ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.1031T>C (p.Leu344Pro)
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.1031T>C (p.Leu344Pro)
Variation ID: 12375 Accession: VCV000012375.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7670678 (GRCh38) [ NCBI UCSC ] 17: 7573996 (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 6, 2017 Apr 20, 2024 Aug 28, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.1031T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Leu344Pro missense NM_000546.5(TP53):c.1031T>C NM_001126112.3:c.1031T>C NP_001119584.1:p.Leu344Pro missense NM_001126113.3:c.*50T>C 3 prime UTR NM_001126114.3:c.*138T>C 3 prime UTR NM_001126115.2:c.635T>C NP_001119587.1:p.Leu212Pro missense NM_001126116.2:c.*138T>C 3 prime UTR NM_001126117.2:c.*50T>C 3 prime UTR NM_001126118.2:c.914T>C NP_001119590.1:p.Leu305Pro missense NM_001276695.3:c.*50T>C 3 prime UTR NM_001276696.3:c.*138T>C 3 prime UTR NM_001276697.3:c.554T>C NP_001263626.1:p.Leu185Pro missense NM_001276698.3:c.*138T>C 3 prime UTR NM_001276699.3:c.*50T>C 3 prime UTR NM_001276760.3:c.914T>C NP_001263689.1:p.Leu305Pro missense NM_001276761.3:c.914T>C NP_001263690.1:p.Leu305Pro missense NC_000017.11:g.7670678A>G NC_000017.10:g.7573996A>G NG_017013.2:g.21873T>C LRG_321:g.21873T>C P04637:p.Leu344Pro - Protein change
- L344P, L212P, L305P, L185P
- Other names
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- Canonical SPDI
- NC_000017.11:7670677:A: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
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 |
3211 | 3306 |
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) |
no assertion criteria provided
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Oct 1, 1999 | RCV000013174.28 | |
Likely pathogenic (1) |
reviewed by expert panel
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Aug 28, 2019 | RCV000991141.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 10, 2015 | RCV002390102.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 13, 2021 | RCV003473083.1 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV003996091.1 |
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
(Aug 28, 2019)
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reviewed by expert panel
Method: curation
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Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen TP53 Variant Curation Expert Panel, ClinGen
Accession: SCV001142539.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
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). Additionally, transactivation assays show a low functioning allele according to Kato, et al. and there is a tetramerization assay demonstrating a mutant protein that only forms dimers (PS3; PMID: 12826609, PMID: 9704930). This variant has been reported in 2 probands meeting classic LI-FRAUMENI SYNDROME criteria (PS4_Moderate; PMID: 8649785, 20522432). In summary, TP53 c.1031T>C; p.Leu344Pro 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, PS3, PS4_Moderate. (less)
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Pathogenic
(Nov 10, 2015)
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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: SCV002699871.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.L344P pathogenic mutation (also known as c.1031T>C), located in coding exon 9 of the TP53 gene, results from a T to C substitution at … (more)
The p.L344P pathogenic mutation (also known as c.1031T>C), located in coding exon 9 of the TP53 gene, results from a T to C substitution at nucleotide position 1031. The leucine at codon 344 is replaced by proline, an amino acid with some similar properties. This alteration occurs at a well-characterized residue involved in the tetramerization of the p53 protein (Mateu and Fersht, EMBO J. 1998 May; 17(10):2748-58). This alteration has been identified in families meeting clinical criteria for Li-Fraumeni syndrome with a tumor spectrum including osteosarcomas, leiomyosarcomas, and early onset breast cancer (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9;Varley J et al., Oncogene 1996 Jun; 12(11):2437-42 ). Evidence from both functional and structural analyses indicate that this alteration is structurally unstable and unable to form tetramers (Ishioka C et al., Oncogene 1995 Apr; 10(8):1485-92; Davison T et al., Oncogene 1998 Aug; 17(5):651-6). Additional functional studies conducted in both yeast and mammalian cells have demonstrated that this alteration produces a protein that cannot activate transcription, is defective in DNA binding, suppression of cell growth, and induction of apoptosis (Monti P et al., Mol. Cancer Res. 2011 Mar; 9(3):271-9. Malcikova Jet al., Biol. Chem. ; 391(2-3):197-205; Lomax M et al., Oncogene 1998 Aug; 17(5):643-9). Based on the available evidence, p.L344P is classified as a pathogenic mutation. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Jun 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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Adrenocortical carcinoma, hereditary
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004204291.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Oct 01, 1999)
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no assertion criteria provided
Method: literature only
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LI-FRAUMENI SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033421.4
First in ClinVar: Apr 04, 2013 Last updated: Jan 06, 2017 |
Comment on evidence:
Varley et al. (1996) described a family with classic Li-Fraumeni syndrome (151623) in which a leu344-to-pro (L344P) mutation was identified in the TP53 gene. Codon … (more)
Varley et al. (1996) described a family with classic Li-Fraumeni syndrome (151623) in which a leu344-to-pro (L344P) mutation was identified in the TP53 gene. Codon 344 is a key residue within the tetramerization domain, and the mutation had profound implications for tetramerization and potentially for DNA binding. This was the first report of a mutation in this residue in either sporadic tumors or in the germline, and it was the first report of a germline mutation within the tetramerization domain. The family did not appear to be remarkable in the spectrum of tumors, and there was loss of the wildtype allele in leiomyosarcoma in the proband. The proband presented at the age of 44 years with a retroperitoneal leiomyosarcoma. Previously he had had leg amputation for osteosarcoma. One brother had died of pancreatic cancer at the age of 49 years, and a second brother had died of osteosarcoma under the age of 40 years. The father had died at age 27 years of esophageal cancer. Many of the family members lived in India. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Adrenocortical carcinoma
Affected status: no
Allele origin:
somatic
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Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University
Accession: SCV004046823.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
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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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Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. | Ruijs MW | Journal of medical genetics | 2010 | PMID: 20522432 |
Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. | Malcikova J | Biological chemistry | 2010 | PMID: 20128691 |
Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors. | Varley JM | American journal of human genetics | 1999 | PMID: 10486318 |
p53 mutants without a functional tetramerisation domain are not oncogenic. | Chène P | Journal of molecular biology | 1999 | PMID: 10064694 |
Characterization of the oligomerization defects of two p53 mutants found in families with Li-Fraumeni and Li-Fraumeni-like syndrome. | Davison TS | Oncogene | 1998 | PMID: 9704931 |
Characterization of p53 oligomerization domain mutations isolated from Li-Fraumeni and Li-Fraumeni like family members. | Lomax ME | Oncogene | 1998 | PMID: 9704930 |
Nine hydrophobic side chains are key determinants of the thermodynamic stability and oligomerization status of tumour suppressor p53 tetramerization domain. | Mateu MG | The EMBO journal | 1998 | PMID: 9582268 |
A previously undescribed mutation within the tetramerisation domain of TP53 in a family with Li-Fraumeni syndrome. | Varley JM | Oncogene | 1996 | PMID: 8649785 |
Mutational analysis of the carboxy-terminal portion of p53 using both yeast and mammalian cell assays in vivo. | Ishioka C | Oncogene | 1995 | PMID: 7731702 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7b4332f9-03a6-43f1-afde-508d91bd92d5 | - | - | - | - |
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Text-mined citations for rs121912662 ...
HelpRecord last updated Apr 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.