ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.993+1G>A
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.993+1G>A
Variation ID: 528261 Accession: VCV000528261.19
- 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 May 28, 2018 Feb 28, 2024 Jan 7, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000017.11:7673533: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 TCC-PAN2 cancer cell line which has TP53 NM_000546.5:c.993+1G>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 |
- | 3291 |
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
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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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Pathogenic (1) |
criteria provided, single submitter
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Jan 7, 2024 | RCV000633368.9 | |
Likely pathogenic (1) |
no assertion criteria provided
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Dec 1, 2018 | RCV000785467.3 | |
Pathogenic (2) |
criteria provided, single submitter
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Nov 8, 2021 | RCV000786816.7 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2022 | RCV002289929.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2022 | RCV002289928.2 |
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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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: SCV002582439.1
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: SCV002583101.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Likely pathogenic
(Jun 01, 2022)
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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: SCV002688828.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.993+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 8 of the TP53 gene. Designated E9+1G>A, this alteration … (more)
The c.993+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 8 of the TP53 gene. Designated E9+1G>A, this alteration was detected in a patient with a personal history of liposarcoma and pancreatic adenocarcinoma (Villani A et al. Lancet Oncol, 2016 Sep;17:1295-305). This alteration has also been reported in individuals with early-onset breast cancer (Sheng S et al. Int J Cancer, 2020 01;146:487-495; Evans DG et al. J Med Genet, 2022 02;59:115-121). This variant is considered to be rare based on population 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 will weaken the native splice donor site. 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)
Number of individuals with the variant: 1
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Pathogenic
(Nov 08, 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: SCV001812152.3
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts … (more)
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31119730, 10980596, 24590827, 27501770, 26667234, 20522432, 30541742, 34441402, 29510530, 22291954, 32256810, 30720243, 31168460, 32164171) (less)
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Pathogenic
(Jan 07, 2024)
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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: SCV000754590.6
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects a donor splice site in intron 9 of the TP53 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 9 of the TP53 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 10980596, 27501770; Invitae). This variant is also known as E9+1 G>A. ClinVar contains an entry for this variant (Variation ID: 528261). RNA analysis provides insufficient evidence to determine the effect of this variant on TP53 splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Dec 01, 2018)
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no assertion criteria provided
Method: research
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Neoplasm of ovary
Affected status: yes
Allele origin:
somatic
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German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000924039.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
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not provided
(-)
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no classification provided
Method: in vitro
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not provided
Affected status: not applicable
Allele origin:
not applicable
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MutSpliceDB: a database of splice sites variants effects on splicing, NIH
Accession: SCV000925708.2
First in ClinVar: Jul 05, 2019 Last updated: Jul 05, 2019 |
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
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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: SCV000925708.2
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Comment:
Intron inclusion between exons 9 & 10, based on review of RNA-seq in TCC-PAN2 cancer cell line which has TP53 NM_000546.5:c.993+1G>A variant.
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 |
Prevalence and clinical impact of TP53 germline mutations in Chinese women with breast cancer. | Sheng S | International journal of cancer | 2020 | PMID: 31119730 |
Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. | Villani A | The Lancet. Oncology | 2016 | PMID: 27501770 |
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=CA397835645 | - | - | - | - |
Text-mined citations for rs11575997 ...
HelpRecord last updated Mar 05, 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.