NM_000546.6(TP53):c.7G>A (p.Glu3Lys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jun 18, 2022
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:: RCV001525558.7

Allele description [Variation Report for NM_000546.6(TP53):c.7G>A (p.Glu3Lys)]

NM_000546.6(TP53):c.7G>A (p.Glu3Lys)

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.7G>A (p.Glu3Lys)

HGVS:

NC_000017.11:g.7676588C>T
NG_017013.2:g.15963G>A
NM_000546.6:c.7G>AMANE SELECT
NM_001126112.3:c.7G>A
NM_001126113.3:c.7G>A
NM_001126114.3:c.7G>A
NM_001126118.2:c.-228G>A
NM_001276695.3:c.-111G>A
NM_001276696.3:c.-111G>A
NM_001276760.3:c.-111G>A
NM_001276761.3:c.-111G>A
NP_000537.3:p.Glu3Lys
NP_001119584.1:p.Glu3Lys
NP_001119585.1:p.Glu3Lys
NP_001119586.1:p.Glu3Lys
LRG_321t1:c.7G>A
LRG_321:g.15963G>A
NC_000017.10:g.7579906C>T
NM_000546.4:c.7G>A
NM_000546.5:c.7G>A

Protein change:

E3K

Links:

dbSNP: rs2073524362

NCBI 1000 Genomes Browser:

rs2073524362

Molecular consequence:

NM_001126118.2:c.-228G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276695.3:c.-111G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276696.3:c.-111G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276760.3:c.-111G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276761.3:c.-111G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000546.6:c.7G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.7G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.7G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.7G>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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protein lin-54 homolog isoform X2 [Homo sapiens]
protein lin-54 homolog isoform X2 [Homo sapiens]
gi|1034638391|ref|XP_016863217.1|

Protein
Chain A, Histone H3.2
Chain A, Histone H3.2
gi|1905004466|pdb|6XJD|A

Protein
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CD34+derived erythoblast co-culture with Plasmodium falciparum 3D7 (Dchip analysis)
Accession: GDS4558

GEO DataSets

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001735714	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 3, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002582191	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002678665	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (May 26, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001735714

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 3, 2020)

germline

clinical testing

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

SCV002582191

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 18, 2022)

germline

clinical testing

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

SCV002678665

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(May 26, 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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001735714.1

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

Description

This missense variant replaces glutamic acid with lysine at codon 3 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 that this variant has above wild-type activity in yeast transactivation assays (PMID: 12826609, IARC database) and is functional in human cell growth suppression assays (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

From Genome-Nilou Lab, SCV002582191.1

#	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

From Ambry Genetics, SCV002678665.2

#	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

Last Updated: Nov 10, 2024

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