VCV000265337.30 - ClinVar

NM_000546.6(TP53):c.643A>G (p.Ser215Gly)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(3); Uncertain significance(3)

7 out of 12 submissions contributed to this classification

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.

Somatic

Clinical impact

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Tier I (Strong) for Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype

This classification is based on the single submission received

The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for oncogenicity

Functional data are available for this variant

Variant Details

Identifiers

NM_000546.6(TP53):c.643A>G (p.Ser215Gly)

Variation ID: 265337 Accession: VCV000265337.30

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	Feb 7, 2026	Jan 15, 2026
Somatic - Clinical impact	Nov 22, 2025	Nov 22, 2025	Nov 7, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_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

... more HGVS ... less HGVS

Protein change

S176G, S215G, S83G, S56G

Other names

Canonical SPDI

NC_000017.11:7674887:T:C

Global minor allele frequency (GMAF) Help The 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

ClinGen: CA10588671 UniProtKB: P04637#VAR_045092 dbSNP: rs886039484 VarSome

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
Gene	OMIM	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	3809	3912

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.
not provided	Likely pathogenic (1)	criteria provided, single submitter	Dec 12, 2023	RCV000255449.6
Li-Fraumeni syndrome	Uncertain significance (1)	criteria provided, single submitter	Jun 2, 2024	RCV000700891.12
Hereditary cancer-predisposing syndrome	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	May 19, 2025	RCV000772138.12
Ovarian neoplasm	Likely pathogenic (1)	no assertion criteria provided	Dec 1, 2018	RCV000785239.3
not specified	Uncertain significance (1)	criteria provided, single submitter	Jan 15, 2026	RCV002282093.3
Li-Fraumeni syndrome 1	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.	Expand all rows Collapse all rows 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) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary cancer-predisposing syndrome	Color Diagnostics, LLC DBA Color Health Accession: SCV000905241.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Likely pathogenic (May 06, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Sema4 Curation Guidelines)	Hereditary cancer-predisposing syndrome	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)	Publications: PubMed (8) PubMed: 12792784‚ 12826609‚ 26619011‚ 28271309‚ 29979965‚ 30216591‚ 30224644‚ 33635883 Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Likely pathogenic (Feb 15, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Li-Fraumeni syndrome 1	Myriad Genetics, Inc. Accession: SCV004933099.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 14559903‚ 20505364‚ 29979965 Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (Dec 12, 2023) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000322124.10 First in ClinVar: Oct 10, 2016 Last updated: Sep 16, 2024	Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Jun 02, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Li-Fraumeni syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000829668.8 First in ClinVar: Oct 10, 2018 Last updated: Feb 25, 2025	Publications: PubMed (5) PubMed: 12826609‚ 28492532‚ 29979965‚ 30216591‚ 30224644 Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (May 19, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV001187417.5 First in ClinVar: Mar 16, 2020 Last updated: Jul 13, 2025	Publications: PubMed (7) PubMed: 12792784‚ 12826609‚ 14559903‚ 17724467‚ 29979965‚ 30216591‚ 30224644 Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jan 15, 2026) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002572405.2 First in ClinVar: Sep 17, 2022 Last updated: Feb 07, 2026	Publications: PubMed (22) PubMed: 11782540‚ 16818505‚ 17606709‚ 20407015‚ 21080251‚ 21343334‚ 21519010‚ 22186996‚ 22862161‚ 22915647‚ 23246812‚ 25952993‚ 26230955‚ 26585234‚ 27276561‚ 27463065‚ 27680515‚ 27895058‚ 27959731‚ 29979965‚ 30216591‚ 30327374 Comment: show 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. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251466 control chromosomes. c.643A>G has been observed in individuals affected with Ovarian cancer or clinical features of Li-Fraumeni syndrome (Weber-Lassalle_2018, internal data) and Gastric cancer (Chen_2011). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Slovackova_2012, Kotler_2018). The most pronounced variant effect results in reduced apoptotic activity compared to wild-type Tp53, but greater activity when compared to null variants when introduced to cancer cell lines. The following publications have been ascertained in the context of this evaluation (PMID: 23246812, 21080251, 27895058, 16818505, 11782540, 22915647, 26230955, 21519010, 20407015, 27463065, 29979965, 30327374, 17606709, 21343334, 26585234, 25952993, 27276561, 22186996, 22862161, 27680515, 30216591, 27959731). ClinVar contains an entry for this variant (Variation ID: 265337). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Dec 01, 2018) N Not contributing to aggregate classification	no assertion criteria provided	Ovarian neoplasm	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	Observation: 1 Collection method: research Allele origin: germline Affected status: yes more Observation 1 Collection method: research Allele origin: germline Affected status: yes Platform type: next-gen sequencing

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 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)

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). 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.

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 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.

Comment:

Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant. 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705254, 28912153, 34848827).

