This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.839G>C (p.Arg280Thr)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
3 out of 6 submissions contributed to this classification
Help
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.
6
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000546.6(TP53):c.839G>C (p.Arg280Thr)
Variation ID: 12368 Accession: VCV000012368.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7673781 (GRCh38) [ NCBI UCSC ] 17: 7577099 (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 4, 2013 Feb 16, 2025 Aug 27, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.839G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg280Thr missense NM_001126112.3:c.839G>C NP_001119584.1:p.Arg280Thr missense NM_001126113.3:c.839G>C NP_001119585.1:p.Arg280Thr missense NM_001126114.3:c.839G>C NP_001119586.1:p.Arg280Thr missense NM_001126115.2:c.443G>C NP_001119587.1:p.Arg148Thr missense NM_001126116.2:c.443G>C NP_001119588.1:p.Arg148Thr missense NM_001126117.2:c.443G>C NP_001119589.1:p.Arg148Thr missense NM_001126118.2:c.722G>C NP_001119590.1:p.Arg241Thr missense NM_001276695.3:c.722G>C NP_001263624.1:p.Arg241Thr missense NM_001276696.3:c.722G>C NP_001263625.1:p.Arg241Thr missense NM_001276697.3:c.362G>C NP_001263626.1:p.Arg121Thr missense NM_001276698.3:c.362G>C NP_001263627.1:p.Arg121Thr missense NM_001276699.3:c.362G>C NP_001263628.1:p.Arg121Thr missense NM_001276760.3:c.722G>C NP_001263689.1:p.Arg241Thr missense NM_001276761.3:c.722G>C NP_001263690.1:p.Arg241Thr missense NC_000017.11:g.7673781C>G NC_000017.10:g.7577099C>G NG_017013.2:g.18770G>C LRG_321:g.18770G>C LRG_321t1:c.839G>C LRG_321p1:p.Arg280Thr P04637:p.Arg280Thr - Protein change
- R280T, R148T, R241T, R121T
- Other names
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- Canonical SPDI
- NC_000017.11:7673780: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
Help
The frequency of the allele represented by this VCV record.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
3607 | 3708 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Jul 15, 1992 | RCV000013167.5 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 27, 2024 | RCV000198779.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV000423074.4 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV003332081.1 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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Feb 20, 2024 | RCV004018618.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 10, 2021 | RCV002433452.3 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Feb 20, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004932391.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad … (more)
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Pathogenic
(Jun 10, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002677931.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R280T pathogenic mutation (also known as c.839G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at … (more)
The p.R280T pathogenic mutation (also known as c.839G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at nucleotide position 839. The arginine at codon 280 is replaced by threonine, an amino acid with similar properties. This alteration has been reported as a somatic mutation 108 times in various tumors by the IARC TP53 database (Bouaoun L et al. IARC TP53 database [version 20, July 2019]. Hum. Mutat. 2016 Sep;37:865-76). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation and dominant negative activity in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9; Dearth LR et al. Carcinogenesis, 2007 Feb;28:289-98). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient at growth suppression (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 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)
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Likely pathogenic
(Aug 27, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000254639.8
First in ClinVar: Oct 11, 2015 Last updated: Feb 16, 2025 |
Comment:
This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 280 of the TP53 protein (p.Arg280Thr). … (more)
This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 280 of the TP53 protein (p.Arg280Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 25927356, 28135145; internal data). ClinVar contains an entry for this variant (Variation ID: 12368). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 22999923, 29979965, 30224644). 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. (less)
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Pathogenic
(Jul 15, 1992)
N
Not contributing to aggregate classification
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no assertion criteria provided
Method: literature only
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NASOPHARYNGEAL CARCINOMA, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000033414.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Nasopharyngeal carcinoma (607107) occurs with a particularly high frequency in southern China and Southeast Asia. It has been proposed that initiation of nasopharyngeal carcinoma requires … (more)
Nasopharyngeal carcinoma (607107) occurs with a particularly high frequency in southern China and Southeast Asia. It has been proposed that initiation of nasopharyngeal carcinoma requires expression of the Epstein-Barr virus, but that induction of preneoplastic events and maintenance of the tumor-cell phenotype require critical cellular genes. Sun et al. (1992) found a heterozygous G-to-C transversion at codon 280 (exon 8), position 2, of the TP53 gene, predicted to change arginine to threonine (R280T), in a nasopharyngeal carcinoma cell line originating from Guangdong, a province in the People's Republic of China that leads the world in NPC incidence. However, the mutation was found in only 1 of 12 NPC samples from Hunan, another province in the PRC with high NPC incidence, and in none of 10 biopsies from Taiwan. Sun et al. (1992) concluded that alterations in the TP53 gene are not common in NPC. Normal expression of p53 mRNA in NPC cells as well as no loss of heterozygosity or gross structural alteration of the TP53 gene was observed in NPC cell lines and biopsies. (less)
