ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.245C>T (p.Pro82Leu)
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.245C>T (p.Pro82Leu)
Variation ID: 182946 Accession: VCV000182946.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7676124 (GRCh38) [ NCBI UCSC ] 17: 7579442 (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 Sep 24, 2016 May 1, 2024 Aug 28, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.245C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Pro82Leu missense NM_000546.5(TP53):c.245C>T missense NM_001126112.3:c.245C>T NP_001119584.1:p.Pro82Leu missense NM_001126113.3:c.245C>T NP_001119585.1:p.Pro82Leu missense NM_001126114.3:c.245C>T NP_001119586.1:p.Pro82Leu missense NM_001126118.2:c.128C>T NP_001119590.1:p.Pro43Leu missense NM_001276695.3:c.128C>T NP_001263624.1:p.Pro43Leu missense NM_001276696.3:c.128C>T NP_001263625.1:p.Pro43Leu missense NM_001276760.3:c.128C>T NP_001263689.1:p.Pro43Leu missense NM_001276761.3:c.128C>T NP_001263690.1:p.Pro43Leu missense NM_001407262.1:c.245C>T NP_001394191.1:p.Pro82Leu missense NM_001407263.1:c.128C>T NP_001394192.1:p.Pro43Leu missense NM_001407264.1:c.245C>T NP_001394193.1:p.Pro82Leu missense NM_001407265.1:c.128C>T NP_001394194.1:p.Pro43Leu missense NM_001407266.1:c.245C>T NP_001394195.1:p.Pro82Leu missense NM_001407267.1:c.128C>T NP_001394196.1:p.Pro43Leu missense NM_001407268.1:c.245C>T NP_001394197.1:p.Pro82Leu missense NM_001407269.1:c.128C>T NP_001394198.1:p.Pro43Leu missense NM_001407270.1:c.245C>T NP_001394199.1:p.Pro82Leu missense NM_001407271.1:c.128C>T NP_001394200.1:p.Pro43Leu missense NR_176326.1:n.387C>T non-coding transcript variant NC_000017.11:g.7676124G>A NC_000017.10:g.7579442G>A NG_017013.2:g.16427C>T LRG_321:g.16427C>T LRG_321t1:c.245C>T LRG_321p1:p.Pro82Leu LRG_321t2:c.245C>T LRG_321:p.Pro82Leu LRG_321t3:c.245C>T LRG_321p3:p.Pro82Leu LRG_321t4:c.245C>T LRG_321p4:p.Pro82Leu LRG_321t7:c.-909C>T LRG_321t8:c.128C>T LRG_321p8:p.Pro43Leu P04637:p.Pro82Leu - Protein change
- P43L, P82L
- Other names
- p.P82L:CCG>CTG
- Canonical SPDI
- NC_000017.11:7676123: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) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
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
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
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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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Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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May 20, 2020 | RCV000161047.19 | |
Likely benign (3) |
reviewed by expert panel
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Aug 28, 2019 | RCV000205955.18 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2023 | RCV000213048.14 | |
Benign (1) |
criteria provided, single submitter
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May 28, 2019 | RCV000989726.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 20, 2019 | RCV001250438.9 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001355900.9 | |
Likely benign (1) |
criteria provided, single submitter
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Feb 23, 2020 | RCV003965183.1 |
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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Likely benign
(Aug 28, 2019)
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reviewed by expert panel
Method: curation
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Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen TP53 Variant Curation Expert Panel, ClinGen
Accession: SCV001142533.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
Comment:
This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, transactivation assays show retained function … (more)
This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, transactivation assays show retained 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). In summary, TP53 c.245C>T; p.Pro82Leu meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4 and BS3. (less)
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Likely benign
(Aug 02, 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: SCV000215716.7
First in ClinVar: Mar 24, 2015 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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Likely 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: SCV000911119.2
First in ClinVar: May 20, 2019 Last updated: Jun 19, 2021 |
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Likely benign
(Sep 24, 2018)
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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: SCV000211777.15
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 21343334, 11923604, 17606709, 11948487, 12447671, 21680795, 28202063, 20128691, 21390130, 9114050, 27146902, 27892470, 15964795, 8710380, 16007150, 28861920, … (more)
This variant is associated with the following publications: (PMID: 21343334, 11923604, 17606709, 11948487, 12447671, 21680795, 28202063, 20128691, 21390130, 9114050, 27146902, 27892470, 15964795, 8710380, 16007150, 28861920, 30840781, 33300245) (less)
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Likely benign
(Jan 30, 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: SCV004221349.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
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Uncertain significance
(Dec 11, 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: SCV000259808.8
