ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.643A>G (p.Ser215Gly)
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(1); Likely pathogenic(3); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000546.6(TP53):c.643A>G (p.Ser215Gly)
Variation ID: 265337 Accession: VCV000265337.25
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p13.1 17: 7674888 (GRCh38) [ NCBI UCSC ] 17: 7578206 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 10, 2016 Sep 16, 2024 Feb 15, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000546.6:c.643A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Ser215Gly missense NM_001126112.3:c.643A>G NP_001119584.1:p.Ser215Gly missense NM_001126113.3:c.643A>G NP_001119585.1:p.Ser215Gly missense NM_001126114.3:c.643A>G NP_001119586.1:p.Ser215Gly missense NM_001126115.2:c.247A>G NP_001119587.1:p.Ser83Gly missense NM_001126116.2:c.247A>G NP_001119588.1:p.Ser83Gly missense NM_001126117.2:c.247A>G NP_001119589.1:p.Ser83Gly missense NM_001126118.2:c.526A>G NP_001119590.1:p.Ser176Gly missense NM_001276695.3:c.526A>G NP_001263624.1:p.Ser176Gly missense NM_001276696.3:c.526A>G NP_001263625.1:p.Ser176Gly missense NM_001276697.3:c.166A>G NP_001263626.1:p.Ser56Gly missense NM_001276698.3:c.166A>G NP_001263627.1:p.Ser56Gly missense NM_001276699.3:c.166A>G NP_001263628.1:p.Ser56Gly missense NM_001276760.3:c.526A>G NP_001263689.1:p.Ser176Gly missense NM_001276761.3:c.526A>G NP_001263690.1:p.Ser176Gly missense NC_000017.11:g.7674888T>C NC_000017.10:g.7578206T>C NG_017013.2:g.17663A>G LRG_321:g.17663A>G LRG_321t1:c.643A>G LRG_321p1:p.Ser215Gly P04637:p.Ser215Gly - Protein change
- S176G, S215G, S83G, S56G
- Other names
- -
- Canonical SPDI
- NC_000017.11:7674887:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
TP53 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3409 | 3509 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 12, 2023 | RCV000255449.6 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 25, 2024 | RCV000700891.11 | |
Conflicting classifications of pathogenicity (3) |
criteria provided, conflicting classifications
|
Nov 19, 2021 | RCV000772138.11 | |
Likely pathogenic (1) |
no assertion criteria provided
|
Dec 1, 2018 | RCV000785239.3 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Aug 29, 2022 | RCV002282093.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 15, 2024 | RCV004021028.1 |
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
Help
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Oct 19, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000905241.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
|
|
Likely pathogenic
(May 06, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002532696.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The TP53 c.643A>G (p.S215G) variant has been reported in heterozygosity in at least one individual with ovarian cancer (PMID: 30216591). It has also been observed … (more)
The TP53 c.643A>G (p.S215G) variant has been reported in heterozygosity in at least one individual with ovarian cancer (PMID: 30216591). It has also been observed in numerous tumor types without confirmation of germline status, including breast cancer, lung cancers, myeloid neoplasms, and others (PMID: 26619011, 12792784, 28271309, 33635883). Functional studies have shown that this variant alters the ability to transactivate downstream genes, affects cell survival, and decreases ability to suppress growth (PMID: 12826609, 30224644, 29979965). In silico tools largely support that the impact of the variant on protein function is deleterious. This variant is not reported in the population database Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 265337). Based on the current evidence available, this variant is interpreted as likely pathogenic. (less)
|
|
|
Uncertain significance
(Aug 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002572405.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: TP53 c.643A>G (p.Ser215Gly) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Five … (more)
Variant summary: TP53 c.643A>G (p.Ser215Gly) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251466 control chromosomes (gnomAD). c.643A>G has been reported in the literature in the germline of individuals affected with Ovarian cancer (Weber-Lassalle_2018) and Gastric cancer (Chen_2011). These data do not allow any conclusion about variant significance. In cancer cell culture proliferation/survival assays, the variant was found to have reduced apoptotic activity compared to wild-type Tp53 when introduced to cancer cell lines, but had greater activity when compared to null variants (Slovackova_2012, Kotler_2018). Six ClinVar submitters have assessed the variant since 2014: four classified the variant as likely pathogenic and two as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
|
|
Uncertain significance
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000829668.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 215 of the TP53 protein (p.Ser215Gly). … (more)
This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 215 of the TP53 protein (p.Ser215Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome and/or ovarian cancer (PMID: 30216591; Invitae). ClinVar contains an entry for this variant (Variation ID: 265337). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
Likely pathogenic
(Feb 15, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004933099.1
