ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.1025G>C (p.Arg342Pro)
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.1025G>C (p.Arg342Pro)
Variation ID: 215996 Accession: VCV000215996.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7670684 (GRCh38) [ NCBI UCSC ] 17: 7574002 (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 May 26, 2018 Feb 28, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.1025G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg342Pro missense NM_001126112.3:c.1025G>C NP_001119584.1:p.Arg342Pro missense NM_001126113.3:c.*44G>C 3 prime UTR NM_001126114.3:c.*132G>C 3 prime UTR NM_001126115.2:c.629G>C NP_001119587.1:p.Arg210Pro missense NM_001126116.2:c.*132G>C 3 prime UTR NM_001126117.2:c.*44G>C 3 prime UTR NM_001126118.2:c.908G>C NP_001119590.1:p.Arg303Pro missense NM_001276695.3:c.*44G>C 3 prime UTR NM_001276696.3:c.*132G>C 3 prime UTR NM_001276697.3:c.548G>C NP_001263626.1:p.Arg183Pro missense NM_001276698.3:c.*132G>C 3 prime UTR NM_001276699.3:c.*44G>C 3 prime UTR NM_001276760.3:c.908G>C NP_001263689.1:p.Arg303Pro missense NM_001276761.3:c.908G>C NP_001263690.1:p.Arg303Pro missense NC_000017.11:g.7670684C>G NC_000017.10:g.7574002C>G NG_017013.2:g.21867G>C LRG_321:g.21867G>C LRG_321t1:c.1025G>C LRG_321p1:p.Arg342Pro P04637:p.Arg342Pro - Protein change
- R210P, R303P, R342P, R183P
- Other names
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- Canonical SPDI
- NC_000017.11:7670683: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
Help
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
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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Pathogenic (1) |
criteria provided, single submitter
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Jan 30, 2024 | RCV000198319.12 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 12, 2023 | RCV000213216.8 | |
Likely pathogenic (1) |
no assertion criteria provided
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Dec 1, 2018 | RCV000785264.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 4, 2019 | RCV001538204.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2022 | RCV002288808.2 |
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
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
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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 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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GeneKor MSA
Accession: SCV000821782.2
First in ClinVar: Oct 10, 2018 Last updated: Apr 22, 2020 |
Comment:
This missense variant is a single nucleotide substitution resulting in the replacement of amino acid arginine with proline at codon 342 of the TP53 protein. … (more)
This missense variant is a single nucleotide substitution resulting in the replacement of amino acid arginine with proline at codon 342 of the TP53 protein. This variant is not present in population databases (ExAC no frequency). It has been reported in literature in Li-Fraumeni syndrome families (PMID: 25981898) and experimental studies have shown is pathogenic effect through inactivation of the TP53 protein (PMID: 20978130, PMID: 9766574, PMID: 19806023, PMID: 10064694). The mutation database ClinVar contains entries for this variant (Variation ID: 215996). (less)
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Pathogenic
(Nov 04, 2019)
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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: SCV001755819.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Comment:
Published functional studies demonstrate a damaging effect: non-functional transactivation and inability to form tetramers (Kamada 2011, Muscolini 2009, Imawaga 2009, IARC); Not observed in large … (more)
Published functional studies demonstrate a damaging effect: non-functional transactivation and inability to form tetramers (Kamada 2011, Muscolini 2009, Imawaga 2009, IARC); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33138793, 31105275, 31159747, 30840781, 25226867, 25981898, 30720243, 19714490, 9766574, 19454241, 19806023, 20978130, 16007150, 10064694, 29085664, 23973262, 29620582) (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: SCV002582331.1
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: SCV002582993.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Pathogenic
(May 12, 2023)
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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: SCV000273412.8
First in ClinVar: May 29, 2016 Last updated: Jul 08, 2023 |
Comment:
The p.R342P pathogenic mutation (also known as c.1025G>C), located in coding exon 9 of the TP53 gene, results from a G to C substitution at … (more)
The p.R342P pathogenic mutation (also known as c.1025G>C), located in coding exon 9 of the TP53 gene, results from a G to C substitution at nucleotide position 1025. The arginine at codon 342 is replaced by proline, an amino acid with dissimilar properties. This alteration has been reported in multiple families meeting classic LFS criteria (Fiszer-Maliszewska L, Fam. Cancer 2009 ; 8(4):541-6; Etzold A et al., Fam. Cancer 2015 Mar; 14(1):161-5; Kappel S et al. Breast Cancer Res Treat, 2015 Jun;151:671-8). This alteration has also been reported as a de novo finding in a patient with a personal history of rectal cancer diagnosed at age 25 and ovarian angiosarcoma diagnosed at age 35 (Crafton SM et al. Int J Gynecol Pathol, 2019 May;38:258-262). This alteration is located in the tetramerization domain, and renders the protein unable to form tetramers (Kawaguchi T, Oncogene 2005 Oct; 24(46):6976-81). Functional studies have indicated that this variant is deficient in transactivation activity in assays performed in both yeast and mammalian cells (Rollenhagen C, Int. J. Cancer 1998 Oct; 78(3):372-6; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has no dominant negative effect (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is not well 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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Pathogenic
(Jan 30, 2024)
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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: SCV000253700.9
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 342 of the TP53 protein (p.Arg342Pro). … (more)
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 342 of the TP53 protein (p.Arg342Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni syndrome cancers (PMID: 19714490, 25226867, 25981898). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215996). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 9766574, 10064694, 16007150, 19454241, 19806023, 20978130). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Dec 01, 2018)
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no assertion criteria provided
Method: research
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Neoplasm of ovary
Affected status: yes
Allele origin:
somatic
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German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000923832.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
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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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Germline Variants Identified in Patients with Early-onset Renal Cell Carcinoma Referred for Germline Genetic Testing. | Truong H | European urology oncology | 2021 | PMID: 34654685 |
Radiation-associated Angiosarcoma Mimicking Fallopian Tube High-grade Serous Carcinoma in a Woman With De Novo Li-Fraumeni Syndrome. | Crafton SM | International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists | 2019 | PMID: 29620582 |
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 |
TP53 germline mutation may affect response to anticancer treatments: analysis of an intensively treated Li-Fraumeni family. | Kappel S | Breast cancer research and treatment | 2015 | PMID: 25981898 |
Cancer-associated p53 tetramerization domain mutants: quantitative analysis reveals a low threshold for tumor suppressor inactivation. | Kamada R | The Journal of biological chemistry | 2011 | PMID: 20978130 |
Characterization of a new cancer-associated mutant of p53 with a missense mutation (K351N) in the tetramerization domain. | Muscolini M | Cell cycle (Georgetown, Tex.) | 2009 | PMID: 19806023 |
p53 Tetramerization domain mutations: germline R342X and R342P, and somatic R337G identified in pediatric patients with Li-Fraumeni syndrome and a child with adrenocortical carcinoma. | Fiszer-Maliszewska L | Familial cancer | 2009 | PMID: 19714490 |
Evaluation of transcriptional activity of p53 in individual living mammalian cells. | Imagawa T | Analytical biochemistry | 2009 | PMID: 19454241 |
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 mutants without a functional tetramerisation domain are not oncogenic. | Chène P | Journal of molecular biology | 1999 | PMID: 10064694 |
Characterization of p53 mutants identified in human tumors with a missense mutation in the tetramerization domain. | Rollenhagen C | International journal of cancer | 1998 | PMID: 9766574 |
Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. | Cho Y | Science (New York, N.Y.) | 1994 | PMID: 8023157 |
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Text-mined citations for rs375338359 ...
HelpRecord last updated Mar 05, 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.