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. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251466 control chromosomes. c.643A>G has been observed in individuals affected with Ovarian cancer or clinical features of Li-Fraumeni syndrome (Weber-Lassalle_2018, internal data) and Gastric cancer (Chen_2011). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Slovackova_2012, Kotler_2018). The most pronounced variant effect results in reduced apoptotic activity compared to wild-type Tp53, but greater activity when compared to null variants when introduced to cancer cell lines. The following publications have been ascertained in the context of this evaluation (PMID: 23246812, 21080251, 27895058, 16818505, 11782540, 22915647, 26230955, 21519010, 20407015, 27463065, 29979965, 30327374, 17606709, 21343334, 26585234, 25952993, 27276561, 22186996, 22862161, 27680515, 30216591, 27959731). ClinVar contains an entry for this variant (Variation ID: 265337). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Citations for germline classification of this variant

Title	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
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Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype	Tier I (Strong) - diagnostic - supports diagnosis (1)		Nov 7, 2022	RCV006253934.1

Submissions - Somatic

Clinical impact Help The submitted somatic clinical impact 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)	Tumor type Help The tumor type 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.	Expand all rows Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Tier I (Strong) - Diagnostic - supports diagnosis (Nov 07, 2022) C Contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007104797.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (3) PubMed: 24705254‚ 28912153‚ 34848827 Comment: show Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant. 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705254, 28912153, 34848827). (less) Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes

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 structure [Myriad internal data].

Comment:

Citations for somatic classification of this variant

Title	Author	Journal	Year	Link
Sporadic and Lynch syndrome-associated mismatch repair-deficient brain tumors.	Kim H	Laboratory investigation; a journal of technical methods and pathology	2022	PMID: 34848827
Comprehensive Genomic Profiling of 282 Pediatric Low- and High-Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures.	Johnson A	The oncologist	2017	PMID: 28912153
Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations.	Buczkowicz P	Nature genetics	2014	PMID: 24705254

Submissions - Functional Data

functionally abnormal -- retained intron

assessed by RNAseq

Result:

junction spanning - intron inclusion with mutation (p=0.0)

Modifies an exonic cryptic donor site at NC_000017.10:g.7578205 from 1.26 to 4.27 bits. Significant p-values: junction spanning - intron inclusion with mutation (8 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.

Citation: PubMed: 31275557

Dr. Peter K. Rogan Lab, Western University

Accession: SCV006900340.1

Submitted: 2025-10-17

Assay description:

In the sample (TCGA-56-8625), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)

Disease context: Squamous cell lung carcinoma
Transcript, protein change: NM_000546.6:c.643A>G, S215G
Molecular phenotype measured: splicing
Cell line: TCGA-56-8625
Tissue: Lung Squamous Cell Carcinoma (LUSC)
Collection method: in vitro
Species: human
Number of controls: 330

functionally abnormal -- retained intron

assessed by RNAseq

Result:

junction spanning - intron inclusion with mutation (p=0.0)

Modifies an exonic cryptic donor site at NC_000017.10:g.7578205 from 1.26 to 4.27 bits. Significant p-values: junction spanning - intron inclusion with mutation (1 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.

Citation: PubMed: 31275557

Dr. Peter K. Rogan Lab, Western University

Accession: SCV006900341.1

Submitted: 2025-10-17

Assay description:

In the sample (TCGA-TM-A7CF), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)

Disease context: Glioma susceptibility 1
Transcript, protein change: NM_000546.6:c.643A>G, S215G
Molecular phenotype measured: splicing
Cell line: TCGA-TM-A7CF
Tissue: Brain Lower Grade Glioma (LGG)
Collection method: in vitro
Species: human
Number of controls: 609

functionally abnormal -- retained intron

assessed by RNAseq

Result:

junction spanning - intron inclusion with mutation (p=0.0)

Modifies an exonic cryptic donor site at NC_000017.10:g.7578205 from 1.26 to 4.27 bits. Significant p-values: junction spanning - intron inclusion with mutation (2 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.

Citation: PubMed: 31275557

Dr. Peter K. Rogan Lab, Western University

Accession: SCV006900342.1

Submitted: 2025-10-17

Assay description:

In the sample (TCGA-DU-7014), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)

Disease context: Glioma susceptibility 1
Transcript, protein change: NM_000546.6:c.643A>G, S215G
Molecular phenotype measured: splicing
Cell line: TCGA-DU-7014
Tissue: Brain Lower Grade Glioma (LGG)
Collection method: in vitro
Species: human
Number of controls: 609

functionally abnormal -- retained intron

assessed by RNAseq

Result:

junction spanning - intron inclusion (p=0.0312),junction spanning - intron inclusion with mutation (p=0.0)

Modifies an exonic cryptic donor site at NC_000017.10:g.7578205 from 1.26 to 4.27 bits. Significant p-values: junction spanning - intron inclusion (10 reads, p=0.0312), junction spanning - intron inclusion with mutation (8 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.

Citation: PubMed: 31275557

Dr. Peter K. Rogan Lab, Western University

Accession: SCV006900343.1

Submitted: 2025-10-17

Assay description:

In the sample (TCGA-IB-7887), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)

Disease context: Pancreatic adenocarcinoma
Transcript, protein change: NM_000546.6:c.643A>G, S215G
Molecular phenotype measured: splicing
Cell line: TCGA-IB-7887
Tissue: Pancreatic Adenocarcinoma (PAAD)
Collection method: in vitro
Species: human
Number of controls: 180

Text-mined citations for rs886039484 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 08, 2026