This TP53 c.993+1G>C variant destroys a canonical splicedonor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject tononsense-mediated mRNA decay or to an abnormal protein product. TP53 993+1G>C has been reported as asomatic variant, observed in both ovarian and liver tumors (COSMIC). We consider this variant to be pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.993+1G>C
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000546.6(TP53):c.993+1G>C
Variation ID: 379801 Accession: VCV000379801.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7673534 (GRCh38) [ NCBI UCSC ] 17: 7576852 (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 Mar 8, 2017 May 1, 2024 Jun 18, 2022 - HGVS
- ... more HGVS ... less HGVS
- Protein change
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- Other names
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- Canonical SPDI
- NC_000017.11:7673533:C:G
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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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sequence_variant_affecting_splicing; Sequence Ontology [ SO:1000071]Intron inclusion between exons 9 & 10, based on review of RNA-seq in TCGA-22-5483-01A tumor which has TP53 NM_000546.6:c.993+1G>C 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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
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| 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 (2) |
criteria provided, single submitter
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May 20, 2015 | RCV000429174.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 21, 2020 | RCV000799825.10 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2022 | RCV002289556.2 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2022 | RCV002289557.4 |
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. |
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Pathogenic
(May 20, 2015)
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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: SCV000517237.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
This TP53 c.993+1G>C variant destroys a canonical splicedonor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is … (more)
This TP53 c.993+1G>C variant destroys a canonical splicedonor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject tononsense-mediated mRNA decay or to an abnormal protein product. TP53 993+1G>C has been reported as asomatic variant, observed in both ovarian and liver tumors (COSMIC). We consider this variant to be pathogenic. (less)
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Pathogenic
(Feb 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000939507.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: … (more)
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). Disruption of this splice site has been observed to segregate with Li Fraumeni syndrome in a family (PMID: 10980596). ClinVar contains an entry for this variant (Variation ID: 379801). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 9 of the TP53 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. (less)
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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: SCV002582440.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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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: SCV002583102.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Likely pathogenic
(Nov 11, 2019)
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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: SCV002688829.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.993+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 8 of the TP53 gene. Using the BDGP and … (more)
The c.993+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 8 of the TP53 gene. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish this splice donor site; however direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. (less)
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not provided
(-)
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no classification provided
Method: in vivo
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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: SCV001749007.1
First in ClinVar: Jul 10, 2021 Last updated: Jul 10, 2021 |
Comment on evidence:
Intron inclusion between exons 9 & 10, based on review of RNA-seq in TCGA-22-5483-01A tumor which has TP53 NM_000546.6:c.993+1G>C variant
Method: Based on review of RNA-seq data in sample with variant.
Result:
Intron inclusion between exons 9 & 10
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). Disruption of this splice site has been observed to segregate with Li Fraumeni syndrome in a family (PMID: 10980596). ClinVar contains an entry for this variant (Variation ID: 379801). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 9 of the TP53 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Comment:
The c.993+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 8 of the TP53 gene. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish this splice donor site; however direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
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: SCV001749007.1
|
Comment:
Intron inclusion between exons 9 & 10, based on review of RNA-seq in TCGA-22-5483-01A tumor which has TP53 NM_000546.6:c.993+1G>C variant
|
Comment:
This TP53 c.993+1G>C variant destroys a canonical splicedonor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject tononsense-mediated mRNA decay or to an abnormal protein product. TP53 993+1G>C has been reported as asomatic variant, observed in both ovarian and liver tumors (COSMIC). We consider this variant to be pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). Disruption of this splice site has been observed to segregate with Li Fraumeni syndrome in a family (PMID: 10980596). ClinVar contains an entry for this variant (Variation ID: 379801). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 9 of the TP53 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Comment:
The c.993+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 8 of the TP53 gene. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish this splice donor site; however direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| Novel p53 splice site mutations in three families with Li-Fraumeni syndrome. | Verselis SJ | Oncogene | 2000 | PMID: 10980596 |
| https://brb.nci.nih.gov/cgi-bin/splicing/splicing_evidence.cgi?caid=CA16607519 | - | - | - | - |
Text-mined citations for rs11575997 ...
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.