ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.524G>T (p.Arg175Leu)
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.524G>T (p.Arg175Leu)
Variation ID: 182963 Accession: VCV000182963.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7675088 (GRCh38) [ NCBI UCSC ] 17: 7578406 (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 Mar 8, 2017 Feb 14, 2024 Aug 16, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.524G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg175Leu missense NM_001126112.3:c.524G>T NP_001119584.1:p.Arg175Leu missense NM_001126113.3:c.524G>T NP_001119585.1:p.Arg175Leu missense NM_001126114.3:c.524G>T NP_001119586.1:p.Arg175Leu missense NM_001126115.2:c.128G>T NP_001119587.1:p.Arg43Leu missense NM_001126116.2:c.128G>T NP_001119588.1:p.Arg43Leu missense NM_001126117.2:c.128G>T NP_001119589.1:p.Arg43Leu missense NM_001126118.2:c.407G>T NP_001119590.1:p.Arg136Leu missense NM_001276695.3:c.407G>T NP_001263624.1:p.Arg136Leu missense NM_001276696.3:c.407G>T NP_001263625.1:p.Arg136Leu missense NM_001276697.3:c.47G>T NP_001263626.1:p.Arg16Leu missense NM_001276698.3:c.47G>T NP_001263627.1:p.Arg16Leu missense NM_001276699.3:c.47G>T NP_001263628.1:p.Arg16Leu missense NM_001276760.3:c.407G>T NP_001263689.1:p.Arg136Leu missense NM_001276761.3:c.407G>T NP_001263690.1:p.Arg136Leu missense NC_000017.11:g.7675088C>A NC_000017.10:g.7578406C>A NG_017013.2:g.17463G>T LRG_321:g.17463G>T LRG_321t1:c.524G>T LRG_321p1:p.Arg175Leu P04637:p.Arg175Leu - Protein change
- R136L, R175L, R43L, R16L
- Other names
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- Canonical SPDI
- NC_000017.11:7675087:C: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
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 |
3211 | 3306 |
Conditions - Germline
Condition
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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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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2022 | RCV000161065.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 16, 2022 | RCV000810785.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2022 | RCV002288703.2 |
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
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
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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 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: SCV002582385.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Likely pathogenic
(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: SCV002583047.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Pathogenic
(Sep 17, 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: SCV000275440.7
First in ClinVar: Feb 24, 2015 Last updated: Nov 29, 2022 |
Comment:
The p.R175L pathogenic mutation (also known as c.524G>T), located in coding exon 4 of the TP53 gene, results from a G to T substitution at … (more)
The p.R175L pathogenic mutation (also known as c.524G>T), located in coding exon 4 of the TP53 gene, results from a G to T substitution at nucleotide position 524. The arginine at codon 175 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been identified in pediatric patients with adrenal cortical carcinoma and in families meeting Chompret criteria for Li-Fraumeni syndrome (West AN et al. Cancer Res. 2006 May; 66(10):5056-62; Ambry internal data). This alteration is located in the DNA binding domain and has shown a partial loss of transactivation activity, and temperature sensitivity in yeast and mammalian cell in vitro assays (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Shiraishi K et al. J. Biol. Chem. 2004 Jan; 279(1):348-55; Dearth LR et al. Carcinogenesis 2007 Feb; 28(2):289-98). More extensive evaluation of this variant showed that it was able to suppress cell growth similar to wild type p53, yet was deficient in apoptotic activity (West AN et al. Cancer Res. 2006 May; 66(10):5056-62). Structural modeling by this same group determined that the leucine substitution may destabilize the native structure, yet not necessarily disrupt the overall conformation of the DNA binding domain. Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Another alteration at this same position, p.R175H, is a well-characterized mutation hotspot known to be associated with classic Li-Fraumeni syndrome (McIntyre et al. J Clin Oncol. 1994. 12(5):925-930; Melhem-Bertrandt et al. Cancer. 2012. 118(4):908-13; Choong et al. Clin Genet. 2012. 82(6):564-8; Varley et al. J Med Genet. 1995. 32:942-945). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 16, 2022)
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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: SCV000951018.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg175 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.Arg175 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8164043, 8825920, 11370630, 21761402, 22006311, 25927356). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 16707427, 16861262). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 182963). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 16707427; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 175 of the TP53 protein (p.Arg175Leu). (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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Identification of a comprehensive spectrum of genetic factors for hereditary breast cancer in a Chinese population by next-generation sequencing. | Yang X | PloS one | 2015 | PMID: 25927356 |
Early onset HER2-positive breast cancer is associated with germline TP53 mutations. | Melhem-Bertrandt A | Cancer | 2012 | PMID: 21761402 |
Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. | Walsh T | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 22006311 |
Inactive full-length p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers. | Dearth LR | Carcinogenesis | 2007 | PMID: 16861262 |
Identification of a novel germ line variant hotspot mutant p53-R175L in pediatric adrenal cortical carcinoma. | West AN | Cancer research | 2006 | PMID: 16707427 |
Isolation of temperature-sensitive p53 mutations from a comprehensive missense mutation library. | Shiraishi K | The Journal of biological chemistry | 2004 | PMID: 14559903 |
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 |
Detection of 11 germline inactivating TP53 mutations and absence of TP63 and HCHK2 mutations in 17 French families with Li-Fraumeni or Li-Fraumeni-like syndrome. | Bougeard G | Journal of medical genetics | 2001 | PMID: 11370630 |
An extended Li-Fraumeni kindred with gastric carcinoma and a codon 175 mutation in TP53. | Varley JM | Journal of medical genetics | 1995 | PMID: 8825920 |
Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. | McIntyre JF | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 1994 | PMID: 8164043 |
Text-mined citations for rs28934578 ...
HelpRecord last updated Feb 14, 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.