ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.794T>A (p.Leu265Gln)
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
-
NM_000546.6(TP53):c.794T>A (p.Leu265Gln)
Variation ID: 953467 Accession: VCV000953467.12
- 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 16, 2020 May 1, 2024 Apr 24, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000546.6:c.794T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Leu265Gln missense NM_001126112.3:c.794T>A NP_001119584.1:p.Leu265Gln missense NM_001126113.3:c.794T>A NP_001119585.1:p.Leu265Gln missense NM_001126114.3:c.794T>A NP_001119586.1:p.Leu265Gln missense NM_001126115.2:c.398T>A NP_001119587.1:p.Leu133Gln missense NM_001126116.2:c.398T>A NP_001119588.1:p.Leu133Gln missense NM_001126117.2:c.398T>A NP_001119589.1:p.Leu133Gln missense NM_001126118.2:c.677T>A NP_001119590.1:p.Leu226Gln missense NM_001276695.3:c.677T>A NP_001263624.1:p.Leu226Gln missense NM_001276696.3:c.677T>A NP_001263625.1:p.Leu226Gln missense NM_001276697.3:c.317T>A NP_001263626.1:p.Leu106Gln missense NM_001276698.3:c.317T>A NP_001263627.1:p.Leu106Gln missense NM_001276699.3:c.317T>A NP_001263628.1:p.Leu106Gln missense NM_001276760.3:c.677T>A NP_001263689.1:p.Leu226Gln missense NM_001276761.3:c.677T>A NP_001263690.1:p.Leu226Gln missense NC_000017.11:g.7673826A>T NC_000017.10:g.7577144A>T NG_017013.2:g.18725T>A LRG_321:g.18725T>A LRG_321t1:c.794T>A - Protein change
- L106Q, L226Q, L133Q, L265Q
- Other names
- -
- Canonical SPDI
- NC_000017.11:7673825:A:T
-
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 |
3361 | 3460 |
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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 24, 2023 | RCV001225765.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 26, 2018 | RCV002418782.2 |
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
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Oct 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni Syndrome
Affected status: yes
Allele origin:
germline
|
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London
Accession: SCV001429674.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Comment:
Data included in classification: Absent from gnomAD (PM2_sup). Align GVGD: Class 65, Revel: 0.964. Bayes del: 0.601. TP53 ConSurf plot shows this residue to be … (more)
Data included in classification: Absent from gnomAD (PM2_sup). Align GVGD: Class 65, Revel: 0.964. Bayes del: 0.601. TP53 ConSurf plot shows this residue to be 9 on the conservation scale (predicted to be a highly conserved and buried structural residue). (PP3_mod). Kato et al. 2003 (PMID 12826609) Transactivation class: Non functional. Giacomelli et al. 2018 (PMID 30224644) DNE and LOF variant. Fortuno et al, 2018 (PMID: 29775997) Suggested prediction: non-functional. (PS3_strong). Data not included in classification: UK Family 1: Variant identified in a child with adrenocortical cancer (1 proband meeting Chompret criteria). Pathogenic variant that affects same residue with 2* ClinVar status p.Leu265Pro (BLOSUM62: -3 compared to -2 for current variant). (less)
Number of individuals with the variant: 1
Geographic origin: UK
Testing laboratory: UK Molecular Diagnostic Labs
|
|
Pathogenic
(Apr 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001398055.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is … (more)
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 265 of the TP53 protein (p.Leu265Gln). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 34240179; Invitae). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu265 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9067756, 12826609, 16861262, 17606709, 20128691, 20522432, 21343334). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609). 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: 953467). (less)
|
|
Likely pathogenic
(Jul 26, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002677988.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.L265Q variant (also known as c.794T>A), located in coding exon 7 of the TP53 gene, results from a T to A substitution at nucleotide … (more)
The p.L265Q variant (also known as c.794T>A), located in coding exon 7 of the TP53 gene, results from a T to A substitution at nucleotide position 794. The leucine at codon 265 is replaced by glutamine, an amino acid with dissimilar properties. This variant is located in the highly-conserved DNA binding domain of the p53 protein and is reported to have loss of transactivation capacity in yeast based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Another alteration at this same position (p.L265P) was identified in a family with Li Fraumeni Syndrome, and was demonstrated to have reduced DNA binding capability (Cornelis RS et al. Hum. Mutat. 1997;9(2):157-63; Malcikova et al. J. Biol. Chem. 391(2-3):197-205). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91), and is highly 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)
|
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 |
---|---|---|---|---|
Paired Tumor-Normal Sequencing Provides Insights Into the TP53-Related Cancer Spectrum in Patients With Li-Fraumeni Syndrome. | Ceyhan-Birsoy O | Journal of the National Cancer Institute | 2021 | PMID: 34240179 |
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 |
Three germline mutations in the TP53 gene. | Cornelis RS | Human mutation | 1997 | PMID: 9067756 |
Text-mined citations for rs879253942 ...
HelpRecord last updated May 01, 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.