ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.993G>A (p.Gln331=)
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.993G>A (p.Gln331=)
Variation ID: 428868 Accession: VCV000428868.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7673535 (GRCh38) [ NCBI UCSC ] 17: 7576853 (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 Dec 19, 2017 Feb 14, 2024 Aug 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.993G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Gln331= synonymous NM_001126112.3:c.993G>A NP_001119584.1:p.Gln331= synonymous NM_001126113.3:c.993G>A NP_001119585.1:p.Gln331= synonymous NM_001126114.3:c.993G>A NP_001119586.1:p.Gln331= synonymous NM_001126115.2:c.597G>A NP_001119587.1:p.Gln199= synonymous NM_001126116.2:c.597G>A NP_001119588.1:p.Gln199= synonymous NM_001126117.2:c.597G>A NP_001119589.1:p.Gln199= synonymous NM_001126118.2:c.876G>A NP_001119590.1:p.Gln292= synonymous NM_001276695.3:c.876G>A NP_001263624.1:p.Gln292= synonymous NM_001276696.3:c.876G>A NP_001263625.1:p.Gln292= synonymous NM_001276697.3:c.516G>A NP_001263626.1:p.Gln172= synonymous NM_001276698.3:c.516G>A NP_001263627.1:p.Gln172= synonymous NM_001276699.3:c.516G>A NP_001263628.1:p.Gln172= synonymous NM_001276760.3:c.876G>A NP_001263689.1:p.Gln292= synonymous NM_001276761.3:c.876G>A NP_001263690.1:p.Gln292= synonymous NC_000017.11:g.7673535C>T NC_000017.10:g.7576853C>T NG_017013.2:g.19016G>A LRG_321:g.19016G>A LRG_321t1:c.993G>A LRG_321p1:p.Gln331= - Protein change
- Other names
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- Canonical SPDI
- NC_000017.11:7673534:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- sequence_variant_affecting_splicing Sequence Ontology [SO:1000071]
- Intron inclusion between exons 9 & 10, based on review of RNA-seq in TCGA-MP-A4T9-01A tumor which has TP53 NM_000546.6:c.993G>A variant [submitted by MutSpliceDB: a database of splice sites variants effects on splicing, NIH]
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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
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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
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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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Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2022 | RCV000492456.6 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Feb 22, 2021 | RCV000521745.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 10, 2023 | RCV000685844.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2022 | RCV002289663.2 |
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
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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
(Jun 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002582338.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Likely pathogenic
(Jun 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome 1
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002583000.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Likely pathogenic
(Feb 24, 2021)
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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: SCV000581098.5
First in ClinVar: Jul 01, 2017 Last updated: Nov 29, 2022 |
Comment:
The c.993G>A variant (also known as p.Q331Q) is located in coding exon 8 of the TP53 gene. This variant results from a G to A … (more)
The c.993G>A variant (also known as p.Q331Q) is located in coding exon 8 of the TP53 gene. This variant results from a G to A substitution at nucleotide position 993. This nucleotide substitution does not change the glutamine at amino acid 331. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This variant was detected in a child with adrenocortical carcinoma at age six whose mother was diagnosed with breast cancer at age 37. Sequence analysis of cDNA showed expression of the wild type allele only, indicating that the alteration may lead to unstable mRNA transcript that is subject to nonsense mediated decay (Magnusson S et al. Pediatr Blood Cancer. 2012 Nov;59(5):846-53). The c.933G>A variant has also been reported in a female diagnosed with breast cancer at age 35 (Stoltze U et al. PLoS One. 2018 Jan;13:e0190050). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Feb 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000617733.3
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing; Published functional studies revealed … (more)
Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing; Published functional studies revealed expression of only the wild-type allele, suggesting that the variant resulted in an unstable transcript that was degraded (Magnusson 2012); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 14678961, 30720243, 24665023, 15347601, 17062677, 18798306, 22653678, 29324801, 31081129) (less)
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Pathogenic
(Aug 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000813343.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects codon 331 of the TP53 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 331 of the TP53 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TP53 protein. This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of TP53 related conditions (PMID: 22653678, 29324801, 33674644). ClinVar contains an entry for this variant (Variation ID: 428868). Studies have shown that this variant alters TP53 gene expression (PMID: 22653678). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 26, 2022)
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no assertion criteria provided
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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BRCAlab, Lund University
Accession: SCV002589038.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
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not provided
(-)
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no classification provided
Method: research
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not provided
Affected status: not applicable
Allele origin:
somatic
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MutSpliceDB: a database of splice sites variants effects on splicing, NIH
Accession: SCV002822971.1
First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023 |
Comment on evidence:
Intron inclusion between exons 9 & 10, based on review of RNA-seq in TCGA-MP-A4T9-01A tumor which has TP53 NM_000546.6:c.993G>A variant
Method: Based on review of RNA-seq data in sample with variant.
Result:
Intron inclusion between exons 9 & 10
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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sequence_variant_affecting_splicing
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MutSpliceDB: a database of splice sites variants effects on splicing, NIH
Accession: SCV002822971.1
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Comment:
Intron inclusion between exons 9 & 10, based on review of RNA-seq in TCGA-MP-A4T9-01A tumor which has TP53 NM_000546.6:c.993G>A variant
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Prevalence of germline pathogenic variants in 22 cancer susceptibility genes in Swedish pediatric cancer patients. | von Stedingk K | Scientific reports | 2021 | PMID: 33674644 |
Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark. | Stoltze U | PloS one | 2018 | PMID: 29324801 |
Prevalence of germline TP53 mutations and history of Li-Fraumeni syndrome in families with childhood adrenocortical tumors, choroid plexus tumors, and rhabdomyosarcoma: a population-based survey. | Magnusson S | Pediatric blood & cancer | 2012 | PMID: 22653678 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
https://brb.nci.nih.gov/cgi-bin/splicing/splicing_evidence.cgi?caid=CA10590137 | - | - | - | - |
Text-mined citations for rs11575996 ...
HelpRecord last updated Feb 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.