VCV000634768.14 - ClinVar

NM_000546.6(TP53):c.467G>C (p.Arg156Pro)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (1); Likely pathogenic (3)

4 out of 5 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 midline glioma, H3 K27M-mutant

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

Variant Details

Identifiers

NM_000546.6(TP53):c.467G>C (p.Arg156Pro)

Variation ID: 634768 Accession: VCV000634768.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7675145 (GRCh38) [ NCBI UCSC ] 17: 7578463 (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	Jun 17, 2019	May 30, 2026	Mar 11, 2026
Somatic - Clinical impact	Nov 22, 2025	Nov 22, 2025	Nov 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.467G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000537.3:p.Arg156Pro	missense
NM_001126112.3:c.467G>C	NP_001119584.1:p.Arg156Pro	missense
NM_001126113.3:c.467G>C	NP_001119585.1:p.Arg156Pro	missense
NM_001126114.3:c.467G>C	NP_001119586.1:p.Arg156Pro	missense
NM_001126115.2:c.71G>C	NP_001119587.1:p.Arg24Pro	missense
NM_001126116.2:c.71G>C	NP_001119588.1:p.Arg24Pro	missense
NM_001126117.2:c.71G>C	NP_001119589.1:p.Arg24Pro	missense
NM_001126118.2:c.350G>C	NP_001119590.1:p.Arg117Pro	missense
NM_001276695.3:c.350G>C	NP_001263624.1:p.Arg117Pro	missense
NM_001276696.3:c.350G>C	NP_001263625.1:p.Arg117Pro	missense
NM_001276697.3:c.-11G>C		5 prime UTR
NM_001276698.3:c.-11G>C		5 prime UTR
NM_001276699.3:c.-11G>C		5 prime UTR
NM_001276760.3:c.350G>C	NP_001263689.1:p.Arg117Pro	missense
NM_001276761.3:c.350G>C	NP_001263690.1:p.Arg117Pro	missense
NC_000017.11:g.7675145C>G
NC_000017.10:g.7578463C>G
NG_017013.2:g.17406G>C
LRG_321:g.17406G>C
LRG_321t1:c.467G>C	LRG_321p1:p.Arg156Pro

... more HGVS ... less HGVS

Protein change

R117P, R156P, R24P

Other names

Canonical SPDI

NC_000017.11:7675144:C:G

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: CA397842068 dbSNP: rs371524413 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	3930	4035

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.
Ovarian neoplasm	Likely pathogenic (1)	no assertion criteria provided	Dec 1, 2018	RCV000785506.2
Hereditary cancer-predisposing syndrome	Likely pathogenic (1)	criteria provided, single submitter	Jan 12, 2024	RCV001022886.3
Li-Fraumeni syndrome	Pathogenic (1)	criteria provided, single submitter	Sep 29, 2024	RCV002536879.5
not provided	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 11, 2026	RCV004777866.2

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.
Likely pathogenic (Jan 12, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV001184673.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Publications: PubMed (8) PubMed: 11429705‚ 11896595‚ 12826609‚ 27621308‚ 29979965‚ 35974385‚ 7732013‚ 8208536 Comment: show The p.R156P variant (also known as c.467G>C), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide position 467. The arginine at codon 156 is replaced by proline, an amino acid with dissimilar properties. This variant has been reported in a family with strong history of AML and other cancers (Zebisch A et al. Blood. 2016 11;128:2270-2272). This alteration has also been reported in an individual with a personal history of glioma/PNET and gliosarcoma with a family history of breast cancer and leukemia (Penkert J et al. J Hematol Oncol, 2022 Aug;15:107). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 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). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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) 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 (May 03, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV005387970.1 First in ClinVar: Nov 10, 2024 Last updated: Nov 10, 2024	Comment: show Published functional studies demonstrate a damaging effect: non-functional transactivation and impaired growth suppression ability (PMID: 12826609, 29979965, 30224644); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30224644, 29979965, 30720243, 30840781, 11429705, 9268986, 7732013, 15510160, 7935394, 9364015, 11896595, 14559903, 12917626, 7718482, 18489080, 12826609, 8208536, 35974385, 27621308) (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

