NM_000546.6(TP53):c.730G>T (p.Gly244Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 10, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002379286.4

Allele description [Variation Report for NM_000546.6(TP53):c.730G>T (p.Gly244Cys)]

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

Gene:

TP53:tumor protein p53 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

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

HGVS:

NC_000017.11:g.7674233C>A
NG_017013.2:g.18318G>T
NM_000546.6:c.730G>TMANE SELECT
NM_001126112.3:c.730G>T
NM_001126113.3:c.730G>T
NM_001126114.3:c.730G>T
NM_001126115.2:c.334G>T
NM_001126116.2:c.334G>T
NM_001126117.2:c.334G>T
NM_001126118.2:c.613G>T
NM_001276695.3:c.613G>T
NM_001276696.3:c.613G>T
NM_001276697.3:c.253G>T
NM_001276698.3:c.253G>T
NM_001276699.3:c.253G>T
NM_001276760.3:c.613G>T
NM_001276761.3:c.613G>T
NP_000537.3:p.Gly244Cys
NP_000537.3:p.Gly244Cys
NP_001119584.1:p.Gly244Cys
NP_001119585.1:p.Gly244Cys
NP_001119586.1:p.Gly244Cys
NP_001119587.1:p.Gly112Cys
NP_001119588.1:p.Gly112Cys
NP_001119589.1:p.Gly112Cys
NP_001119590.1:p.Gly205Cys
NP_001263624.1:p.Gly205Cys
NP_001263625.1:p.Gly205Cys
NP_001263626.1:p.Gly85Cys
NP_001263627.1:p.Gly85Cys
NP_001263628.1:p.Gly85Cys
NP_001263689.1:p.Gly205Cys
NP_001263690.1:p.Gly205Cys
LRG_321t1:c.730G>T
LRG_321:g.18318G>T
LRG_321p1:p.Gly244Cys
NC_000017.10:g.7577551C>A
NM_000546.4:c.730G>T
NM_000546.5:c.730G>T

Protein change:

G112C

Links:

dbSNP: rs1057519989

NCBI 1000 Genomes Browser:

rs1057519989

Molecular consequence:

NM_000546.6:c.730G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.730G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.730G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.730G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.334G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.334G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.334G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.613G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.613G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.613G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.253G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.253G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.253G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.613G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.613G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Hereditary neoplastic syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002674361	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jul 14, 2022)	germline	clinical testing	Citation Link,
SCV006059708	Department of Pathology and Laboratory Medicine, Sinai Health System	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12826609, 29979965, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002674361

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jul 14, 2022)

germline

clinical testing

Citation Link,

SCV006059708

Department of Pathology and Laboratory Medicine, Sinai Health System

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 10, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.

Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R, Ishioka C.

Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8424-9. Epub 2003 Jun 25.

PubMed [citation]

PMID:: 12826609
PMCID:: PMC166245

A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.

Kotler E, Shani O, Goldfeld G, Lotan-Pompan M, Tarcic O, Gershoni A, Hopf TA, Marks DS, Oren M, Segal E.

Mol Cell. 2018 Jul 5;71(1):178-190.e8. doi: 10.1016/j.molcel.2018.06.012. Erratum in: Mol Cell. 2018 Sep 6;71(5):873. doi: 10.1016/j.molcel.2018.08.013..

PubMed [citation]

PMID:: 29979965

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002674361.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System, SCV006059708.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

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