Nonsense variant predicted to result in protein truncation nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate evidence for loss of growth suppression ability (Giacomelli et al., 2018); This variant is associated with the following publications: (PMID: 16322298, 18555592, 16000567, 12067251, 23117049, 31447099, 20522432, 35486574, 36269546, 35672466, 34779821, 34188747, 35884448, 36167829, 32817165, 31719099, 30224644, 33758026)
ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.949C>T (p.Gln317Ter)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
7 out of 7 submissions contributed to this 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.
7
Somatic
No data submitted for somatic clinical impact
Somatic
Oncogenicity
Help
criteria provided, single submitter. Learn more about how ClinVar calculates review status.
Oncogenic
This classification is based on the single submission received
Help
The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
1
Variant Details
- Identifiers
-
NM_000546.6(TP53):c.949C>T (p.Gln317Ter)
Variation ID: 450344 Accession: VCV000450344.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7673579 (GRCh38) [ NCBI UCSC ] 17: 7576897 (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 Dec 19, 2017 May 3, 2025 Jun 4, 2024 Somatic - Oncogenicity Aug 11, 2024 Mar 11, 2025 Mar 4, 2025 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.949C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Gln317Ter nonsense NM_001126112.3:c.949C>T NP_001119584.1:p.Gln317Ter nonsense NM_001126113.3:c.949C>T NP_001119585.1:p.Gln317Ter nonsense NM_001126114.3:c.949C>T NP_001119586.1:p.Gln317Ter nonsense NM_001126115.2:c.553C>T NP_001119587.1:p.Gln185Ter nonsense NM_001126116.2:c.553C>T NP_001119588.1:p.Gln185Ter nonsense NM_001126117.2:c.553C>T NP_001119589.1:p.Gln185Ter nonsense NM_001126118.2:c.832C>T NP_001119590.1:p.Gln278Ter nonsense NM_001276695.3:c.832C>T NP_001263624.1:p.Gln278Ter nonsense NM_001276696.3:c.832C>T NP_001263625.1:p.Gln278Ter nonsense NM_001276697.3:c.472C>T NP_001263626.1:p.Gln158Ter nonsense NM_001276698.3:c.472C>T NP_001263627.1:p.Gln158Ter nonsense NM_001276699.3:c.472C>T NP_001263628.1:p.Gln158Ter nonsense NM_001276760.3:c.832C>T NP_001263689.1:p.Gln278Ter nonsense NM_001276761.3:c.832C>T NP_001263690.1:p.Gln278Ter nonsense NC_000017.11:g.7673579G>A NC_000017.10:g.7576897G>A NG_017013.2:g.18972C>T LRG_321:g.18972C>T LRG_321t1:c.949C>T LRG_321p1:p.Gln317Ter - Protein change
- Q185*, Q278*, Q317*, Q158*
- Other names
- -
- Canonical SPDI
- NC_000017.11:7673578:G:A
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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 |
3607 | 3708 | |
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
|
Mar 15, 2023 | RCV000520579.3 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 18, 2022 | RCV000583201.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 4, 2024 | RCV000615397.10 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 18, 2022 | RCV002289710.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 15, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000618916.2
First in ClinVar: Dec 19, 2017 Last updated: Mar 26, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; … (more)
Nonsense variant predicted to result in protein truncation nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate evidence for loss of growth suppression ability (Giacomelli et al., 2018); This variant is associated with the following publications: (PMID: 16322298, 18555592, 16000567, 12067251, 23117049, 31447099, 20522432, 35486574, 36269546, 35672466, 34779821, 34188747, 35884448, 36167829, 32817165, 31719099, 30224644, 33758026) (less)
|
|
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Pathogenic
(Mar 16, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000691666.4
First in ClinVar: Feb 19, 2018 Last updated: May 03, 2025 |
Comment:
This variant changes 1 nucleotide in exon 9 of the TP53 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 9 of the TP53 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with early onset bilateral breast cancer (PMID: 33758026; Color Health internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Platform type: NGS
|
|
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Pathogenic
(Mar 13, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731540.3
First in ClinVar: Apr 09, 2018 Last updated: Jul 03, 2020 |
Comment:
The p.Gln317X variant in TP53 has not been previously reported in individuals with Li-Fraumeni syndrome or in large population studies. This nonsense variant leads to … (more)
The p.Gln317X variant in TP53 has not been previously reported in individuals with Li-Fraumeni syndrome or in large population studies. This nonsense variant leads to a premature termination codon at position 317, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TP53 gene is an established disease mechanism in individuals with Li-Fraumeni syndrome. In summary, this variant meets criteria to be classified as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner based on predicted impact to the protein and absence in controls. (less)
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Jun 18, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002582339.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
|
|
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Likely pathogenic
(Jun 18, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002583001.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
|
|
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Pathogenic
(Jan 17, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002686961.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.Q317* pathogenic mutation (also known as c.949C>T), located in coding exon 8 of the TP53 gene, results from a C to T substitution at … (more)
The p.Q317* pathogenic mutation (also known as c.949C>T), located in coding exon 8 of the TP53 gene, results from a C to T substitution at nucleotide position 949. This changes the amino acid from a glutamine to a stop codon within coding exon 8. 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
(Jun 04, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002969083.3
First in ClinVar: Feb 07, 2023 Last updated: Feb 16, 2025 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln317*) in the TP53 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln317*) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 450344). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Comment:
Comment:
This variant changes 1 nucleotide in exon 9 of the TP53 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with early onset bilateral breast cancer (PMID: 33758026; Color Health internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The p.Gln317X variant in TP53 has not been previously reported in individuals with Li-Fraumeni syndrome or in large population studies. This nonsense variant leads to a premature termination codon at position 317, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TP53 gene is an established disease mechanism in individuals with Li-Fraumeni syndrome. In summary, this variant meets criteria to be classified as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner based on predicted impact to the protein and absence in controls.