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Likely pathogenic
(-)
N
Not contributing to aggregate classification
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no assertion criteria provided
Method: clinical testing
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Acute Myeloid Leukemia
Affected status: yes
Allele origin:
somatic
|
Ayesha Lab, University of the Punjab
Accession: SCV004024442.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 |
Ethnicity/Population group: South Asian
Geographic origin: Pakistan
|
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Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: research
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Malignant tumor of urinary bladder
Affected status: yes
Allele origin:
somatic
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Laboratory of Urology, Hospital Clinic de Barcelona
Accession: SCV004040609.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
|
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Comment:
Comment:
The p.R280T pathogenic mutation (also known as c.839G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at nucleotide position 839. The arginine at codon 280 is replaced by threonine, an amino acid with similar properties. This alteration has been reported as a somatic mutation 108 times in various tumors by the IARC TP53 database (Bouaoun L et al. IARC TP53 database [version 20, July 2019]. Hum. Mutat. 2016 Sep;37:865-76). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation and dominant negative activity in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9; Dearth LR et al. Carcinogenesis, 2007 Feb;28:289-98). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient at growth suppression (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 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.
Comment:
This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 280 of the TP53 protein (p.Arg280Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 25927356, 28135145; internal data). ClinVar contains an entry for this variant (Variation ID: 12368). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 22999923, 29979965, 30224644). 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.
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. |
Comment:
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Comment:
The p.R280T pathogenic mutation (also known as c.839G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at nucleotide position 839. The arginine at codon 280 is replaced by threonine, an amino acid with similar properties. This alteration has been reported as a somatic mutation 108 times in various tumors by the IARC TP53 database (Bouaoun L et al. IARC TP53 database [version 20, July 2019]. Hum. Mutat. 2016 Sep;37:865-76). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation and dominant negative activity in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9; Dearth LR et al. Carcinogenesis, 2007 Feb;28:289-98). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient at growth suppression (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 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.
Comment:
This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 280 of the TP53 protein (p.Arg280Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 25927356, 28135145; internal data). ClinVar contains an entry for this variant (Variation ID: 12368). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 22999923, 29979965, 30224644). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A quantitative model to predict pathogenicity of missense variants in the TP53 gene. | Fortuno C | Human mutation | 2019 | PMID: 30840781 |
| High prevalence of cancer-associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering. | Soussi T | Human mutation | 2019 | PMID: 30720243 |
| 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 |
| Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
| 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 |
| R280T mutation of p53 gene promotes proliferation of human glioma cells through GSK-3β/PTEN pathway. | Lin C | Neuroscience letters | 2012 | PMID: 22999923 |
| Presence of dominant negative mutation of TP53 is a risk of early recurrence in oral cancer. | Hassan NM | Cancer letters | 2008 | PMID: 18555592 |
| 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 |
| 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 |
| Dominant-negative p53 mutations selected in yeast hit cancer hot spots. | Brachmann RK | Proceedings of the National Academy of Sciences of the United States of America | 1996 | PMID: 8633021 |
| Progression toward tumor cell phenotype is enhanced by overexpression of a mutant p53 tumor-suppressor gene isolated from nasopharyngeal carcinoma. | Sun Y | Proceedings of the National Academy of Sciences of the United States of America | 1993 | PMID: 8464896 |
| Dosage-dependent dominance over wild-type p53 of a mutant p53 isolated from nasopharyngeal carcinoma. | Sun Y | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 1993 | PMID: 8344492 |
| An infrequent point mutation of the p53 gene in human nasopharyngeal carcinoma. | Sun Y | Proceedings of the National Academy of Sciences of the United States of America | 1992 | PMID: 1631151 |
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Text-mined citations for rs121912660 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated May 17, 2025
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.