NM_000546.6(TP53):c.843C>A (p.Asp281Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 20, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002446795.4

Allele description [Variation Report for NM_000546.6(TP53):c.843C>A (p.Asp281Glu)]

NM_000546.6(TP53):c.843C>A (p.Asp281Glu)

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.843C>A (p.Asp281Glu)

HGVS:

NC_000017.11:g.7673777G>T
NG_017013.2:g.18774C>A
NM_000546.6:c.843C>AMANE SELECT
NM_001126112.3:c.843C>A
NM_001126113.3:c.843C>A
NM_001126114.3:c.843C>A
NM_001126115.2:c.447C>A
NM_001126116.2:c.447C>A
NM_001126117.2:c.447C>A
NM_001126118.2:c.726C>A
NM_001276695.3:c.726C>A
NM_001276696.3:c.726C>A
NM_001276697.3:c.366C>A
NM_001276698.3:c.366C>A
NM_001276699.3:c.366C>A
NM_001276760.3:c.726C>A
NM_001276761.3:c.726C>A
NP_000537.3:p.Asp281Glu
NP_000537.3:p.Asp281Glu
NP_001119584.1:p.Asp281Glu
NP_001119585.1:p.Asp281Glu
NP_001119586.1:p.Asp281Glu
NP_001119587.1:p.Asp149Glu
NP_001119588.1:p.Asp149Glu
NP_001119589.1:p.Asp149Glu
NP_001119590.1:p.Asp242Glu
NP_001263624.1:p.Asp242Glu
NP_001263625.1:p.Asp242Glu
NP_001263626.1:p.Asp122Glu
NP_001263627.1:p.Asp122Glu
NP_001263628.1:p.Asp122Glu
NP_001263689.1:p.Asp242Glu
NP_001263690.1:p.Asp242Glu
LRG_321t1:c.843C>A
LRG_321:g.18774C>A
LRG_321p1:p.Asp281Glu
NC_000017.10:g.7577095G>T
NM_000546.4:c.843C>A
NM_000546.5:c.843C>A

Protein change:

D122E

Links:

dbSNP: rs1057519984

NCBI 1000 Genomes Browser:

rs1057519984

Molecular consequence:

NM_000546.6:c.843C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.843C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.843C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.843C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.447C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.447C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.447C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.726C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.726C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.726C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.366C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.366C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.366C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.726C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.726C>A - 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
SCV002677815	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jan 20, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002677815

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jan 20, 2021)

germline

clinical testing

Citation Link

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

Details of each submission

From Ambry Genetics, SCV002677815.2

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

Description

The p.D281E variant (also known as c.843C>A), located in coding exon 7 of the TP53 gene, results from a C to A substitution at nucleotide position 843. The aspartic acid at codon 281 is replaced by glutamic acid, an amino acid with highly similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). This alteration has been identified in a family meeting criteria for Li-Fraumeni syndrome; of note, an alteration in PTEN (designated as IVS1-1G>A) was also identified in this family (Akouchekian M et al. Med J Islam Repub Iran 2016 May;30:378). This alteration has also been identified in a 19-year-old proband with osteosarcoma (Mitchell G et al. PLoS ONE 2013 Jul;8(7):e69026). 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 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 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 majority of available evidence to date, this variant is likely to be pathogenic.

#	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 25, 2025

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