NM_000546.6(TP53):c.731G>A (p.Gly244Asp) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 18, 2022
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:: RCV000561866.8

Allele description [Variation Report for NM_000546.6(TP53):c.731G>A (p.Gly244Asp)]

NM_000546.6(TP53):c.731G>A (p.Gly244Asp)

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.731G>A (p.Gly244Asp)

HGVS:

NC_000017.11:g.7674232C>T
NG_017013.2:g.18319G>A
NM_000546.6:c.731G>AMANE SELECT
NM_001126112.3:c.731G>A
NM_001126113.3:c.731G>A
NM_001126114.3:c.731G>A
NM_001126115.2:c.335G>A
NM_001126116.2:c.335G>A
NM_001126117.2:c.335G>A
NM_001126118.2:c.614G>A
NM_001276695.3:c.614G>A
NM_001276696.3:c.614G>A
NM_001276697.3:c.254G>A
NM_001276698.3:c.254G>A
NM_001276699.3:c.254G>A
NM_001276760.3:c.614G>A
NM_001276761.3:c.614G>A
NP_000537.3:p.Gly244Asp
NP_000537.3:p.Gly244Asp
NP_001119584.1:p.Gly244Asp
NP_001119585.1:p.Gly244Asp
NP_001119586.1:p.Gly244Asp
NP_001119587.1:p.Gly112Asp
NP_001119588.1:p.Gly112Asp
NP_001119589.1:p.Gly112Asp
NP_001119590.1:p.Gly205Asp
NP_001263624.1:p.Gly205Asp
NP_001263625.1:p.Gly205Asp
NP_001263626.1:p.Gly85Asp
NP_001263627.1:p.Gly85Asp
NP_001263628.1:p.Gly85Asp
NP_001263689.1:p.Gly205Asp
NP_001263690.1:p.Gly205Asp
LRG_321t1:c.731G>A
LRG_321:g.18319G>A
LRG_321p1:p.Gly244Asp
NC_000017.10:g.7577550C>T
NM_000546.4:c.731G>A
NM_000546.5:c.731G>A

Protein change:

G112D

Links:

dbSNP: rs985033810

NCBI 1000 Genomes Browser:

rs985033810

Molecular consequence:

NM_000546.6:c.731G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.731G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.731G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.731G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.335G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.335G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.335G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.614G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.614G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.614G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.254G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.254G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.254G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.614G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.614G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; 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
SCV000667184	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Jun 4, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16861262, 29470806, 8023157 Citation Link,
SCV002582467	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000667184

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Jun 4, 2021)

germline

clinical testing

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

Citation Link,

SCV002582467

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 18, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Inactive full-length p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers.

Dearth LR, Qian H, Wang T, Baroni TE, Zeng J, Chen SW, Yi SY, Brachmann RK.

Carcinogenesis. 2007 Feb;28(2):289-98. Epub 2006 Jul 21.

PubMed [citation]

PMID:: 16861262

Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations.

Singh J, Thota N, Singh S, Padhi S, Mohan P, Deshwal S, Sur S, Ghosh M, Agarwal A, Sarin R, Ahmed R, Almel S, Chakraborti B, Raina V, DadiReddy PK, Smruti BK, Rajappa S, Dodagoudar C, Aggarwal S, Singhal M, Joshi A, Kumar R, et al.

Breast Cancer Res Treat. 2018 Jul;170(1):189-196. doi: 10.1007/s10549-018-4726-x. Epub 2018 Feb 22.

PubMed [citation]

PMID:: 29470806

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000667184.4

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

Description

The p.G244D pathogenic mutation (also known as c.731G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 731. The glycine at codon 244 is replaced by aspartic acid, an amino acid with similar properties. This variant has been detected in a Brazilian individual diagnosed with breast cancer at 40y and colorectal cancer (age unspecified) with a family history of early-onset bone cancer, breast cancer, sarcoma, and cancer of the female genital organs (Achatz MI et al. Cancer Lett. 2007 Jan 8;245(1-2):96-102). This variant was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170:189-196). The p.G244D variant has also been reported in children with Li-Fraumeni syndrome-related cancers (Renaux-Petel M et al. J. Med. Genet. 2018 03;55(3):173-180. Grobner S et al. Nature. 2018 03;555(7696):321-327). The p.G244D 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). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science. 1994 Jul; 265(5170):346-55). In addition, two alterations at this same position (p.G244S and p.G244V) have been identified in individuals meeting Chompret criteria (Krutilkova V et al. Eur J Cancer. 2005 Jul;41(11):1597-603; Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). 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	1	not provided	not provided		1	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002582467.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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