ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.1093C>T (p.His365Tyr)
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.1093C>T (p.His365Tyr)
Variation ID: 80708 Accession: VCV000080708.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7670616 (GRCh38) [ NCBI UCSC ] 17: 7573934 (GRCh37) [ NCBI UCSC ] 17: 7514659 (NCBI36) [ 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 Sep 24, 2016 May 1, 2024 Aug 28, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.1093C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.His365Tyr missense NM_000546.5(TP53):c.1093C>T NM_001126112.3:c.1093C>T NP_001119584.1:p.His365Tyr missense NM_001126113.3:c.*112C>T 3 prime UTR NM_001126114.3:c.*200C>T 3 prime UTR NM_001126115.2:c.697C>T NP_001119587.1:p.His233Tyr missense NM_001126116.2:c.*200C>T 3 prime UTR NM_001126117.2:c.*112C>T 3 prime UTR NM_001126118.2:c.976C>T NP_001119590.1:p.His326Tyr missense NM_001276695.3:c.*112C>T 3 prime UTR NM_001276696.3:c.*200C>T 3 prime UTR NM_001276697.3:c.616C>T NP_001263626.1:p.His206Tyr missense NM_001276698.3:c.*200C>T 3 prime UTR NM_001276699.3:c.*112C>T 3 prime UTR NM_001276760.3:c.976C>T NP_001263689.1:p.His326Tyr missense NM_001276761.3:c.976C>T NP_001263690.1:p.His326Tyr missense NC_000017.11:g.7670616G>A NC_000017.10:g.7573934G>A NG_017013.2:g.21935C>T LRG_321:g.21935C>T LRG_321t1:c.1093C>T LRG_321p1:p.His365Tyr P04637:p.His365Tyr - Protein change
- H233Y, H326Y, H365Y, H206Y
- Other names
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- Canonical SPDI
- NC_000017.11:7670615:G:A
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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.
Exome Aggregation Consortium (ExAC) 0.00001
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
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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
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 |
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
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
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 22, 2023 | RCV000129635.14 | |
Likely benign (2) |
reviewed by expert panel
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Aug 28, 2019 | RCV000701624.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001127281.6 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001358057.3 | |
TP53-related disorder
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Likely benign (1) |
criteria provided, single submitter
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Oct 9, 2023 | RCV003894916.1 |
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
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
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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 benign
(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
FDA Recognized Database
Accession: SCV001142538.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, transactivation assays show retained function … (more)
This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). In summary, TP53 c.1093C>T; p.His365Tyr meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4 and BS3. (less)
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Likely benign
(Jan 25, 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: SCV000830434.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001286576.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Feb 22, 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: SCV001359322.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces histidine with tyrosine at codon 365 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces histidine with tyrosine at codon 365 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). However, experimental studies have shown that this variant did not impact function in transactivation assays (PMID: 12826609, 21343334) and cell growth suppression assays (PMID: 30224644). The variant has been identified in two individuals affected with cancer (PMID 12610779, 17606709). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Oct 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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TP53-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004714881.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Likely benign
(Aug 19, 2020)
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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: SCV000184430.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553701.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The TP53 p.His365Tyr variant was identified in 2 of 246 proband chromosomes (frequency: 0.008) from individuals or families with lung cancer or soft tissue sarcoma … (more)
The TP53 p.His365Tyr variant was identified in 2 of 246 proband chromosomes (frequency: 0.008) from individuals or families with lung cancer or soft tissue sarcoma (Hayes 1999, Hwang 2003). The variant was also identified in dbSNP (ID: rs267605075) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics and True Health Diagnostics), Cosmic (1x in Stomach tissue), and in IARC TP53 Database (3x). The variant was not identified in COGR, or LOVD 3.0 databases. The variant was identified in control databases in 1 of 244474 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 110730 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.His365 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In yeast-based systematic analysis the variant was classified as a partial deficiency allele based on its ability to transactivate a set of human target sequences and showed ~25% of wild-type activity toward at least one response element (Monti 2007, Monti 2011). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Uncertain significance
(Sep 07, 2017)
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no assertion criteria provided
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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True Health Diagnostics
Accession: SCV000788224.1
First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016 |
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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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Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
Identification of new p53 target microRNAs by bioinformatics and functional analysis. | Bisio A | BMC cancer | 2013 | PMID: 24256616 |
Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
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 |
Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. | Kato S | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12826609 |
Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. | Hwang SJ | American journal of human genetics | 2003 | PMID: 12610779 |
Comprehensive TP53-denaturing gradient gel electrophoresis mutation detection assay also applicable to archival paraffin-embedded tissue. | Hayes VM | Diagnostic molecular pathology : the American journal of surgical pathology, part B | 1999 | PMID: 10408787 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/9285e818-17ae-4db4-83fa-16f6628f6cd6 | - | - | - | - |
Text-mined citations for rs267605075 ...
HelpRecord last updated May 19, 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.