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 82 of the TP53 protein (p.Pro82Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 82 of the TP53 protein (p.Pro82Leu). This variant is present in population databases (rs534447939, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer and colon cancer (PMID: 8710380, 28202063, 33309985). ClinVar contains an entry for this variant (Variation ID: 182946). 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, 17606709, 20128691, 21343334, 24256616, 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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Likely benign
(Feb 23, 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: SCV004777479.1
First in ClinVar: Mar 16, 2024 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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Likely Benign
(Oct 30, 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: SCV004823828.1
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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Number of individuals with the variant: 5
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Benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Squamous cell carcinoma of the head and neck
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140269.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
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Uncertain significance
(May 20, 2019)
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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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Division of Medical Genetics, University of Washington
Study: CSER_CHARM
Accession: SCV001424812.1 First in ClinVar: Aug 03, 2020 Last updated: Aug 03, 2020 |
Comment:
The c.245C>T variant was identified in three of five women with breast cancer in a late-onset breast cancer family (Sun 1996). The c.245C>T variant has … (more)
The c.245C>T variant was identified in three of five women with breast cancer in a late-onset breast cancer family (Sun 1996). The c.245C>T variant has an allele frequency of 0.00002 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). Thus, it is unknown at this time whether this variant increases cancer risk. (less)
Indication for testing: family history of ovarian cancer, Ashkenazi Jewish ancestry
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550917.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The TP53 p.Pro82Leu variant was not identified in the literature in an affected population. The variant was also identified in dbSNP (ID: rs534447939) as "With … (more)
The TP53 p.Pro82Leu variant was not identified in the literature in an affected population. The variant was also identified in dbSNP (ID: rs534447939) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae; as uncertain significance by GeneDx and Ambry Genetics), Cosmic (9x in skin, soft tissue, salivary gland, large intestine, haematopoietic and lymphoid tissue, upper aerodigestive tract), LOVD 3.0, and the IARC TP53 Database (7x in somatic and 2x in germline count). The variant was not identified in the GeneInsight-COGR database. The variant was identified in control databases in 5 of 246174 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15290 chromosomes (freq: 0.00007), European in 3 of 111654 chromosomes (freq: 0.00003), and South Asian in 1 of 30780 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, and Finnish, populations. The variant showed a DNA binding activity similar to wild type p53 and did not show dominant negative activity (Malcikova 2010, Monti 2011). The p.Pro82 residue is conserved in mammals but not in more distantly related organisms. However, 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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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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Population-based Screening for Hereditary Colorectal Cancer Variants in Japan. | Fujita M | Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association | 2022 | PMID: 33309985 |
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 |
Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants. | Fortuno C | Human mutation | 2021 | PMID: 33300245 |
A quantitative model to predict pathogenicity of missense variants in the TP53 gene. | Fortuno C | Human mutation | 2019 | PMID: 30840781 |
Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history. | de Andrade KC | Human mutation | 2017 | PMID: 28861920 |
Next-generation sequencing in familial breast cancer patients from Lebanon. | Jalkh N | BMC medical genomics | 2017 | PMID: 28202063 |
Identification of new p53 target microRNAs by bioinformatics and functional analysis. | Bisio A | BMC cancer | 2013 | PMID: 24256616 |
Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. | Malcikova J | Biological chemistry | 2010 | PMID: 20128691 |
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 |
Mutations in proline 82 of p53 impair its activation by Pin1 and Chk2 in response to DNA damage. | Berger M | Molecular and cellular biology | 2005 | PMID: 15964795 |
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 novel p53 germline alteration identified in a late onset breast cancer kindred. | Sun XF | Oncogene | 1996 | PMID: 8710380 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/9c16efaa-0151-4cfa-a50b-acebbb823912 | - | - | - | - |
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Text-mined citations for rs534447939 ...
HelpRecord last updated May 08, 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.