ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.919+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.919+1G>A
Variation ID: 633606 Accession: VCV000633606.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7673700 (GRCh38) [ NCBI UCSC ] 17: 7577018 (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 Jun 9, 2019 Apr 15, 2024 Aug 28, 2019 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
- NM_001276761.1:c.802+1G>A
- Canonical SPDI
- NC_000017.11:7673699: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]
- Intron inclusion between exons 8 & 9, based on review of RNA-seq in TCGA-V5-A7RC-01B tumor which has TP53 NM_000546.6:c.919+1G>A 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 |
3196 | 3291 |
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
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
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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 (1) |
no assertion criteria provided
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May 21, 2019 | RCV000782136.3 | |
Likely pathogenic (2) |
reviewed by expert panel
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Aug 28, 2019 | RCV000991150.8 | |
not provided (1) |
no classification provided
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- | RCV001578272.3 | |
Pathogenic (1) |
criteria provided, single submitter
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May 11, 2023 | RCV003307417.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 4, 2024 | RCV003992389.1 |
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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Likely pathogenic
(Aug 28, 2019)
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reviewed by expert panel
Method: curation
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Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen TP53 Variant Curation Expert Panel, ClinGen
Accession: SCV001142564.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
Comment:
The c.919+1G>A is canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong). This variant is absent in the gnomAD cohort (PM2_Supporting; … (more)
The c.919+1G>A is canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is a proband with a de novo observation with bilateral, metachronous breast cancer without mention of parental confirmation (PM6_Supporting; PMID: 28509937). In summary, TP53 c.919+1G>A meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PVS1_Strong, PM2_Supporting, PM6_Supporting. (less)
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Pathogenic
(May 11, 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: SCV003998799.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Comment:
The c.919+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 7 of the TP53 gene. This alteration has … (more)
The c.919+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 7 of the TP53 gene. This alteration has been reported in families meeting classic Li Fraumeni syndrome criteria and/or Chompret criteria for LFS (Marcel V et al. J Med Genet, 2009 Nov;46:766-72; Wilson JR et al. J Med Genet, 2010 Nov;47:771-4; Wong ESY et al. NPJ Genom Med, 2016 Jan;1:15003; Aceto GM et al. Breast Cancer Res Treat, 2019 Jun;175:479-485; Haque MM et al. Sci Rep, 2018 Aug;8:11705; Stoltze U et al. PLoS One, 2018 Jan;13:e0190050). This alteration has also been reported as a de novo observation with bilateral, metachronous breast cancer without mention of parental confirmation (O'Shea R et al. Fam Cancer, 2018 Jan;17:123-128). 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. 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jan 29, 2024)
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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: SCV001382474.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 8 of the TP53 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor 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). 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: 20805372, 29070607, 29324801). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 633606). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Adrenocortical carcinoma, hereditary
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809802.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Pathogenic
(May 21, 2019)
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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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Academic Center for Education, Culture and Research, Motamed Cancer Institute
Accession: SCV000914200.1
First in ClinVar: Jun 09, 2019 Last updated: Jun 09, 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: SCV001805840.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment on evidence:
Intron inclusion between exons 8 & 9, based on review of RNA-seq in TCGA-V5-A7RC-01B tumor which has TP53 NM_000546.6:c.919+1G>A 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
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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: SCV001805840.1
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Comment:
Intron inclusion between exons 8 & 9, based on review of RNA-seq in TCGA-V5-A7RC-01B tumor which has TP53 NM_000546.6:c.919+1G>A variant
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer. | Evans DG | Journal of medical genetics | 2022 | PMID: 33758026 |
Germline TP53 mutation spectrum in Sudanese premenopausal breast cancer patients: correlations with reproductive factors. | Aceto GM | Breast cancer research and treatment | 2019 | PMID: 30796655 |
Identification and characterization of TP53 gene Allele Dropout in Li-Fraumeni syndrome and Oral cancer cohorts. | Haque MM | Scientific reports | 2018 | PMID: 30076369 |
Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark. | Stoltze U | PloS one | 2018 | PMID: 29324801 |
Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome. | Renaux-Petel M | Journal of medical genetics | 2018 | PMID: 29070607 |
Next generation sequencing is informing phenotype: a TP53 example. | O'Shea R | Familial cancer | 2018 | PMID: 28509937 |
Inherited breast cancer predisposition in Asians: multigene panel testing outcomes from Singapore. | Wong ESY | NPJ genomic medicine | 2016 | PMID: 29263802 |
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 |
TP53 PIN3 and MDM2 SNP309 polymorphisms as genetic modifiers in the Li-Fraumeni syndrome: impact on age at first diagnosis. | Marcel V | Journal of medical genetics | 2009 | PMID: 19542078 |
A novel splice mutation in the TP53 gene associated with Leydig cell tumor and primitive neuroectodermal tumor. | Stecher CW | Pediatric blood & cancer | 2008 | PMID: 17066464 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
https://brb.nci.nih.gov/cgi-bin/splicing/splicing_evidence.cgi?caid=CA397836247 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/e5597807-7124-425a-b33a-5c6af85c5edc | - | - | - | - |
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Text-mined citations for rs1131691039 ...
HelpRecord last updated Apr 15, 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.