ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.248C>T (p.Ala83Val)
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(2); Benign(2); Likely benign(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000546.6(TP53):c.248C>T (p.Ala83Val)
Variation ID: 127805 Accession: VCV000127805.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7676121 (GRCh38) [ NCBI UCSC ] 17: 7579439 (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 Jan 7, 2017 May 1, 2024 Jan 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.248C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Ala83Val missense NM_001126112.3:c.248C>T NP_001119584.1:p.Ala83Val missense NM_001126113.3:c.248C>T NP_001119585.1:p.Ala83Val missense NM_001126114.3:c.248C>T NP_001119586.1:p.Ala83Val missense NM_001126118.2:c.131C>T NP_001119590.1:p.Ala44Val missense NM_001276695.3:c.131C>T NP_001263624.1:p.Ala44Val missense NM_001276696.3:c.131C>T NP_001263625.1:p.Ala44Val missense NM_001276760.3:c.131C>T NP_001263689.1:p.Ala44Val missense NM_001276761.3:c.131C>T NP_001263690.1:p.Ala44Val missense NM_001407262.1:c.248C>T NP_001394191.1:p.Ala83Val missense NM_001407263.1:c.131C>T NP_001394192.1:p.Ala44Val missense NM_001407264.1:c.248C>T NP_001394193.1:p.Ala83Val missense NM_001407265.1:c.131C>T NP_001394194.1:p.Ala44Val missense NM_001407266.1:c.248C>T NP_001394195.1:p.Ala83Val missense NM_001407267.1:c.131C>T NP_001394196.1:p.Ala44Val missense NM_001407268.1:c.248C>T NP_001394197.1:p.Ala83Val missense NM_001407269.1:c.131C>T NP_001394198.1:p.Ala44Val missense NM_001407270.1:c.248C>T NP_001394199.1:p.Ala83Val missense NM_001407271.1:c.131C>T NP_001394200.1:p.Ala44Val missense NR_176326.1:n.390C>T non-coding transcript variant NC_000017.11:g.7676121G>A NC_000017.10:g.7579439G>A NG_017013.2:g.16430C>T LRG_321:g.16430C>T LRG_321t1:c.248C>T LRG_321p1:p.Ala83Val LRG_321t2:c.248C>T LRG_321:p.Ala83Val LRG_321t3:c.248C>T LRG_321p3:p.Ala83Val LRG_321t4:c.248C>T LRG_321p4:p.Ala83Val LRG_321t6:c.-906C>T LRG_321t8:c.131C>T LRG_321p8:p.Ala44Val P04637:p.Ala83Val - Protein change
- A44V, A83V
- Other names
- p.A83V:GCG>GTG
- Canonical SPDI
- NC_000017.11:7676120: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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00006
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
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
Help
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
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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Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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May 6, 2021 | RCV000115716.22 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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May 11, 2023 | RCV000679367.16 | |
Benign (1) |
criteria provided, multiple submitters, no conflicts
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Mar 27, 2023 | RCV001796963.15 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 27, 2024 | RCV001082818.15 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 12, 2023 | RCV000409540.11 | |
TP53-related disorder
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Likely benign (1) |
criteria provided, single submitter
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Oct 26, 2020 | RCV003891612.1 |
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 13, 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: SCV000489472.2
First in ClinVar: Jan 07, 2017 Last updated: Dec 24, 2022 |
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Likely benign
(May 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: SCV001134864.4
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
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Likely benign
(Sep 23, 2018)
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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: SCV000187107.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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)
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Benign
(May 20, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000910716.2
First in ClinVar: May 20, 2019 Last updated: Mar 25, 2020 |
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Likely benign
(Jul 26, 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: SCV000149625.14
First in ClinVar: May 17, 2014 Last updated: Jul 18, 2021 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30352134, 10854221, 22923433, 24665023, 24729566, 25986173, 27621404, 27022066, 19509155, 14559903, 24652989) (less)
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Likely benign
(May 06, 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: SCV002530439.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Benign