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, 14559903, 20505364]. This variant is expected to disrupt protein … (more)
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 14559903, 20505364]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
|
|
Pathogenic
(Nov 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001187417.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.S215G variant (also known as c.643A>G), located in coding exon 5 of the TP53 gene, results from an A to G substitution at nucleotide … (more)
The p.S215G variant (also known as c.643A>G), located in coding exon 5 of the TP53 gene, results from an A to G substitution at nucleotide position 643. The serine at codon 215 is replaced by glycine, an amino acid with similar properties. This variant has been identified in an individual with a history consistent with Li Fraumeni syndrome (Ambry internal data) as well as in an individual diagnosed with ovarian cancer at age 49 (Weber-Lassalle K et al. Hum. Mutat. 2018 12;39:2040-2046). This alteration has been shown to be temperature sensitive and have a loss of transactivation activity in yeast based functional studies (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. U.S.A., 2003 Jul;100:8424-9; Shiraishi K et al. J. Biol. Chem. 2004 Jan;279:348-55). Additional yeast based assays showed retained tranactivation for some but not all p53 response elements (Grochova D et al. Oncogene. 2008 Feb; 27:1243-52; Pavlova S et al. Int. J. Oncol. 2003 Jul;23:121-31). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Cho Y et al. Science. 1994 Jul; 265(5170):346-55). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
Likely pathogenic
(Dec 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322124.10
First in ClinVar: Oct 10, 2016 Last updated: Sep 16, 2024 |
Comment:
Reported as germline variant in an individual with ovarian cancer (PMID: 30216591); In silico analysis supports that this missense variant has a deleterious effect on … (more)
Reported as germline variant in an individual with ovarian cancer (PMID: 30216591); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17724467, 15138567, 14559903, 8361764, 12792784, 20505364, 29979965, 30720243, 30840781, 34863587, 30224644, 17606709, 11782540, 16818505, 20407015, 33558336, 15510160, 34273903, 30216591) (less)
|
|
Likely pathogenic
(Dec 01, 2018)
|
no assertion criteria provided
Method: research
|
Ovarian neoplasm
Affected status: yes
Allele origin:
germline
|
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000923807.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
|
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 |
---|---|---|---|---|
Clinical benefit for clinical sequencing using cancer panel testing. | Nishimura S | PloS one | 2021 | PMID: 33635883 |
The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes. | McNamara CJ | Blood advances | 2018 | PMID: 30327374 |
Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
Diagnosis of Li-Fraumeni Syndrome: Differentiating TP53 germline mutations from clonal hematopoiesis: Results of the observational AGO-TR1 trial. | Weber-Lassalle K | Human mutation | 2018 | PMID: 30216591 |
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. | Kotler E | Molecular cell | 2018 | PMID: 29979965 |
Mutational studies on single circulating tumor cells isolated from the blood of inflammatory breast cancer patients. | Bingham C | Breast cancer research and treatment | 2017 | PMID: 28271309 |
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 |
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. | Chang MT | Nature biotechnology | 2016 | PMID: 26619011 |
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 |
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 |
Roscovitine-induced apoptosis of H1299 cells depends on functional status of p53. | Slovackova J | Neoplasma | 2012 | PMID: 22862161 |
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 |
Genetic mutations of p53 and k-ras in gastric carcinoma patients from Hunan, China. | Chen HC | Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine | 2011 | PMID: 21080251 |
Transactivation by temperature-dependent p53 mutants in yeast and human cells. | Slovackova J | Cell cycle (Georgetown, Tex.) | 2010 | PMID: 20505364 |
Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. | Jordan JJ | Molecular cancer research : MCR | 2010 | PMID: 20407015 |
Analysis of transactivation capability and conformation of p53 temperature-dependent mutants and their reactivation by amifostine in yeast. | Grochova D | Oncogene | 2008 | PMID: 17724467 |
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 |
Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y). | Ferrone M | Molecular cancer therapeutics | 2006 | PMID: 16818505 |
Isolation of temperature-sensitive p53 mutations from a comprehensive missense mutation library. | Shiraishi K | The Journal of biological chemistry | 2004 | PMID: 14559903 |
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 |
High frequency of temperature-sensitive mutations of p53 tumor suppressor in acute myeloid leukemia revealed by functional assay in yeast. | Pavlova S | International journal of oncology | 2003 | PMID: 12792784 |
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 |
click to load more click to collapse |
Text-mined citations for rs886039484 ...
HelpRecord last updated Jan 19, 2025
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.