ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.672+1G>T
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>T
Variation ID: 630765 Accession: VCV000630765.14
- 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 May 20, 2019 Feb 14, 2024 May 3, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000017.11:7674857:C:A
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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 6 & 7, based on review of RNA-seq in KMRC-20 cancer cell line which has TP53 NM_000546.5:c.672+1G>T 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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- Links
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 |
3307 | 3402 |
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 18, 2022 | RCV000776760.6 | |
not provided (1) |
no classification provided
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- | RCV000786829.2 | |
Likely pathogenic (1) |
no assertion criteria provided
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Dec 1, 2018 | RCV000785529.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 3, 2023 | RCV001269151.5 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 14, 2021 | RCV001644809.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2022 | RCV002290025.2 |
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
(Nov 05, 2020)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001448415.1
First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020 |
Comment:
Variant summary: TP53 c.672+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: TP53 c.672+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251208 control chromosomes (gnomAD). c.672+1G>T has been reported in the literature in multiple individuals affected with primary tumors belonging to the Li-Fraumeni Syndrome (LFS) spectrum (e.g. Achatz_2006, Fitarelli-Kiehl_2015, Eccles_2016, Wilson_2010, Renaux-Petel_2017, Pondrom_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant in the germline state to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 03, 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: SCV002243941.3
First in ClinVar: Mar 28, 2022 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: 630765). This variant is also known as IVS6 +1G>T. 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. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 6 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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Likely pathogenic
(Mar 11, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000912404.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G to T nucleotide substitution at the +1 position of intron 6 of the TP53 gene. Splice site prediction tools predict … (more)
This variant causes a G to T nucleotide substitution at the +1 position of intron 6 of the TP53 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with rhabdomyosarcoma meeting Chompret criteria (PMID: 32658383), breast cancer (PMID: 20805372, 25564201), and hairy cell leukemia variant (PMID 34607348). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely 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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Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002582371.1
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: SCV002583031.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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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: SCV000924101.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
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Pathogenic
(Sep 14, 2021)
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no assertion criteria provided
Method: clinical testing
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Breast carcinoma
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Accession: SCV001860282.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Sex: female
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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: SCV000925723.2
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
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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
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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: SCV000925723.2
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Comment:
Intron inclusion between exons 6 & 7, based on review of RNA-seq in KMRC-20 cancer cell line which has TP53 NM_000546.5:c.672+1G>T variant.
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Long term follow-up of a phase II study of cladribine with concurrent rituximab with hairy cell leukemia variant. | Chihara D | Blood advances | 2021 | PMID: 34607348 |
Rhabdomyosarcoma associated with germline TP53 alteration in children and adolescents: The French experience. | Pondrom M | Pediatric blood & cancer | 2020 | PMID: 32658383 |
The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes. | McNamara CJ | Blood advances | 2018 | PMID: 30327374 |
Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome. | Renaux-Petel M | Journal of medical genetics | 2018 | PMID: 29070607 |
Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. | Döhner H | Blood | 2017 | PMID: 27895058 |
The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases. | Stengel A | Leukemia | 2017 | PMID: 27680515 |
TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. | Welch JS | The New England journal of medicine | 2016 | PMID: 27959731 |
TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. | Kadia TM | Cancer | 2016 | PMID: 27463065 |
Genomic Classification and Prognosis in Acute Myeloid Leukemia. | Papaemmanuil E | The New England journal of medicine | 2016 | PMID: 27276561 |
Genetic testing in a cohort of young patients with HER2-amplified breast cancer. | Eccles DM | Annals of oncology : official journal of the European Society for Medical Oncology | 2016 | PMID: 26681682 |
Specific TP53 Mutants Overrepresented in Ovarian Cancer Impact CNV, TP53 Activity, Responses to Nutlin-3a, and Cell Survival. | Mullany LK | Neoplasia (New York, N.Y.) | 2015 | PMID: 26585234 |
TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. | Hou HA | Blood cancer journal | 2015 | PMID: 26230955 |
TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases. | Ok CY | Journal of hematology & oncology | 2015 | PMID: 25952993 |
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 characterisation of p53 mutants identified in breast cancers with suboptimal responses to anthracyclines or mitomycin. | Berge EO | Biochimica et biophysica acta | 2013 | PMID: 23246812 |
A novel hierarchical prognostic model of AML solely based on molecular mutations. | Grossmann V | Blood | 2012 | PMID: 22915647 |
TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. | Rücker FG | Blood | 2012 | PMID: 22186996 |
TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. | Jädersten M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21519010 |
Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations. | Wilson JR | Journal of medical genetics | 2010 | PMID: 20805372 |
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 |
Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. | Jordan JJ | Molecular cancer research : MCR | 2010 | PMID: 20407015 |
Transcriptional functionality of germ line p53 mutants influences cancer phenotype. | Monti P | Clinical cancer research : an official journal of the American Association for Cancer Research | 2007 | PMID: 17606709 |
The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. | Achatz MI | Cancer letters | 2007 | PMID: 16494995 |
Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y). | Ferrone M | Molecular cancer therapeutics | 2006 | PMID: 16818505 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. | Friedler A | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 11782540 |
https://brb.nci.nih.gov/cgi-bin/splicing/splicing_evidence.cgi?caid=CA397839769 | - | - | - | - |
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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.