/family-specific attributes and classifiers. | Wang M | Scientific reports | 2016 | PMID: 27527004 |
Spontaneous multiple mutations show both proximal spacing consistent with chronocoordinate events and alterations with p53-deficiency. | Hill KA | Mutation research | 2004 | PMID: 15450421 |
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 corepressor mSin3a interacts with the proline-rich domain of p53 and protects p53 from proteasome-mediated degradation. | Zilfou JT | Molecular and cellular biology | 2001 | PMID: 11359905 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/e2b86e34-c2dd-4cfe-97f2-92af3ac253cc | - | - | - | - |
Text-mined citations for rs372201428 ...
HelpRecord last updated Apr 20, 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.