VCV000376605.14 - ClinVar

NM_000546.6(TP53):c.796G>C (p.Gly266Arg)

Germline

Classification

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

Pathogenic

4 out of 4 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

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000546.6(TP53):c.796G>C (p.Gly266Arg)

Variation ID: 376605 Accession: VCV000376605.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7673824 (GRCh38) [ NCBI UCSC ] 17: 7577142 (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	Mar 8, 2017	Feb 25, 2025	Jun 18, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.796G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000537.3:p.Gly266Arg	missense
NM_001126112.3:c.796G>C	NP_001119584.1:p.Gly266Arg	missense
NM_001126113.3:c.796G>C	NP_001119585.1:p.Gly266Arg	missense
NM_001126114.3:c.796G>C	NP_001119586.1:p.Gly266Arg	missense
NM_001126115.2:c.400G>C	NP_001119587.1:p.Gly134Arg	missense
NM_001126116.2:c.400G>C	NP_001119588.1:p.Gly134Arg	missense
NM_001126117.2:c.400G>C	NP_001119589.1:p.Gly134Arg	missense
NM_001126118.2:c.679G>C	NP_001119590.1:p.Gly227Arg	missense
NM_001276695.3:c.679G>C	NP_001263624.1:p.Gly227Arg	missense
NM_001276696.3:c.679G>C	NP_001263625.1:p.Gly227Arg	missense
NM_001276697.3:c.319G>C	NP_001263626.1:p.Gly107Arg	missense
NM_001276698.3:c.319G>C	NP_001263627.1:p.Gly107Arg	missense
NM_001276699.3:c.319G>C	NP_001263628.1:p.Gly107Arg	missense
NM_001276760.3:c.679G>C	NP_001263689.1:p.Gly227Arg	missense
NM_001276761.3:c.679G>C	NP_001263690.1:p.Gly227Arg	missense
NC_000017.11:g.7673824C>G
NC_000017.10:g.7577142C>G
NG_017013.2:g.18727G>C
LRG_321:g.18727G>C
LRG_321t1:c.796G>C	LRG_321p1:p.Gly266Arg

... more HGVS ... less HGVS

Protein change

G134R, G227R, G266R, G107R

Other names

Canonical SPDI

NC_000017.11:7673823:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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: CA16603026 dbSNP: rs1057519990 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	3540	3639

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.
Li-Fraumeni syndrome 1	Pathogenic (1)	criteria provided, single submitter	Jun 18, 2022	RCV002289526.3
Li-Fraumeni syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 29, 2022	RCV000803659.10
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 18, 2022	RCV001027017.6

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.
Pathogenic (Jun 18, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002582459.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Pathogenic (Jun 18, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002583119.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Pathogenic (Jul 02, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001189505.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 27523101 Comment: The p.G266R pathogenic mutation (also known as c.796G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at … (more) The p.G266R pathogenic mutation (also known as c.796G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at nucleotide position 796. The glycine at codon 266 is replaced by arginine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (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 (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 leading to the same amino acid change (c.796G>A) was reported in an individual with adrenocortical carcinoma and gliosarcoma and a family history of leiomyosarcoma, acute myeloid leukemia, breast cancer and melanoma (Guidi M et al. Future Oncol. 2017 Jan;13(1):9-12). In addition, another alteration at this amino acid position [p.G266E (c.797G>A)] was observed in an individual with medulloblastoma (Kool M et al. Cancer Cell. 2014 Mar; 25(3):393-405), and in patients meeting Chompret criteria (Ambry internal data). 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)
Pathogenic (Apr 29, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000943541.5 First in ClinVar: Aug 14, 2019 Last updated: Feb 25, 2025	Publications: PubMed (6) PubMed: 27523101‚ 12826609‚ 16827139‚ 20407015‚ 29979965‚ 30224644 Comment: This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 27523101; external communication). This variant is not present in population … (more) This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 27523101; external communication). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 266 of the TP53 protein (p.Gly266Arg). ClinVar contains an entry for this variant (Variation ID: 376605). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16827139, 20407015, 29979965, 30224644). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. (less)

Comment:

The p.G266R pathogenic mutation (also known as c.796G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at nucleotide position 796. The glycine at codon 266 is replaced by arginine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (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 (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 leading to the same amino acid change (c.796G>A) was reported in an individual with adrenocortical carcinoma and gliosarcoma and a family history of leiomyosarcoma, acute myeloid leukemia, breast cancer and melanoma (Guidi M et al. Future Oncol. 2017 Jan;13(1):9-12). In addition, another alteration at this amino acid position [p.G266E (c.797G>A)] was observed in an individual with medulloblastoma (Kool M et al. Cancer Cell. 2014 Mar; 25(3):393-405), and in patients meeting Chompret criteria (Ambry internal data). 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:

This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 27523101; external communication). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 266 of the TP53 protein (p.Gly266Arg). ClinVar contains an entry for this variant (Variation ID: 376605). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16827139, 20407015, 29979965, 30224644). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Brain tumors in Li-Fraumeni syndrome: a commentary and a case of a gliosarcoma patient.	Guidi M	Future oncology (London, England)	2017	PMID: 27523101
Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation.	Jordan JJ	Molecular cancer research : MCR	2010	PMID: 20407015
P53 mutants suppress ZBP-89 function.	Okada M	Anticancer research	2006	PMID: 16827139
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 rs1057519990 ...

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 26, 2025

ClinVar Genomic variation as it relates to human health

NM_000546.6(TP53):c.796G>C (p.Gly266Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1057519990 ...