Comment:
The p.Q317* pathogenic mutation (also known as c.949C>T), located in coding exon 8 of the TP53 gene, results from a C to T substitution at nucleotide position 949. This changes the amino acid from a glutamine to a stop codon within coding exon 8. 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 sequence change creates a premature translational stop signal (p.Gln317*) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 450344). For these reasons, this variant has been classified as Pathogenic.
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:
Nonsense variant predicted to result in protein truncation nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate evidence for loss of growth suppression ability (Giacomelli et al., 2018); This variant is associated with the following publications: (PMID: 16322298, 18555592, 16000567, 12067251, 23117049, 31447099, 20522432, 35486574, 36269546, 35672466, 34779821, 34188747, 35884448, 36167829, 32817165, 31719099, 30224644, 33758026)
Comment:
This variant changes 1 nucleotide in exon 9 of the TP53 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with early onset bilateral breast cancer (PMID: 33758026; Color Health internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The p.Gln317X variant in TP53 has not been previously reported in individuals with Li-Fraumeni syndrome or in large population studies. This nonsense variant leads to a premature termination codon at position 317, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TP53 gene is an established disease mechanism in individuals with Li-Fraumeni syndrome. In summary, this variant meets criteria to be classified as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner based on predicted impact to the protein and absence in controls.
Comment:
The p.Q317* pathogenic mutation (also known as c.949C>T), located in coding exon 8 of the TP53 gene, results from a C to T substitution at nucleotide position 949. This changes the amino acid from a glutamine to a stop codon within coding exon 8. 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 sequence change creates a premature translational stop signal (p.Gln317*) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 450344). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer. | Evans DG | Journal of medical genetics | 2022 | PMID: 33758026 |
| 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 |
Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
|---|---|---|---|---|
|
Oncogenic
criteria provided, single submitter
|
Mar 4, 2025 | RCV004669021.2 |
Submissions - Somatic
|
Oncogenicity
Help
The submitted oncogenicity 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) |
Tumor type
Help
The tumor type 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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
Oncogenic
(Mar 04, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Neoplasm
Affected status: unknown
Allele origin:
somatic
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094378.2
First In ClinVar: Aug 11, 2024 Last updated: Mar 11, 2025 |
|
|
Comment:
Nonsense variant predicted to result in protein truncation nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate evidence for loss of growth suppression ability (Giacomelli et al., 2018); This variant is associated with the following publications: (PMID: 16322298, 18555592, 16000567, 12067251, 23117049, 31447099, 20522432, 35486574, 36269546, 35672466, 34779821, 34188747, 35884448, 36167829, 32817165, 31719099, 30224644, 33758026)
Comment:
This variant changes 1 nucleotide in exon 9 of the TP53 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with early onset bilateral breast cancer (PMID: 33758026; Color Health internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The p.Gln317X variant in TP53 has not been previously reported in individuals with Li-Fraumeni syndrome or in large population studies. This nonsense variant leads to a premature termination codon at position 317, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TP53 gene is an established disease mechanism in individuals with Li-Fraumeni syndrome. In summary, this variant meets criteria to be classified as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner based on predicted impact to the protein and absence in controls.
Comment:
The p.Q317* pathogenic mutation (also known as c.949C>T), located in coding exon 8 of the TP53 gene, results from a C to T substitution at nucleotide position 949. This changes the amino acid from a glutamine to a stop codon within coding exon 8. 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 sequence change creates a premature translational stop signal (p.Gln317*) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 450344). For these reasons, this variant has been classified as Pathogenic.
Citations for somatic classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutant p53 activates hnRNPA2B1-AGAP1-mediated exosome formation to promote esophageal squamous cell carcinoma progression. | Feng R | Cancer letters | 2023 | PMID: 37030635 |
| Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
| Oligomerization of p53 precedes its association with dynein and nuclear accumulation. | Trostel SY | Cell cycle (Georgetown, Tex.) | 2006 | PMID: 16969106 |
| Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. | O'Connor PM | Cancer research | 1997 | PMID: 9331090 |
Text-mined citations for rs764735889 ...
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 May 17, 2025
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.