ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.1101-2A>G
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
-
NM_000546.6(TP53):c.1101-2A>G
Variation ID: 141332 Accession: VCV000141332.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p13.1 17: 7669692 (GRCh38) [ NCBI UCSC ] 17: 7573010 (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 Mar 8, 2017 Feb 20, 2024 Jan 16, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
- -
- Canonical SPDI
- NC_000017.11:7669691:T:C
-
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 10 & 11, based on review of RNA-seq in TCGA-G2-A2EL-01A tumor which has TP53 NM_000546.6:c.1101-2A>G variant [submitted by MutSpliceDB: a database of splice sites variants effects on splicing, NIH]
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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 |
3211 | 3306 |
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. |
---|---|---|---|---|
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 30, 2023 | RCV000129814.11 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 16, 2024 | RCV000206779.11 | |
Likely pathogenic (2) |
criteria provided, single submitter
|
Jul 27, 2023 | RCV000213070.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 18, 2022 | RCV002288631.2 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Jun 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002582330.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
|
|
Likely pathogenic
(Jun 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002582992.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
|
|
Likely pathogenic
(Aug 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000184628.9
First in ClinVar: Aug 06, 2014 Last updated: Oct 28, 2023 |
Comment:
The c.1101-2A>G intronic variant results from a A to G substitution two nucleotides before coding exon 10 of the TP53 gene. This alteration was identified … (more)
The c.1101-2A>G intronic variant results from a A to G substitution two nucleotides before coding exon 10 of the TP53 gene. This alteration was identified in a 2 year-old Asian child with adrenocortical tumor by one study. The same study conducted an analysis of the tumor tissue, demonstrating loss of heterozygosity and the utilization of an alternative acceptor site leading to a frameshift and alternate termination of the resulting protein (Pinto E et al Fam Cancer. 2011 Mar;10(1):141-6). This alteration was also identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel, in a proband with breast cancer (Susswein et al. Genet. Med. 2016 Aug;18(8):823-32). However, this alteration has also been observed in several individuals with TP53-related cancers, but not meeting classic LFS or Chompret criteria (Ambry internal data). 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). 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)
|
|
Pathogenic
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000261653.10
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 10 of the TP53 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects an acceptor splice site in intron 10 of the TP53 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer or an adrenocortical tumor (PMID: 20967502, 26681312). This variant is also known as IVS10-2 A>G . ClinVar contains an entry for this variant (Variation ID: 141332). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a new termination codon (PMID: 20967502). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts the C-terminal domain of the TP53 protein, which is required for DNA binding and transactivation activity (PMID: 22178617, 25794615, 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)
|
|
Likely pathogenic
(Jul 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000211769.13
First in ClinVar: Feb 24, 2015 Last updated: Aug 05, 2023 |
Comment:
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a … (more)
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26681312, 22495821, 26205489, 20932800, 20967502, 34863587, 31105275) (less)
|
|
not provided
(-)
|
no classification provided
Method: in vivo
|
not provided
Affected status: not applicable
Allele origin:
somatic
|
MutSpliceDB: a database of splice sites variants effects on splicing, NIH
Accession: SCV001762399.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
Comment on evidence:
Intron inclusion between exons 10 & 11, based on review of RNA-seq in TCGA-G2-A2EL-01A tumor which has TP53 NM_000546.6:c.1101-2A>G variant
Method: Based on review of RNA-seq data in sample with variant.
Result:
Intron inclusion between exons 10 & 11
|
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. |
---|---|---|---|---|
sequence_variant_affecting_splicing
|
|
|
MutSpliceDB: a database of splice sites variants effects on splicing, NIH
Accession: SCV001762399.1
|
Comment:
Intron inclusion between exons 10 & 11, based on review of RNA-seq in TCGA-G2-A2EL-01A tumor which has TP53 NM_000546.6:c.1101-2A>G variant
|
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Inherited TP53 Variants and Risk of Prostate Cancer. | Maxwell KN | European urology | 2022 | PMID: 34863587 |
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
Regulation of the p53 response and its relationship to cancer. | Meek DW | The Biochemical journal | 2015 | PMID: 26205489 |
The p53 C terminus controls site-specific DNA binding and promotes structural changes within the central DNA binding domain. | Laptenko O | Molecular cell | 2015 | PMID: 25794615 |
p53 requires an intact C-terminal domain for DNA binding and transactivation. | Kim H | Journal of molecular biology | 2012 | PMID: 22178617 |
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 |
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=CA000038 | - | - | - | - |
Text-mined citations for rs587781664 ...
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.