This pathogenic variant is denoted TP53 c.794T>C at the cDNA level, p.Leu265Pro (L265P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). This variant was observed in at least two families with classic Li-Fraumeni syndrome (Cornelis 1997, Ruijs 2010). Several yeast based functional assays have demonstrated that this mutation severely impacts p53 function and stability (Brachmann 1996, Dearth 2007, Monti 2007, Monti 2011). In addition, this mutation conferred reduced DNA binding activity and expression of downstream target genes in an in vitro functional assay (Malcikova 2010). This variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Leu265Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Leu265Pro occurs at a position that is conserved across species and is located in the DNA binding domain and region of interaction with HIPK1, ZNF385A, AXIN1 and E4F1 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider this variant to be pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.794T>C (p.Leu265Pro)
Germline
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.
(8)
Help
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.
Pathogenic/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000546.6(TP53):c.794T>C (p.Leu265Pro)
Variation ID: 245777 Accession: VCV000245777.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p13.1 17: 7673826 (GRCh38) [ NCBI UCSC ] 17: 7577144 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jul 25, 2016 May 1, 2024 Aug 1, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.794T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Leu265Pro missense NM_001126112.3:c.794T>C NP_001119584.1:p.Leu265Pro missense NM_001126113.3:c.794T>C NP_001119585.1:p.Leu265Pro missense NM_001126114.3:c.794T>C NP_001119586.1:p.Leu265Pro missense NM_001126115.2:c.398T>C NP_001119587.1:p.Leu133Pro missense NM_001126116.2:c.398T>C NP_001119588.1:p.Leu133Pro missense NM_001126117.2:c.398T>C NP_001119589.1:p.Leu133Pro missense NM_001126118.2:c.677T>C NP_001119590.1:p.Leu226Pro missense NM_001276695.3:c.677T>C NP_001263624.1:p.Leu226Pro missense NM_001276696.3:c.677T>C NP_001263625.1:p.Leu226Pro missense NM_001276697.3:c.317T>C NP_001263626.1:p.Leu106Pro missense NM_001276698.3:c.317T>C NP_001263627.1:p.Leu106Pro missense NM_001276699.3:c.317T>C NP_001263628.1:p.Leu106Pro missense NM_001276760.3:c.677T>C NP_001263689.1:p.Leu226Pro missense NM_001276761.3:c.677T>C NP_001263690.1:p.Leu226Pro missense NC_000017.11:g.7673826A>G NC_000017.10:g.7577144A>G NG_017013.2:g.18725T>C LRG_321:g.18725T>C LRG_321t1:c.794T>C LRG_321p1:p.Leu265Pro P04637:p.Leu265Pro - Protein change
- L133P, L226P, L265P, L106P
- Other names
- -
- Canonical SPDI
- NC_000017.11:7673825:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| TP53 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3367 | 3466 | |
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) |
criteria provided, single submitter
|
May 12, 2015 | RCV000235981.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 1, 2023 | RCV000554509.8 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 8, 2022 | RCV000564617.8 | |
| Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 11, 2023 | RCV000662855.5 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 1, 2020 | RCV001257518.3 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 12, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000292887.9
First in ClinVar: Jul 25, 2016 Last updated: Jul 25, 2016 |
Comment:
This pathogenic variant is denoted TP53 c.794T>C at the cDNA level, p.Leu265Pro (L265P) at the protein level, and results in the change of a Leucine … (more)
This pathogenic variant is denoted TP53 c.794T>C at the cDNA level, p.Leu265Pro (L265P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). This variant was observed in at least two families with classic Li-Fraumeni syndrome (Cornelis 1997, Ruijs 2010). Several yeast based functional assays have demonstrated that this mutation severely impacts p53 function and stability (Brachmann 1996, Dearth 2007, Monti 2007, Monti 2011). In addition, this mutation conferred reduced DNA binding activity and expression of downstream target genes in an in vitro functional assay (Malcikova 2010). This variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Leu265Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Leu265Pro occurs at a position that is conserved across species and is located in the DNA binding domain and region of interaction with HIPK1, ZNF385A, AXIN1 and E4F1 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider this variant to be pathogenic. (less)
|
|
|
Pathogenic
(Aug 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000629871.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 265 of the TP53 protein (p.Leu265Pro). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 265 of the TP53 protein (p.Leu265Pro). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16861262, 17606709, 20128691, 21343334). 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. ClinVar contains an entry for this variant (Variation ID: 245777). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 9067756, 20522432). It has also been observed to segregate with disease in related individuals. (less)
|
|
|
Likely pathogenic
(Nov 10, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000785730.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
|
|
|
Likely pathogenic
(Jun 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002582356.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
|
|
|
Likely pathogenic
(Jun 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002583017.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
|
|
|
Likely pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004017893.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9067756, 20522432]. This variant … (more)
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9067756, 20522432]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
|
|
|
Pathogenic
(Nov 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000672371.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.L265P pathogenic mutation (also known as c.794T>C), located in coding exon 7 of the TP53 gene, results from a T to C substitution at … (more)
The p.L265P pathogenic mutation (also known as c.794T>C), located in coding exon 7 of the TP53 gene, results from a T to C substitution at nucleotide position 794. The leucine at codon 265 is replaced by proline, an amino acid with similar properties. This alteration has been reported in multiple individuals in families meeting both classic Li-Fraumeni syndrome (LFS) criteria and Chompret criteria (Cornelis RS et al, Hum. Mutat. 1997; 9(2):157-63; Ruijs MW et al. J. Med. Genet. 2010 Jun;47(6):421-8; IARC TP53 database). In a study of TP53 genotype-phenotype associations, this variant was classified as a severe deficiency allele based on in vitro luciferase assays (Monti P et al, Mol Cancer Res 2011. 9:271-279). The authors observed that severe deficiency alleles are associated with more severe clinical features than alleles classified as partial deficiency. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity, dominant negative effect and predicted to affect several p53 isoforms in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). 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)
|
|
|
Pathogenic
(Sep 01, 2020)
|
no assertion criteria provided
Method: provider interpretation
|
Rhabdomyosarcoma
Affected status: yes
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434344.1
First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020 |
|
Comment:
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 265 of the TP53 protein (p.Leu265Pro). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16861262, 17606709, 20128691, 21343334). 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. ClinVar contains an entry for this variant (Variation ID: 245777). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 9067756, 20522432). It has also been observed to segregate with disease in related individuals.
