VCV000376599.16 - ClinVar

NM_000546.6(TP53):c.730G>T (p.Gly244Cys)

Germline

Classification

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

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

5 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

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000546.6(TP53):c.730G>T (p.Gly244Cys)

Variation ID: 376599 Accession: VCV000376599.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7674233 (GRCh38) [ NCBI UCSC ] 17: 7577551 (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	Apr 28, 2025	Apr 15, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.730G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000537.3:p.Gly244Cys	missense
NM_001126112.3:c.730G>T	NP_001119584.1:p.Gly244Cys	missense
NM_001126113.3:c.730G>T	NP_001119585.1:p.Gly244Cys	missense
NM_001126114.3:c.730G>T	NP_001119586.1:p.Gly244Cys	missense
NM_001126115.2:c.334G>T	NP_001119587.1:p.Gly112Cys	missense
NM_001126116.2:c.334G>T	NP_001119588.1:p.Gly112Cys	missense
NM_001126117.2:c.334G>T	NP_001119589.1:p.Gly112Cys	missense
NM_001126118.2:c.613G>T	NP_001119590.1:p.Gly205Cys	missense
NM_001276695.3:c.613G>T	NP_001263624.1:p.Gly205Cys	missense
NM_001276696.3:c.613G>T	NP_001263625.1:p.Gly205Cys	missense
NM_001276697.3:c.253G>T	NP_001263626.1:p.Gly85Cys	missense
NM_001276698.3:c.253G>T	NP_001263627.1:p.Gly85Cys	missense
NM_001276699.3:c.253G>T	NP_001263628.1:p.Gly85Cys	missense
NM_001276760.3:c.613G>T	NP_001263689.1:p.Gly205Cys	missense
NM_001276761.3:c.613G>T	NP_001263690.1:p.Gly205Cys	missense
NC_000017.11:g.7674233C>A
NC_000017.10:g.7577551C>A
NG_017013.2:g.18318G>T
LRG_321:g.18318G>T
LRG_321t1:c.730G>T	LRG_321p1:p.Gly244Cys

... more HGVS ... less HGVS

Protein change

G112C, G205C, G244C, G85C

Other names

Canonical SPDI

NC_000017.11:7674232:C:A

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: CA16603021 dbSNP: rs1057519989 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	3584	3685

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	Uncertain significance (1)	criteria provided, single submitter	Apr 15, 2024	RCV000538079.9
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 30, 2019	RCV001567979.5
Familial cancer of breast	Pathogenic (1)	criteria provided, single submitter	-	RCV001270273.4
Hereditary cancer-predisposing syndrome	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 10, 2023	RCV002379286.4

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 (Dec 30, 2019) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001791762.1 First in ClinVar: Aug 19, 2021 Last updated: Aug 19, 2021	Comment: Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression ability (Kato 2003, Kotler 2018); Not observed in large population cohorts … (more) Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression ability (Kato 2003, Kotler 2018); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31711486, 30123427, 31186738, 31588418, 29979965, 10226610, 20557307, 22931248, 22551440, 15580553, 11307149, 15902285, 14722922, 19558493, 31168460) (less)

Pathogenic (Jul 14, 2022) 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: SCV002674361.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.G244C pathogenic mutation (also known as c.730G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at … (more) The p.G244C pathogenic mutation (also known as c.730G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 730. The glycine at codon 244 is replaced by cysteine, an amino acid with highly 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). Another alteration at this position [p.G244S (c.730G>A)] has been reported in individuals with features of Li-Fraumeni syndrome (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9; Arcand SL et al. BMC Med. Genet. 2015 Apr;16:24; Hu H et al. Sci Rep. 2016 Jan;6:20221). The p.G244C alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). 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 was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, p.G244C is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)

Uncertain significance (Apr 15, 2024) 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: SCV000629861.6 First in ClinVar: Dec 26, 2017 Last updated: Feb 25, 2025	Publications: PubMed (3) PubMed: 12826609‚ 29979965‚ 30224644 Comment: This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 244 of the TP53 protein … (more) This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 244 of the TP53 protein (p.Gly244Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376599). 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). 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)

Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: case-control	Familial cancer of breast Affected status: yes Allele origin: somatic	Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo Accession: SCV001450490.2 First in ClinVar: Dec 12, 2020 Last updated: Apr 13, 2025	Publications: PubMed (2) PubMed: 30816478‚ 32000721 Age: 60-69 years Sex: female Geographic origin: Sri Lanka

Likely pathogenic (Nov 10, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Department of Pathology and Laboratory Medicine, Sinai Health System Accession: SCV006059708.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025	Publications: PubMed (2) PubMed: 12826609‚ 29979965

Comment:

Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression ability (Kato 2003, Kotler 2018); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31711486, 30123427, 31186738, 31588418, 29979965, 10226610, 20557307, 22931248, 22551440, 15580553, 11307149, 15902285, 14722922, 19558493, 31168460)

Comment:

The p.G244C pathogenic mutation (also known as c.730G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 730. The glycine at codon 244 is replaced by cysteine, an amino acid with highly 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). Another alteration at this position [p.G244S (c.730G>A)] has been reported in individuals with features of Li-Fraumeni syndrome (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9; Arcand SL et al. BMC Med. Genet. 2015 Apr;16:24; Hu H et al. Sci Rep. 2016 Jan;6:20221). The p.G244C alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). 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 was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, p.G244C 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 sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 244 of the TP53 protein (p.Gly244Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376599). 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). 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.

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
Pattern of nucleotide variants of TP53 and their correlation with the expression of p53 and its downstream proteins in a Sri Lankan cohort of breast and colorectal cancer patients.	Manoharan V	BMC cancer	2020	PMID: 32000721
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
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 rs1057519989 ...

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 May 17, 2025

ClinVar Genomic variation as it relates to human health

NM_000546.6(TP53):c.730G>T (p.Gly244Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1057519989 ...