ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.1010G>C (p.Arg337Pro)
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.1010G>C (p.Arg337Pro)
Variation ID: 177879 Accession: VCV000177879.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7670699 (GRCh38) [ NCBI UCSC ] 17: 7574017 (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 31, 2015 Feb 14, 2024 Jun 18, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.1010G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg337Pro missense NM_001126112.3:c.1010G>C NP_001119584.1:p.Arg337Pro missense NM_001126113.3:c.*29G>C 3 prime UTR NM_001126114.3:c.*117G>C 3 prime UTR NM_001126115.2:c.614G>C NP_001119587.1:p.Arg205Pro missense NM_001126116.2:c.*117G>C 3 prime UTR NM_001126117.2:c.*29G>C 3 prime UTR NM_001126118.2:c.893G>C NP_001119590.1:p.Arg298Pro missense NM_001276695.3:c.*29G>C 3 prime UTR NM_001276696.3:c.*117G>C 3 prime UTR NM_001276697.3:c.533G>C NP_001263626.1:p.Arg178Pro missense NM_001276698.3:c.*117G>C 3 prime UTR NM_001276699.3:c.*29G>C 3 prime UTR NM_001276760.3:c.893G>C NP_001263689.1:p.Arg298Pro missense NM_001276761.3:c.893G>C NP_001263690.1:p.Arg298Pro missense NC_000017.11:g.7670699C>G NC_000017.10:g.7574017C>G NG_017013.2:g.21852G>C LRG_321:g.21852G>C LRG_321t1:c.1010G>C LRG_321p1:p.Arg337Pro P04637:p.Arg337Pro - Protein change
- R205P, R298P, R337P, R178P
- Other names
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- Canonical SPDI
- NC_000017.11:7670698:C:G
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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
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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 |
3195 | 3292 |
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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Likely pathogenic (2) |
criteria provided, single submitter
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Apr 23, 2021 | RCV000154527.11 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2022 | RCV001187412.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2022 | RCV002288666.2 |
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
(Jan 14, 2021)
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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: SCV001354217.2
First in ClinVar: Jun 22, 2020 Last updated: Jun 19, 2021 |
Comment:
This missense variant replaces arginine with proline at codon 337 in the tetramerization domain of the TP53 protein. Computational prediction suggests that this variant may … (more)
This missense variant replaces arginine with proline at codon 337 in the tetramerization domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein to be defective in tetramer formation (PMID: 19454241, 20978130, 29955864) and transactivation function (PMID: 10519380, 10719737, 12826609, 19454241, 29955864). This variant has been reported in three individuals affected with Li-Fraumeni syndrome (PMID: 2042652, 29955864). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same amino acid position, p.Arg337His, is known to be disease-causing (ClinVar variation ID: 12379), indicating that arginine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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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: SCV002582332.1
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: SCV002582994.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Likely pathogenic
(Apr 28, 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: SCV002610440.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R337P variant (also known as c.1010G>C), located in coding exon 9 of the TP53 gene, results from a G to C substitution at nucleotide … (more)
The p.R337P variant (also known as c.1010G>C), located in coding exon 9 of the TP53 gene, results from a G to C substitution at nucleotide position 1010. The arginine at codon 337 is replaced by proline, an amino acid with dissimilar properties. This alteration was identified in a 5 year old patient with acute lymphoblastic leukemia and adrenocortical carcinoma, as well as several family members with cancer (Karakas Z et al. Pediatr Hematol Oncol, 2010 May;27:297-305). This variant is in the oligomerization domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays, and loss of tetramer formation in studies conducted in human cell lines (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9; Fischer NW et al. J. Natl. Cancer Inst., 2018 12;110:1418-1421). 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
(Apr 23, 2021)
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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: SCV001577877.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg337 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10864200, 16033918, 16494995, 21192060). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect TP53 protein function (PMID: 12826609, 19454241, 29955864). This variant has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 20426520). ClinVar contains an entry for this variant (Variation ID: 177879). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 337 of the TP53 protein (p.Arg337Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. (less)
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Likely pathogenic
(Aug 13, 2009)
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no assertion criteria provided
Method: clinical testing
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Li-Fraumeni syndrome
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000204199.4
First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015 |
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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Association Between the Oligomeric Status of p53 and Clinical Outcomes in Li-Fraumeni Syndrome. | Fischer NW | Journal of the National Cancer Institute | 2018 | PMID: 29955864 |
Li-Fraumeni syndrome in a Turkish family. | Karakas Z | Pediatric hematology and oncology | 2010 | PMID: 20426520 |
Evaluation of transcriptional activity of p53 in individual living mammalian cells. | Imagawa T | Analytical biochemistry | 2009 | PMID: 19454241 |
The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. | Achatz MI | Cancer letters | 2007 | PMID: 16494995 |
Geographical variations in TP53 mutational spectrum in ovarian carcinomas. | Dansonka-Mieszkowska A | Annals of human genetics | 2006 | PMID: 16907706 |
Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation. | Figueiredo BC | Journal of medical genetics | 2006 | PMID: 16033918 |
The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library. | Kawaguchi T | Oncogene | 2005 | PMID: 16007150 |
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 |
p53 status correlates with the differential expression of the DNA mismatch repair protein MSH2 in non-small cell lung carcinoma. | Xinarianos G | International journal of cancer | 2002 | PMID: 12209975 |
P53 germline mutations in childhood cancers and cancer risk for carrier individuals. | Chompret A | British journal of cancer | 2000 | PMID: 10864200 |
Distinct prognostic values of p53 mutations and loss of estrogen receptor and their cumulative effect in primary breast cancers. | Takahashi M | International journal of cancer | 2000 | PMID: 10719737 |
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Text-mined citations for rs121912664 ...
HelpRecord last updated Feb 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.