Comment:
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9067756, 20522432]. This variant is expected to disrupt protein structure [Myriad internal data].
Comment:
The p.L265P pathogenic mutation (also known as c.794T>C), located in coding exon 7 of the TP53 gene, results from a T to C substitution at nucleotide position 794. The leucine at codon 265 is replaced by proline, an amino acid with similar properties. This alteration has been reported in multiple individuals in families meeting both classic Li-Fraumeni syndrome (LFS) criteria and Chompret criteria (Cornelis RS et al, Hum. Mutat. 1997; 9(2):157-63; Ruijs MW et al. J. Med. Genet. 2010 Jun;47(6):421-8; IARC TP53 database). In a study of TP53 genotype-phenotype associations, this variant was classified as a severe deficiency allele based on in vitro luciferase assays (Monti P et al, Mol Cancer Res 2011. 9:271-279). The authors observed that severe deficiency alleles are associated with more severe clinical features than alleles classified as partial deficiency. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity, dominant negative effect and predicted to affect several p53 isoforms in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). 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.
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 pathogenic variant is denoted TP53 c.794T>C at the cDNA level, p.Leu265Pro (L265P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). This variant was observed in at least two families with classic Li-Fraumeni syndrome (Cornelis 1997, Ruijs 2010). Several yeast based functional assays have demonstrated that this mutation severely impacts p53 function and stability (Brachmann 1996, Dearth 2007, Monti 2007, Monti 2011). In addition, this mutation conferred reduced DNA binding activity and expression of downstream target genes in an in vitro functional assay (Malcikova 2010). This variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Leu265Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Leu265Pro occurs at a position that is conserved across species and is located in the DNA binding domain and region of interaction with HIPK1, ZNF385A, AXIN1 and E4F1 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider this variant to be pathogenic.
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 265 of the TP53 protein (p.Leu265Pro). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16861262, 17606709, 20128691, 21343334). 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. ClinVar contains an entry for this variant (Variation ID: 245777). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 9067756, 20522432). It has also been observed to segregate with disease in related individuals.
Comment:
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9067756, 20522432]. This variant is expected to disrupt protein structure [Myriad internal data].
Comment:
The p.L265P pathogenic mutation (also known as c.794T>C), located in coding exon 7 of the TP53 gene, results from a T to C substitution at nucleotide position 794. The leucine at codon 265 is replaced by proline, an amino acid with similar properties. This alteration has been reported in multiple individuals in families meeting both classic Li-Fraumeni syndrome (LFS) criteria and Chompret criteria (Cornelis RS et al, Hum. Mutat. 1997; 9(2):157-63; Ruijs MW et al. J. Med. Genet. 2010 Jun;47(6):421-8; IARC TP53 database). In a study of TP53 genotype-phenotype associations, this variant was classified as a severe deficiency allele based on in vitro luciferase assays (Monti P et al, Mol Cancer Res 2011. 9:271-279). The authors observed that severe deficiency alleles are associated with more severe clinical features than alleles classified as partial deficiency. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity, dominant negative effect and predicted to affect several p53 isoforms in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group. | Li H | Journal of the National Cancer Institute | 2021 | PMID: 33372952 |
| 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 |
| 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 |
| Transcriptional functionality of germ line p53 mutants influences cancer phenotype. | Monti P | Clinical cancer research : an official journal of the American Association for Cancer Research | 2007 | PMID: 17606709 |
| 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 |
| High frequency in esophageal cancers of p53 alterations inactivating the regulation of genes involved in cell cycle and apoptosis. | Robert V | Carcinogenesis | 2000 | PMID: 10753186 |
| Three germline mutations in the TP53 gene. | Cornelis RS | Human mutation | 1997 | PMID: 9067756 |
| 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 |
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Text-mined citations for rs879253942 ...
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 Sep 29, 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.