(Mar 27, 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: SCV003922732.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: TP53 c.248C>T (p.Ala83Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: TP53 c.248C>T (p.Ala83Val) results in a non-conservative amino acid change in 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 0.00014 in 250368 control chromosomes, predominantly at a frequency of 0.00062 within the South Asian subpopulation in the gnomAD database. The observed variant frequency in control chromosomes is approximately 3.5 fold (and ~15.5 fold within the South Asian subpopulation) of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.248C>T in individuals affected with Li-Fraumeni Syndrome has been reported. At least two publications report experimental evidence evaluating an impact on protein function, and their results showed no damaging effect of this variant (e.g., Kato_2003, Giacomelli_2018). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Multiple laboratories reported the variant with conflicting assessments (benign, n = 1; likely benign, n=6; VUS, n = 1). Based on the evidence outlined above, the variant was classified as benign. (less)
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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: SCV004017905.1
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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Likely benign
(Jan 27, 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: SCV000166396.11
First in ClinVar: Jun 15, 2014 Last updated: Feb 20, 2024 |
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Likely benign
(Oct 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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TP53-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000806236.3
First in ClinVar: Sep 14, 2018 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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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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Criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for the Classification of Germline Sequence Variants in Risk Genes for Hereditary Breast and Ovarian Cancer. | Wappenschmidt B | Geburtshilfe und Frauenheilkunde | 2020 | PMID: 32322110 |
Berberine and palmatine inhibit the growth of human rhabdomyosarcoma cells. | Shinji S | Bioscience, biotechnology, and biochemistry | 2020 | PMID: 31462179 |
Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis. | de Andrade KC | Human mutation | 2019 | PMID: 30352134 |
The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes. | McNamara CJ | Blood advances | 2018 | PMID: 30327374 |
Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. | Döhner H | Blood | 2017 | PMID: 27895058 |
The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases. | Stengel A | Leukemia | 2017 | PMID: 27680515 |
TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. | Welch JS | The New England journal of medicine | 2016 | PMID: 27959731 |
TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. | Kadia TM | Cancer | 2016 | PMID: 27463065 |
Genomic Classification and Prognosis in Acute Myeloid Leukemia. | Papaemmanuil E | The New England journal of medicine | 2016 | PMID: 27276561 |
Specific TP53 Mutants Overrepresented in Ovarian Cancer Impact CNV, TP53 Activity, Responses to Nutlin-3a, and Cell Survival. | Mullany LK | Neoplasia (New York, N.Y.) | 2015 | PMID: 26585234 |
TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. | Hou HA | Blood cancer journal | 2015 | PMID: 26230955 |
TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases. | Ok CY | Journal of hematology & oncology | 2015 | PMID: 25952993 |
Functional characterisation of p53 mutants identified in breast cancers with suboptimal responses to anthracyclines or mitomycin. | Berge EO | Biochimica et biophysica acta | 2013 | PMID: 23246812 |
Genome sequencing identifies a basis for everolimus sensitivity. | Iyer G | Science (New York, N.Y.) | 2012 | PMID: 22923433 |
A novel hierarchical prognostic model of AML solely based on molecular mutations. | Grossmann V | Blood | 2012 | PMID: 22915647 |
TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. | Rücker FG | Blood | 2012 | PMID: 22186996 |
TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. | Jädersten M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21519010 |
Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. | Jordan JJ | Molecular cancer research : MCR | 2010 | PMID: 20407015 |
Transcriptional functionality of germ line p53 mutants influences cancer phenotype. | Monti P | Clinical cancer research : an official journal of the American Association for Cancer Research | 2007 | PMID: 17606709 |
Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y). | Ferrone M | Molecular cancer therapeutics | 2006 | PMID: 16818505 |
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 |
A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. | Friedler A | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 11782540 |
INK4a/ARF locus alterations in human non-Hodgkin's lymphomas mainly occur in tumors with wild-type p53 gene. | Pinyol M | The American journal of pathology | 2000 | PMID: 10854221 |
Frequency and diversity of p53 mutations in childhood rhabdomyosarcoma. | Felix CA | Cancer research | 1992 | PMID: 1559227 |
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Text-mined citations for rs201717599 ...
HelpRecord last updated May 27, 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.