Pathogenic (Sep 29, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Li-Fraumeni syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003442488.4 First in ClinVar: Feb 07, 2023 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 12826609‚ 27621308‚ 29979965‚ 30224644 Comment: show This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 156 of the TP53 protein (p.Arg156Pro). 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 (PMID: 27621308). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 634768). Invitae Evidence Modeling incorporating data from in vitro 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). This variant disrupts the p.Arg156 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as 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 (Mar 11, 2026) C Contributing to aggregate classification	criteria provided, single submitter (DASA Assertion Criteria)	not provided	Dasa Accession: SCV007597824.1 First in ClinVar: May 30, 2026 Last updated: May 30, 2026	Comment: show NM_000546.6(TP53):c.467G>C (p.Arg156Pro) is a missense variant that results in the substitution of arginine with proline. This variant has been reported in individuals with related phenotype. Functional evidence supports a deleterious effect on the gene or gene product. The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as likely 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: SCV000924078.1 First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019	Observation: 1 Collection method: research Allele origin: somatic Affected status: yes more Observation 1 Collection method: research Allele origin: somatic Affected status: yes Platform type: next-gen sequencing

Comment:

The p.R156P variant (also known as c.467G>C), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide position 467. The arginine at codon 156 is replaced by proline, an amino acid with dissimilar properties. This variant has been reported in a family with strong history of AML and other cancers (Zebisch A et al. Blood. 2016 11;128:2270-2272). This alteration has also been reported in an individual with a personal history of glioma/PNET and gliosarcoma with a family history of breast cancer and leukemia (Penkert J et al. J Hematol Oncol, 2022 Aug;15:107). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 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). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

Comment:

Published functional studies demonstrate a damaging effect: non-functional transactivation and impaired growth suppression ability (PMID: 12826609, 29979965, 30224644); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30224644, 29979965, 30720243, 30840781, 11429705, 9268986, 7732013, 15510160, 7935394, 9364015, 11896595, 14559903, 12917626, 7718482, 18489080, 12826609, 8208536, 35974385, 27621308)

Comment:

Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, 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 (PMIDs: 12826609, 30224644). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705251, 28966033, 22661320, 34796414, 33433639).

Comment:

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 156 of the TP53 protein (p.Arg156Pro). 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 (PMID: 27621308). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 634768). Invitae Evidence Modeling incorporating data from in vitro 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). This variant disrupts the p.Arg156 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Comment:

NM_000546.6(TP53):c.467G>C (p.Arg156Pro) is a missense variant that results in the substitution of arginine with proline. This variant has been reported in individuals with related phenotype. Functional evidence supports a deleterious effect on the gene or gene product. The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as likely pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genotype-phenotype associations within the Li-Fraumeni spectrum: a report from the German Registry.	Penkert J	Journal of hematology & oncology	2022	PMID: 35974385
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
Acute myeloid leukemia with TP53 germ line mutations.	Zebisch A	Blood	2016	PMID: 27621308
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
Tumour p53 mutations exhibit promoter selective dominance over wild type p53.	Monti P	Oncogene	2002	PMID: 11896595
p53 mutants can often transactivate promoters containing a p21 but not Bax or PIG3 responsive elements.	Campomenosi P	Oncogene	2001	PMID: 11429705
A simple p53 functional assay for screening cell lines, blood, and tumors.	Flaman JM	Proceedings of the National Academy of Sciences of the United States of America	1995	PMID: 7732013
Transactivational and DNA binding abilities of endogenous p53 in p53 mutant cell lines.	Park DJ	Oncogene	1994	PMID: 8208536

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 midline glioma, H3 K27M-mutant	Tier I (Strong) - diagnostic - supports diagnosis (1)		Nov 28, 2023	RCV006254152.1

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 28, 2023) C Contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Diffuse midline glioma, H3 K27M-mutant	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007104610.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (7) PubMed: 12826609‚ 22661320‚ 24705251‚ 28966033‚ 30224644‚ 33433639‚ 34796414 Comment: show Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, 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 (PMIDs: 12826609, 30224644). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705251, 28966033, 22661320, 34796414, 33433639). (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:

Citations for somatic classification of this variant

Title	Author	Journal	Year	Link
H3K27M-mutant diffuse midline gliomas should be further molecularly stratified: an integrated analysis of 669 patients.	Vuong HG	Journal of neuro-oncology	2021	PMID: 34796414
Mutations within FGFR1 are associated with superior outcome in a series of 83 diffuse midline gliomas with H3F3A K27M mutations.	Schüller U	Acta neuropathologica	2021	PMID: 33433639
Mutational processes shape the landscape of TP53 mutations in human cancer.	Giacomelli AO	Nature genetics	2018	PMID: 30224644
Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.	Mackay A	Cancer cell	2017	PMID: 28966033
The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma.	Wu G	Nature genetics	2014	PMID: 24705251
K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.	Khuong-Quang DA	Acta neuropathologica	2012	PMID: 22661320
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 rs371524413 ...

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 Jun 06, 2026