NM_000546.6(TP53):c.21T>A (p.Asp7Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Mar 7, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000128929.14

Allele description [Variation Report for NM_000546.6(TP53):c.21T>A (p.Asp7Glu)]

NM_000546.6(TP53):c.21T>A (p.Asp7Glu)

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.21T>A (p.Asp7Glu)

Other names:

p.D7E:GAT>GAA; NM_000546.6(TP53):c.21T>A

HGVS:

NC_000017.11:g.7676574A>T
NG_017013.2:g.15977T>A
NM_000546.6:c.21T>AMANE SELECT
NM_001126112.3:c.21T>A
NM_001126113.3:c.21T>A
NM_001126114.3:c.21T>A
NM_001126118.2:c.-214T>A
NM_001276695.3:c.-97T>A
NM_001276696.3:c.-97T>A
NM_001276760.3:c.-97T>A
NM_001276761.3:c.-97T>A
NP_000537.3:p.Asp7Glu
NP_000537.3:p.Asp7Glu
NP_001119584.1:p.Asp7Glu
NP_001119585.1:p.Asp7Glu
NP_001119586.1:p.Asp7Glu
LRG_321t1:c.21T>A
LRG_321:g.15977T>A
LRG_321p1:p.Asp7Glu
NC_000017.10:g.7579892A>T
NC_000017.10:g.7579892A>T
NM_000546.4:c.21T>A
NM_000546.5(TP53):c.21T>A
NM_000546.5:c.21T>A
p.Asp7Glu
p.D7E

Protein change:

D7E

Links:

dbSNP: rs587781277

NCBI 1000 Genomes Browser:

rs587781277

Molecular consequence:

NM_001126118.2:c.-214T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276695.3:c.-97T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276696.3:c.-97T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276760.3:c.-97T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276761.3:c.-97T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000546.6:c.21T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.21T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.21T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.21T>A - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

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phosphatidylinositol glycan, class F, isoform CRA_f [Homo sapiens]
phosphatidylinositol glycan, class F, isoform CRA_f [Homo sapiens]
gi|119620650|gb|EAX00245.1||gnl|WGS |hCP1815788

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000172800	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Jul 24, 2017)	germline	clinical testing	Citation Link,
SCV001736275	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 7, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12826609, 30224644, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000172800

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Jul 24, 2017)

germline

clinical testing

Citation Link,

SCV001736275

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 7, 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

Mutational processes shape the landscape of TP53 mutations in human cancer.

Giacomelli AO, Yang X, Lintner RE, McFarland JM, Duby M, Kim J, Howard TP, Takeda DY, Ly SH, Kim E, Gannon HS, Hurhula B, Sharpe T, Goodale A, Fritchman B, Steelman S, Vazquez F, Tsherniak A, Aguirre AJ, Doench JG, Piccioni F, Roberts CWM, et al.

Nat Genet. 2018 Oct;50(10):1381-1387. doi: 10.1038/s41588-018-0204-y. Epub 2018 Sep 17.

PubMed [citation]

PMID:: 30224644
PMCID:: PMC6168352

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000172800.9

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

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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 Color Diagnostics, LLC DBA Color Health, SCV001736275.2

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

Description

This missense variant replaces aspartic acid with glutamic acid at codon 7 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be functional in yeast transactivation assay (PMID: 12826609 and IARC database) and to lack a dominant negative effect or loss-of-function phenotype in human cell growth assay (PMID: 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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: Sep 29, 2024

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