ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.569C>T (p.Pro190Leu)
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.569C>T (p.Pro190Leu)
Variation ID: 418517 Accession: VCV000418517.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7674962 (GRCh38) [ NCBI UCSC ] 17: 7578280 (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 Apr 29, 2017 Feb 20, 2024 Jun 27, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.569C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Pro190Leu missense NM_001126112.3:c.569C>T NP_001119584.1:p.Pro190Leu missense NM_001126113.3:c.569C>T NP_001119585.1:p.Pro190Leu missense NM_001126114.3:c.569C>T NP_001119586.1:p.Pro190Leu missense NM_001126115.2:c.173C>T NP_001119587.1:p.Pro58Leu missense NM_001126116.2:c.173C>T NP_001119588.1:p.Pro58Leu missense NM_001126117.2:c.173C>T NP_001119589.1:p.Pro58Leu missense NM_001126118.2:c.452C>T NP_001119590.1:p.Pro151Leu missense NM_001276695.3:c.452C>T NP_001263624.1:p.Pro151Leu missense NM_001276696.3:c.452C>T NP_001263625.1:p.Pro151Leu missense NM_001276697.3:c.92C>T NP_001263626.1:p.Pro31Leu missense NM_001276698.3:c.92C>T NP_001263627.1:p.Pro31Leu missense NM_001276699.3:c.92C>T NP_001263628.1:p.Pro31Leu missense NM_001276760.3:c.452C>T NP_001263689.1:p.Pro151Leu missense NM_001276761.3:c.452C>T NP_001263690.1:p.Pro151Leu missense NC_000017.11:g.7674962G>A NC_000017.10:g.7578280G>A NG_017013.2:g.17589C>T LRG_321:g.17589C>T LRG_321t1:c.569C>T LRG_321p1:p.Pro190Leu LRG_321t2:c.569C>T - Protein change
- P151L, P190L, P58L, P31L
- Other names
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- Canonical SPDI
- NC_000017.11:7674961: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
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The frequency of the allele represented by this VCV record.
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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
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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 |
3196 | 3291 |
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
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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Pathogenic (1) |
criteria provided, single submitter
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Jun 21, 2023 | RCV000484792.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 9, 2023 | RCV000551566.11 | |
Likely pathogenic (2) |
reviewed by expert panel
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Jun 27, 2022 | RCV001527084.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 21, 2022 | RCV002350050.2 |
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
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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
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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 pathogenic
(Jun 27, 2022)
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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: SCV001737923.2
First in ClinVar: Jun 23, 2021 Last updated: Jul 07, 2022 |
Comment:
This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 … (more)
This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Transactivation assays show a partially functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3_Moderate; PMID: 12826609, 30224644). This variant has been reported in 2 probands meeting Chompret criteria (PS4_Supporting; Invitae, GeneDx/NIH). In summary, TP53 c.569C>T (p.Pro190Leu) meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3_Moderate, PM1, PS3_Moderate, PS4_Supporting. (less)
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Pathogenic
(Jun 21, 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: SCV000565623.4
First in ClinVar: Apr 29, 2017 Last updated: Jul 01, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: loss of growth suppression activity, partially functional transactivation, and a dominant-negative effect (Kato et al., 2003; Jordan et … (more)
Published functional studies demonstrate a damaging effect: loss of growth suppression activity, partially functional transactivation, and a dominant-negative effect (Kato et al., 2003; Jordan et al., 2010; Giacomelli et al., 2018; Kotler et al., 2018); 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; This variant is associated with the following publications: (PMID: 12124823, 15510160, 20407015, 32817165, 34863587, 32658383, 35974385, 30224644, 29979965, 12826609) (less)
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Pathogenic
(Jun 09, 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: SCV000629842.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro190 amino acid residue in TP53. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro190 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 26787237, 28499267). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20407015, 23713777, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 418517). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 17311302, 32658383, 32817165; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 190 of the TP53 protein (p.Pro190Leu). (less)
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Likely pathogenic
(Apr 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002647488.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.P190L variant (also known as c.569C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide … (more)
The p.P190L variant (also known as c.569C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide position 569. The proline at codon 190 is replaced by leucine, an amino acid with similar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TP53-related disease (IARC TP53 database, personal communication). This variant is in the DNA binding domain of the TP53 protein and is reported to have a partial loss of transactivation capacity in two different yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9, Jordan JJ, Mol. Cancer Res. 2010 May; 8(5):701-16). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a 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). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Sep 28, 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: SCV004043214.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 37562436, 35974385, 32658383]. Functional … (more)
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 37562436, 35974385, 32658383]. Functional studies indicate this variant impacts protein function [PMID: 29979965]. (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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Clinical Features of Li-Fraumeni Syndrome in Korea. | Song R | Cancer research and treatment | 2024 | PMID: 37562436 |
Genotype-phenotype associations within the Li-Fraumeni spectrum: a report from the German Registry. | Penkert J | Journal of hematology & oncology | 2022 | PMID: 35974385 |
A pedigree-based prediction model identifies carriers of deleterious de novo mutations in families with Li-Fraumeni syndrome. | Gao F | Genome research | 2020 | PMID: 32817165 |
Rhabdomyosarcoma associated with germline TP53 alteration in children and adolescents: The French experience. | Pondrom M | Pediatric blood & cancer | 2020 | PMID: 32658383 |
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 |
A novel germline TP53 mutation p.Pro190Arg detected in a patient with lung and bilateral breast cancers. | Krześniak M | Advances in medical sciences | 2017 | PMID: 28499267 |
Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol. | Meric-Bernstam F | Annals of oncology : official journal of the European Society for Medical Oncology | 2016 | PMID: 26787237 |
Network effect of Wt-mutant p53 interactions and implications on p53 gene therapy. | Ji X | Current pharmaceutical design | 2014 | PMID: 23713777 |
Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. | Jordan JJ | Molecular cancer research : MCR | 2010 | PMID: 20407015 |
Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. | Petitjean A | Human mutation | 2007 | PMID: 17311302 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/0a1d958f-f7f2-4507-b3b9-11e245172c89 | - | - | - | - |
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Text-mined citations for rs876660825 ...
HelpRecord last updated Feb 28, 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.