ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.1083del (p.Ser362fs)
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.1083del (p.Ser362fs)
Variation ID: 549856 Accession: VCV000549856.6
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7670626 (GRCh38) [ NCBI UCSC ] 17: 7573944 (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 Aug 20, 2018 Oct 28, 2023 Jan 25, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- S323fs, S362fs, S230fs, S203fs
- Other names
- NM_000546.6(TP53):c.1083del
- p.Ser362fs
- Canonical SPDI
- NC_000017.11:7670625:CCCCCC:CCCCC
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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 |
3195 | 3292 |
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 14, 2018 | RCV000677307.2 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2023 | RCV000714961.5 |
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
(Jan 25, 2023)
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criteria provided, single submitter
Method: curation
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Bone marrow failure syndrome 5
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Institute Rare Disease Group, Broad Institute
Accession: SCV003761378.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The heterozygous p.Ser362AlafsTer8 variant in TP53 was identified by our study in one individual with bone marrow failure syndrome 5. The p.Ser362AlafsTer8 variant in TP53 … (more)
The heterozygous p.Ser362AlafsTer8 variant in TP53 was identified by our study in one individual with bone marrow failure syndrome 5. The p.Ser362AlafsTer8 variant in TP53 has been previously reported in 2 unrelated individuals with bone marrow failure syndrome 5 (PMID: 30146126, PMID: 35362179). This variant was found to be de novo in one individual with confirmed maternity and paternity (PMID: 30146126) and is assumed de novo in one individual but maternity and paternity have not been confirmed (PMID: 35362179). The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (ID: 549856) and has been interpreted as pathogenic by the Hirosaki University Graduate School of Medicine Department of Pediatrics and OMIM. This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Ser362AlafsTer8 variant may impact protein function (PMID: 30146126). However, these types of assays may not accurately represent biological function. Animal models in zebrafish have shown that this variant causes bone marrow failure syndrome 5 (PMID: 30146126). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 362 and leads to a premature termination codon 8 amino acids downstream. This termination codon occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. It is of note that loss of function of the TP53 in autosomal dominant bone marrow failure syndrome 5 has not yet been established based on the criteria laid out in Tayoun et al., 2018 (PMID: 30192042), and based on the published literature, this variant appears to cause disease via a gain of function mechanism (PMID: 30146126). In summary, this variant meets criteria to be classified as pathogenic for bone marrow failure syndrome 5. ACMG/AMP Criteria applied: PS2, PS3, PS4_Supporting, PM2_Supporting (Richards 2015). (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Bone marrow failure syndrome 5
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine
Accession: SCV004047084.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The frame shift (c.1083del) variant has been reported previously in heterozygous state in patients affected with Bone marrow failure syndrome 5 (Toki et. al., 2018; … (more)
The frame shift (c.1083del) variant has been reported previously in heterozygous state in patients affected with Bone marrow failure syndrome 5 (Toki et. al., 2018; Hamard et. al., 2013). The p.Ser362AlafsTer8 variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. Experimental studies have demonstrate that the CTD-truncation mutations of TP53 cause a novel inherited bone marrow failure syndrome (Toki et. al., 2018). This variant causes a frameshift starting with codon Serine 362, changes this amino acid to Alanine residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Ser362AlafsTer8. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. Though classified as Pathogenic, Sanger confirmation is required to confirm presence of variant due to low depth (less)
Clinical Features:
Anemia due to reduced life span of red cells (present) , Decreased circulating antibody level (present) , Growth delay (present) , Microcephaly (present) , Delayed … (more)
Anemia due to reduced life span of red cells (present) , Decreased circulating antibody level (present) , Growth delay (present) , Microcephaly (present) , Delayed gross motor development (present) , Microcephaly (present) , Seizure (present) (less)
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Pathogenic
(May 14, 2018)
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no assertion criteria provided
Method: research
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Diamond-Blackfan anemia
(Sporadic)
Affected status: yes
Allele origin:
de novo
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Department of Pediatrics, Hirosaki University Graduate School of Medicine
Accession: SCV000786665.1
First in ClinVar: Aug 20, 2018 Last updated: Aug 20, 2018 |
Comment:
The heterozygous protein-truncating mutations in TP53 (c.1083delG, p.Ser362AlafsX8) was detected in a patient presented with congenital hypoplastic anemia, hypogammaglobulinemia, growth retardation, microcephally and mental retardation. … (more)
The heterozygous protein-truncating mutations in TP53 (c.1083delG, p.Ser362AlafsX8) was detected in a patient presented with congenital hypoplastic anemia, hypogammaglobulinemia, growth retardation, microcephally and mental retardation. The variant resulted in the loss of 32 residues from the C-terminal domain (CTD). Luciferase assay using the promoter of CDKN1A showed the p53 mutant had augmented transcriptional activities. When expressed in zebrafish and human-induced pluripotent stem cells, we observed impaired erythrocyte production. The patient shared several phenotypes with the knock-in mice expressing CTD-truncated p53, including bone marrow failure, microcephaly and severe growth retardation (Simeonova 2013, Hamard 2013). These findings demonstrate that the CTD-truncation mutations of TP53 cause a novel inherited bone marrow failure syndrome. (less)
Clinical Features:
Panhypogammaglobulinemia (present) , Severe postnatal growth retardation (present) , Microcephaly (present)
Age: 10-19 years
Sex: male
Ethnicity/Population group: Asian
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Pathogenic
(May 18, 2020)
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no assertion criteria provided
Method: literature only
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BONE MARROW FAILURE SYNDROME 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000845726.1
First in ClinVar: Nov 05, 2018 Last updated: Nov 05, 2018 |
Comment on evidence:
In a 20-year-old man with bone marrow failure syndrome-5 (BMFS5; 618165), Toki et al. (2018) identified a de novo heterozygous 1-bp deletion (c.1083delG, NM_001126112.2) in … (more)
In a 20-year-old man with bone marrow failure syndrome-5 (BMFS5; 618165), Toki et al. (2018) identified a de novo heterozygous 1-bp deletion (c.1083delG, NM_001126112.2) in exon 10 of the TP53 gene, predicted to result in a frameshift and premature termination (Ser362AlafsTer8). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay and produced a mutant protein. In vitro functional expression studies showed that the TP53 mutant had increased transcriptional activity compared to controls. Human induced pluripotent stem cells expressing a CRISPR/Cas9-derived C-terminal truncated TP53 showed significantly elevated expression of downstream TP53 targets, as well as impaired erythroid differentiation. Toki et al. (2018) postulated that the deletion may compromise binding of negative transcriptional regulators. The findings indicated that augmented p53 function, not loss of function, was responsible for the phenotype. An unrelated patient with the disorder had a different mutation that resulted in the same truncated protein (see 191170.0044). (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome. | Toki T | American journal of human genetics | 2018 | PMID: 30146126 |
Text-mined citations for rs1555524354 ...
HelpRecord last updated Mar 17, 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.