ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.1101-1G>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.1101-1G>A
Variation ID: 231146 Accession: VCV000231146.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7669691 (GRCh38) [ NCBI UCSC ] 17: 7573009 (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 Apr 17, 2017 Feb 20, 2024 Dec 26, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000017.11:7669690: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]
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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 |
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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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Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 14, 2023 | RCV000222547.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 26, 2023 | RCV000466199.6 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Jun 18, 2022 | RCV001252683.6 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Dec 2, 2022 | RCV001535521.4 |
Submissions - Germline
Classification
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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: SCV002582329.1
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: SCV002582991.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Likely pathogenic
(Dec 02, 2022)
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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: SCV003929637.1
First in ClinVar: Jun 10, 2023 Last updated: Jun 10, 2023 |
Comment:
Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is … (more)
Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Identified in an individual meeting Chompret criteria with a personal history of breast cancer and sarcoma and family history of early-onset breast cancer (Prejac et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31105275, 2247074, 15510160, 34452612) (less)
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Likely pathogenic
(Jun 14, 2023)
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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: SCV000274903.8
First in ClinVar: May 29, 2016 Last updated: Jul 08, 2023 |
Comment:
The c.1101-1G>A intronic variant results from a G to A one nucleotide upstream from coding exon 10 of the TP53 gene. This alteration was identified … (more)
The c.1101-1G>A intronic variant results from a G to A one nucleotide upstream from coding exon 10 of the TP53 gene. This alteration was identified in an individual with a personal history of breast cancer and sarcoma (Prejac J et al. World J Surg Oncol, 2021 Aug;19:254). Another alteration at this same splice junction, c.1101-2A>G, was identified in a 2 year old patient with an adrenocortical tumor. RNA analysis from this tumor showed a deletion of the first 10 base pairs of exon 11 (coding exon 10) resulting in a frame shift and a predicted stop codon 82 nucleotides after the wild type termination codon (Pinto EM et al. Fam. Cancer 2011 Mar;10(1):141-6). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. Based on current evidence c.1101-1G>A is interpreted as a likely pathogenic moderate risk allele that may not be associated with classic LFS. Clinical correlation is advised. (less)
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Pathogenic
(Dec 26, 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: SCV000545300.5
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 10 of the TP53 gene. While this variant is not anticipated to result in nonsense … (more)
This sequence change affects an acceptor splice site in intron 10 of the TP53 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. 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: 20967502, 34452612). ClinVar contains an entry for this variant (Variation ID: 231146). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). This variant disrupts the C-terminal region of the TP53 protein important for TP53 regulation and nuclear localization (PMID: 20932800, 26205489). While functional studies have not been performed to directly test the effect of this variant on TP53 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Li-Fraumeni syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Centre for translational and clinical research, University Hospital Centre Zagreb
Accession: SCV001161439.2
First in ClinVar: Aug 16, 2020 Last updated: Sep 08, 2021 |
Comment:
This sequence change affects an acceptor splice site in the last intron (intron 10) of the TP53 gene. It is expected to disrupt mRNA splicing … (more)
This sequence change affects an acceptor splice site in the last intron (intron 10) of the TP53 gene. It is expected to disrupt mRNA splicing and likely results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency) and has not been reported in the literature in individuals with a TP53-related disease. Variant 1bp upstream of this variant is described in patient with pediatric adrenocortical tumor (PMID-20967502). (less)
Sex: female
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not provided
(-)
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no classification provided
Method: phenotyping only
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Not Provided
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749483.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Likely pathogenic and reported on 04-02-2015 by Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the … (more)
Variant interpreted as Likely pathogenic and reported on 04-02-2015 by Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Breast carcinoma (present) , Breast carcinoma (present) , Squamous cell carcinoma (present)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: female
Testing laboratory: Ambry Genetics
Date variant was reported to submitter: 2015-04-02
Testing laboratory interpretation: Likely pathogenic
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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
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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
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A brief description of the result of this method for 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
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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Centre for translational and clinical research, University Hospital Centre Zagreb
Accession: SCV001161439.2
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A first report of a rare TP53 variant associated with Li-Fraumeni syndrome manifesting as invasive breast cancer and malignant solitary fibrous tumor. | Prejac J | World journal of surgical oncology | 2021 | PMID: 34452612 |
Regulation of the p53 response and its relationship to cancer. | Meek DW | The Biochemical journal | 2015 | PMID: 26205489 |
Inherited germline TP53 mutation encodes a protein with an aberrant C-terminal motif in a case of pediatric adrenocortical tumor. | Pinto EM | Familial cancer | 2011 | PMID: 20967502 |
p53 post-translational modification: deregulated in tumorigenesis. | Dai C | Trends in molecular medicine | 2010 | PMID: 20932800 |
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 |
Text-mined citations for rs876658982 ...
HelpRecord last updated Feb 28, 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.