ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.380C>T (p.Ser127Phe)
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.
Pathogenic(2); Likely pathogenic(4); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000546.6(TP53):c.380C>T (p.Ser127Phe)
Variation ID: 182928 Accession: VCV000182928.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7675232 (GRCh38) [ NCBI UCSC ] 17: 7578550 (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 29, 2016 May 1, 2024 Feb 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.380C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Ser127Phe missense NM_001126112.3:c.380C>T NP_001119584.1:p.Ser127Phe missense NM_001126113.3:c.380C>T NP_001119585.1:p.Ser127Phe missense NM_001126114.3:c.380C>T NP_001119586.1:p.Ser127Phe missense NM_001126115.2:c.-17C>T 5 prime UTR NM_001126116.2:c.-17C>T 5 prime UTR NM_001126117.2:c.-17C>T 5 prime UTR NM_001126118.2:c.263C>T NP_001119590.1:p.Ser88Phe missense NM_001276695.3:c.263C>T NP_001263624.1:p.Ser88Phe missense NM_001276696.3:c.263C>T NP_001263625.1:p.Ser88Phe missense NM_001276697.3:c.-98C>T 5 prime UTR NM_001276698.3:c.-98C>T 5 prime UTR NM_001276699.3:c.-98C>T 5 prime UTR NM_001276760.3:c.263C>T NP_001263689.1:p.Ser88Phe missense NM_001276761.3:c.263C>T NP_001263690.1:p.Ser88Phe missense NC_000017.11:g.7675232G>A NC_000017.10:g.7578550G>A NG_017013.2:g.17319C>T LRG_321:g.17319C>T LRG_321t1:c.380C>T LRG_321p1:p.Ser127Phe LRG_321t8:c.263C>T LRG_321p8:p.Ser88Phe P04637:p.Ser127Phe - Protein change
- S127F, S88F
- Other names
- p.S127F:TCC>TTC
- Canonical SPDI
- NC_000017.11:7675231: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.
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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
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 |
3363 | 3462 |
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
Help
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) |
criteria provided, single submitter
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Oct 7, 2021 | RCV000161024.6 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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May 19, 2023 | RCV000606528.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 4, 2023 | RCV000633384.7 | |
Pathogenic/Likely pathogenic (2) |
no assertion criteria provided
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Mar 19, 2021 | RCV000785332.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 9, 2023 | RCV003162681.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 21, 2022 | RCV003474836.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 13, 2024 | RCV004019945.1 |
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
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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
(Oct 04, 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: SCV000754606.7
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 127 of the TP53 protein (p.Ser127Phe). … (more)
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 127 of the TP53 protein (p.Ser127Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome and/or Li-Fraumeni syndrome (PMID: 32817165, 34240179; Invitae; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 182928). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16000567, 16322298, 29979965, 30224644). This variant disrupts the p.Ser127 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29470806; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Nov 22, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712629.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Ser127Phe variant in TP53 has not been previously reported in individuals with Li-Fraumeni syndrome or in large population studies. Computational predicti on tools and … (more)
The p.Ser127Phe variant in TP53 has not been previously reported in individuals with Li-Fraumeni syndrome or in large population studies. Computational predicti on tools and conservation analysis suggest that the p.Ser127Phe variant may impa ct the protein, though this information is not predictive enough to determine pa thogenicity. In summary, the clinical significance of the p.Ser127Phe variant is uncertain. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(May 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002516106.2
First in ClinVar: May 28, 2022 Last updated: May 27, 2023 |
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Likely pathogenic
(Sep 21, 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: SCV004204273.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Feb 13, 2024)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004932421.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad … (more)
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Likely pathogenic
(Mar 09, 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: SCV003878902.2
First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024 |
Comment:
The p.S127F variant (also known as c.380C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide … (more)
The p.S127F variant (also known as c.380C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 380. The serine at codon 127 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was detected in a cohort of 295 women considered at high risk for breast cancer (Guindalini RSC et al. Clin Cancer Res, 2019 Mar;25:1786-1794). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc Natl Acad Sci U S A, 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Another alteration at the same codon, p.S127T (c.379T>A), has been shown to also have non-functional transactivation in yeast based assays, be deficient at growth suppression, and have a dominant negative effect (Ambry internal data; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Oct 07, 2021)
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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: SCV000211743.15
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: reduced transcriptional activation for multiple p53 response elements, loss of growth suppression activity, non-functional transactivation (Kato 2003, Dekairelle … (more)
Published functional studies demonstrate a damaging effect: reduced transcriptional activation for multiple p53 response elements, loss of growth suppression activity, non-functional transactivation (Kato 2003, Dekairelle 2005, Bally 2015, Kotler 2018); Observed in individuals with TP53-related cancers referred for genetic testing at GeneDx in published literature (Guindalini 2018); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25308272, 30312528, 16322298, 16000567, 24280411, 25033756, 21747090, 26271412, 15195137, 16094622, 12826609, 29085664, 29979965, 30154229, 15510160) (less)
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Likely pathogenic
(Dec 01, 2018)
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no assertion criteria provided
Method: research
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Ovarian neoplasm
Affected status: yes
Allele origin:
somatic
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German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000923900.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
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Pathogenic
(Mar 19, 2021)
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no assertion criteria provided
Method: clinical testing
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Ovarian cancer
Affected status: no
Allele origin:
somatic
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University Health Network, Princess Margaret Cancer Centre
Accession: SCV001738483.1
First in ClinVar: Jun 26, 2021 Last updated: Jun 26, 2021 |
Secondary finding: yes
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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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Paired Tumor-Normal Sequencing Provides Insights Into the TP53-Related Cancer Spectrum in Patients With Li-Fraumeni Syndrome. | Ceyhan-Birsoy O | Journal of the National Cancer Institute | 2021 | PMID: 34240179 |
A pedigree-based prediction model identifies carriers of deleterious de novo mutations in families with Li-Fraumeni syndrome. | Gao F | Genome research | 2020 | PMID: 32817165 |
Intensive Surveillance with Biannual Dynamic Contrast-Enhanced Magnetic Resonance Imaging Downstages Breast Cancer in BRCA1 Mutation Carriers. | Guindalini RSC | Clinical cancer research : an official journal of the American Association for Cancer Research | 2019 | PMID: 30154229 |
Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. | Kotler E | Molecular cell | 2018 | PMID: 29979965 |
Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations. | Singh J | Breast cancer research and treatment | 2018 | PMID: 29470806 |
Clinical relevance of dominant-negative p73 isoforms for responsiveness to chemotherapy and survival in ovarian cancer: evidence for a crucial p53-p73 cross-talk in vivo. | Concin N | Clinical cancer research : an official journal of the American Association for Cancer Research | 2005 | PMID: 16322298 |
Assessment of the transcriptional activity of p53 improves the prediction of recurrence in superficial transitional cell carcinoma of the bladder. | Dekairelle AF | Clinical cancer research : an official journal of the American Association for Cancer Research | 2005 | PMID: 16000567 |
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 |
Text-mined citations for rs730881999 ...
HelpRecord last updated Sep 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.