ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.920-2A>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
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NM_000546.6(TP53):c.920-2A>G
Variation ID: 43595 Accession: VCV000043595.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7673610 (GRCh38) [ NCBI UCSC ] 17: 7576928 (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 Feb 24, 2015 Feb 14, 2024 Nov 15, 2022 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000017.11:7673609:T:C
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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 8 & 9, based on review of RNA-seq in TCGA-44-3918-01A tumor which has TP53 NM_000546.6:c.920-2A>G 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
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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 (2) |
criteria provided, single submitter
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Nov 15, 2022 | RCV000036537.20 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2022 | RCV000132190.13 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 7, 2019 | RCV000483617.15 | |
Likely pathogenic (1) |
no assertion criteria provided
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Dec 1, 2018 | RCV000785489.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2022 | RCV002288536.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 24, 2020 | RCV001798102.10 |
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
(Aug 07, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001474488.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The TP53 c.920-2A>G variant (rs397516439) is reported in the literature in colon cancer, thyroid cancer, lung cancer, and ovarian cancer specimens (Grassi 2015, Kandioler 2015, … (more)
The TP53 c.920-2A>G variant (rs397516439) is reported in the literature in colon cancer, thyroid cancer, lung cancer, and ovarian cancer specimens (Grassi 2015, Kandioler 2015, Lee 2010, Wojnarowicz 2012). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 43595). This variant abolishes the canonical splice acceptor site of intron 8, which is likely to disrupt gene function. Other variants that abolish the same splice acceptor site (c.920-1G>A, c.920-1G>T) have been reported in individuals with symptoms or diagnoses of Li-Fraumeni syndrome, suggesting that disruption of this splice site is associated with disease (Gonzalez 2009, Wu 2011). Based on available information, the c.920-2A>G variant is considered to be pathogenic. References: Gonzalez KD et al. High frequency of de novo mutations in Li-Fraumeni syndrome. J Med Genet. 2009 Oct;46(10):689-93. Grassi ES et al. SP600125 has a remarkable anticancer potential against undifferentiated thyroid cancer through selective action on ROCK and p53 pathways. Oncotarget. 2015 Nov 3;6(34):36383-99. Kandioler D et al. TP53 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients. EBioMedicine. 2015 Jun 8;2(8):825-30. Lee EB et al. TP53 mutations in Korean patients with non-small cell lung cancer. J Korean Med Sci. 2010 May;25(5):698-705. Wojnarowicz PM et al. The genomic landscape of TP53 and p53 annotated high grade ovarian serous carcinomas from a defined founder population associated with patient outcome. PLoS One. 2012;7(9):e45484. Wu CC et al. Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome. Hum Genet. 2011 Jun;129(6):663-73. (less)
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Likely pathogenic
(Mar 24, 2020)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042837.1
First in ClinVar: Dec 29, 2021 Last updated: Dec 29, 2021 |
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Pathogenic
(Nov 15, 2022)
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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: SCV001224140.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 43595). This variant is also known as IVS8-2A>G. Disruption of this splice site has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 19556618, 21305319, 32817165; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 8 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). (less)
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Pathogenic
(Aug 24, 2018)
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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: SCV000571425.3
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
This variant is denoted TP53 c.920-2A>G or IVS8-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 8 of the TP53 … (more)
This variant is denoted TP53 c.920-2A>G or IVS8-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 8 of the TP53 gene. This variant destroys a canonical splice site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Although this variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant, other variants impacting the same splice site have been reported in association with Li-Fraumeni syndrome (Gonzalez 2009, Wu 2011). Based on the current available evidence, we consider TP53 c.920-2A>G to be pathogenic. (less)
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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: SCV002583002.1
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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Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002582340.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Likely pathogenic
(May 15, 2017)
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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: SCV000187270.6
First in ClinVar: Aug 06, 2014 Last updated: Nov 29, 2022 |
Comment:
The c.920-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 8 in the TP53 gene. This nucleotide position … (more)
The c.920-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 8 in the TP53 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. 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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Likely pathogenic
(Aug 01, 2008)
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no assertion criteria provided
Method: clinical testing
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Li-Fraumeni syndrome
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060192.5
First in ClinVar: May 03, 2013 Last updated: Feb 24, 2015 |
Number of individuals with the variant: 2
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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: SCV000924061.1
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 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: SCV001762396.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
Comment on evidence:
Intron inclusion between exons 8 & 9, based on review of RNA-seq in TCGA-44-3918-01A tumor which has TP53 NM_000546.6:c.920-2A>G variant
Method: Based on review of RNA-seq data in sample with variant.
Result:
Intron inclusion between exons 8 & 9
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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
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: SCV001762396.1
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Comment:
Intron inclusion between exons 8 & 9, based on review of RNA-seq in TCGA-44-3918-01A tumor which has TP53 NM_000546.6:c.920-2A>G variant
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A pedigree-based prediction model identifies carriers of deleterious de novo mutations in families with Li-Fraumeni syndrome. | Gao F | Genome research | 2020 | PMID: 32817165 |
Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome. | Wu CC | Human genetics | 2011 | PMID: 21305319 |
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 |
High frequency of de novo mutations in Li-Fraumeni syndrome. | Gonzalez KD | Journal of medical genetics | 2009 | PMID: 19556618 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Characterization of germline TP53 splicing mutations and their genetic and functional analysis. | Varley JM | Oncogene | 2001 | PMID: 11420676 |
https://brb.nci.nih.gov/cgi-bin/splicing/splicing_evidence.cgi?caid=CA000500 | - | - | - | - |
Text-mined citations for rs397516439 ...
HelpRecord last updated Apr 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.