ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.672+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.672+1G>A
Variation ID: 216078 Accession: VCV000216078.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7674858 (GRCh38) [ NCBI UCSC ] 17: 7578176 (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 Dec 26, 2017 Feb 14, 2024 Dec 5, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000017.11:7674857:C:T
- 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 6 & 7, based on review of RNA-seq in SCC-15 cancer cell line which has TP53 NM_000546.5:c.672+1G>A 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.
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- Allele frequency Help
The frequency of the allele represented by this VCV record.
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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 | ||
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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 |
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. |
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Pathogenic (1) |
criteria provided, single submitter
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Sep 26, 2023 | RCV000200333.10 | |
Pathogenic (2) |
criteria provided, single submitter
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Aug 2, 2022 | RCV000786828.4 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 5, 2023 | RCV002288814.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 10, 2022 | RCV003474954.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2022 | RCV002288813.2 |
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. |
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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: SCV002582476.1 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: SCV002583137.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Pathogenic
(Aug 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: SCV002559557.2 First in ClinVar: Aug 15, 2022 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Published functional … (more)
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: loss of transcriptional activity, reduced cell cycle check point arrest in comparison to wild type (Piao et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Observed in at least one case of pediatric osteosarcoma in an individual with a family history consistent with Li-Fraumeni like syndrome (Sakurai et al., 2013); This variant is associated with the following publications: (PMID: 22495821, 22911296, 23409989, 16494995, 27352257, 25149524, 27614696, 22703554, 30720243) (less)
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Likely pathogenic
(Feb 16, 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: SCV003911996.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
The c.672+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 5 of the TP53 gene. This alteration has been … (more)
The c.672+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 5 of the TP53 gene. This alteration has been reported in an individual with osteosarcoma diagnosed at age 15 (Sakurai N et al. Pediatr Int, 2013 Feb;55:107-11). Functional studies performed on this alteration include RNA analysis which identified an 18 nucleotide insertion event and functional studies which demonstrated loss of function (Piao J et al. Mol Carcinog, 2013 Oct;52:770-6). 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 and will result in the creation or strengthening of a novel splice donor site. In addition to the clinical data presented in the literature, 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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Pathogenic
(Nov 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Adrenocortical carcinoma, hereditary
Affected status: unknown
Allele origin: unknown
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Baylor Genetics
Accession: SCV004204265.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 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: SCV000253850.9 First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 6 of the TP53 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects a donor splice site in intron 6 of the TP53 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the gain of 6 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 16494995, 23409989, 29070607; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 216078). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects TP53 function (PMID: 22495821). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in intron 6 (PMID: 22495821, 23409989). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 05, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV004359993.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G>A nucleotide substitution at the +1 position of intron 6 of the TP53 gene. Splice site prediction tools suggest that this … (more)
This variant causes a G>A nucleotide substitution at the +1 position of intron 6 of the TP53 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A functional RNA study has shown that this variant may result in the use of a cryptic donor site 18 base pairs into intron 6, resulting in the insertion of 6 amino acids into the DNA binding domain (PMID: 23409989). Functional studies using this 6 amino acid construct showed impaired TP53 transcriptional transactivation, reduced cell cycle arrest at G0/G1 in response to DNA damage, and impaired ability to inhibit cell growth (PMID: 22495821). This variant has been reported in individuals affected with osteosarcoma and rhabdomyosarcoma, the latter of which was confirmed de novo (PMID: 22495821, 23409989, 29070607). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. (less)
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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: SCV000925722.2 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 6 & 7
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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: SCV000925722.2
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Comment:
Intron inclusion between exons 6 & 7, based on review of RNA-seq in SCC-15 cancer cell line which has TP53 NM_000546.5:c.672+1G>A variant.
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome. | Renaux-Petel M | Journal of medical genetics | 2018 | PMID: 29070607 |
Novel p53 splicing site mutation in Li-Fraumeni-like syndrome with osteosarcoma. | Sakurai N | Pediatrics international : official journal of the Japan Pediatric Society | 2013 | PMID: 23409989 |
Functional studies of a novel germline p53 splicing mutation identified in a patient with Li-Fraumeni-like syndrome. | Piao J | Molecular carcinogenesis | 2013 | PMID: 22495821 |
The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. | Achatz MI | Cancer letters | 2007 | PMID: 16494995 |
https://brb.nci.nih.gov/cgi-bin/splicing/splicing_evidence.cgi?caid=CA339249 | - | - | - | - |
Text-mined citations for rs863224499 ...
HelpRecord last updated Feb 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.