This variant is denoted TP53 c.273G>A at the cDNA level and p.Trp91Ter (W91X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. TP53 Trp91Ter has been reported in two individuals with breast cancer diagnosed at age 30 or younger, one of whom also had a family history of early onset breast cancer, pancreatic cancer, and astrocytoma (Lalloo 2003). This variant is considered pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.273G>A (p.Trp91Ter)
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.
(10)
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
10
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.273G>A (p.Trp91Ter)
Variation ID: 233650 Accession: VCV000233650.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7676096 (GRCh38) [ NCBI UCSC ] 17: 7579414 (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 Jul 1, 2016 Oct 20, 2024 Feb 12, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.273G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Trp91Ter nonsense NM_001126112.3:c.273G>A NP_001119584.1:p.Trp91Ter nonsense NM_001126113.3:c.273G>A NP_001119585.1:p.Trp91Ter nonsense NM_001126114.3:c.273G>A NP_001119586.1:p.Trp91Ter nonsense NM_001126118.2:c.156G>A NP_001119590.1:p.Trp52Ter nonsense NM_001276695.3:c.156G>A NP_001263624.1:p.Trp52Ter nonsense NM_001276696.3:c.156G>A NP_001263625.1:p.Trp52Ter nonsense NM_001276760.3:c.156G>A NP_001263689.1:p.Trp52Ter nonsense NM_001276761.3:c.156G>A NP_001263690.1:p.Trp52Ter nonsense NC_000017.11:g.7676096C>T NC_000017.10:g.7579414C>T NG_017013.2:g.16455G>A LRG_321:g.16455G>A LRG_321t1:c.273G>A LRG_321p1:p.Trp91Ter LRG_321t2:c.273G>A LRG_321:p.Trp91Ter - Protein change
- W52*, W91*
- Other names
- -
- Canonical SPDI
- NC_000017.11:7676095:C:T
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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.
- -
- 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 |
3368 | 3467 | |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 14, 2022 | RCV000220815.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 11, 2023 | RCV000233967.8 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 1, 2022 | RCV000657656.17 | |
| Pathogenic (1) |
no assertion criteria provided
|
Dec 1, 2018 | RCV000785284.3 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 12, 2024 | RCV001028065.5 |
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
(Oct 26, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000779404.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
Comment:
This variant is denoted TP53 c.273G>A at the cDNA level and p.Trp91Ter (W91X) at the protein level. The substitution creates a nonsense variant, which changes … (more)
This variant is denoted TP53 c.273G>A at the cDNA level and p.Trp91Ter (W91X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. TP53 Trp91Ter has been reported in two individuals with breast cancer diagnosed at age 30 or younger, one of whom also had a family history of early onset breast cancer, pancreatic cancer, and astrocytoma (Lalloo 2003). This variant is considered pathogenic. (less)
|
|
|
Pathogenic
(Sep 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000285181.7
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 233650). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 12672316, 31060593). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp91*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). (less)
|
|
|
Pathogenic
(Oct 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000278071.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.W91* pathogenic mutation (also known as c.273G>A) located in coding exon 3 of the TP53 gene, results from a G to A substitution at … (more)
The p.W91* pathogenic mutation (also known as c.273G>A) located in coding exon 3 of the TP53 gene, results from a G to A substitution at nucleotide position 273. This changes the amino acid from a tryptophan to a stop codon within coding exon 3. This alteration has been identified in a female patient with breast cancer at the age of 28 and 30, and a clear-cell renal cell carcinoma at age 31 (Lalloo F et al. Eur. J. Cancer 2006 May; 42(8):1143-50). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Dec 15, 2020)
|
criteria provided, single submitter
Method: research
|
Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
germline
|
Department of Pediatrics, Memorial Sloan Kettering Cancer Center
Accession: SCV001478189.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
|
|
|
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: SCV002582619.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
|
|
|
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: SCV002583181.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
|
|
|
Pathogenic
(Feb 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004930654.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
|
|
|
Pathogenic
(Dec 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002822359.14
First in ClinVar: Jan 21, 2023 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
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Pathogenic
(Dec 01, 2018)
|
no assertion criteria provided
Method: research
|
Ovarian neoplasm
Affected status: yes
Allele origin:
somatic
|
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000923852.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
|
|
|
Pathogenic
(Feb 05, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001190843.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 233650). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 12672316, 31060593). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp91*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432).
Comment:
The p.W91* pathogenic mutation (also known as c.273G>A) located in coding exon 3 of the TP53 gene, results from a G to A substitution at nucleotide position 273. This changes the amino acid from a tryptophan to a stop codon within coding exon 3. This alteration has been identified in a female patient with breast cancer at the age of 28 and 30, and a clear-cell renal cell carcinoma at age 31 (Lalloo F et al. Eur. J. Cancer 2006 May; 42(8):1143-50). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
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 denoted TP53 c.273G>A at the cDNA level and p.Trp91Ter (W91X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. TP53 Trp91Ter has been reported in two individuals with breast cancer diagnosed at age 30 or younger, one of whom also had a family history of early onset breast cancer, pancreatic cancer, and astrocytoma (Lalloo 2003). This variant is considered pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 233650). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 12672316, 31060593). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp91*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432).
Comment:
The p.W91* pathogenic mutation (also known as c.273G>A) located in coding exon 3 of the TP53 gene, results from a G to A substitution at nucleotide position 273. This changes the amino acid from a tryptophan to a stop codon within coding exon 3. This alteration has been identified in a female patient with breast cancer at the age of 28 and 30, and a clear-cell renal cell carcinoma at age 31 (Lalloo F et al. Eur. J. Cancer 2006 May; 42(8):1143-50). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Frequency of pathogenic germline variants in BRCA1, BRCA2, PALB2, CHEK2 and TP53 in ductal carcinoma in situ diagnosed in women under the age of 50 years. | Petridis C | Breast cancer research : BCR | 2019 | PMID: 31060593 |
| Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
| 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 |
| BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. | Lalloo F | European journal of cancer (Oxford, England : 1990) | 2006 | PMID: 16644204 |
| Prediction of pathogenic mutations in patients with early-onset breast cancer by family history. | Lalloo F | Lancet (London, England) | 2003 | PMID: 12672316 |
Text-mined citations for rs876660548 ...
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 Nov 10, 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.