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NM_000546.6(TP53):c.892G>A (p.Glu298Lys) AND Hereditary cancer-predisposing syndrome

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Dec 15, 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:
RCV000130033.14

Allele description [Variation Report for NM_000546.6(TP53):c.892G>A (p.Glu298Lys)]

NM_000546.6(TP53):c.892G>A (p.Glu298Lys)

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.892G>A (p.Glu298Lys)
HGVS:
  • NC_000017.11:g.7673728C>T
  • NG_017013.2:g.18823G>A
  • NM_000546.6:c.892G>AMANE SELECT
  • NM_001126112.3:c.892G>A
  • NM_001126113.3:c.892G>A
  • NM_001126114.3:c.892G>A
  • NM_001126115.2:c.496G>A
  • NM_001126116.2:c.496G>A
  • NM_001126117.2:c.496G>A
  • NM_001126118.2:c.775G>A
  • NM_001276695.3:c.775G>A
  • NM_001276696.3:c.775G>A
  • NM_001276697.3:c.415G>A
  • NM_001276698.3:c.415G>A
  • NM_001276699.3:c.415G>A
  • NM_001276760.3:c.775G>A
  • NM_001276761.3:c.775G>A
  • NP_000537.3:p.Glu298Lys
  • NP_000537.3:p.Glu298Lys
  • NP_001119584.1:p.Glu298Lys
  • NP_001119585.1:p.Glu298Lys
  • NP_001119586.1:p.Glu298Lys
  • NP_001119587.1:p.Glu166Lys
  • NP_001119588.1:p.Glu166Lys
  • NP_001119589.1:p.Glu166Lys
  • NP_001119590.1:p.Glu259Lys
  • NP_001263624.1:p.Glu259Lys
  • NP_001263625.1:p.Glu259Lys
  • NP_001263626.1:p.Glu139Lys
  • NP_001263627.1:p.Glu139Lys
  • NP_001263628.1:p.Glu139Lys
  • NP_001263689.1:p.Glu259Lys
  • NP_001263690.1:p.Glu259Lys
  • LRG_321t1:c.892G>A
  • LRG_321:g.18823G>A
  • LRG_321p1:p.Glu298Lys
  • NC_000017.10:g.7577046C>T
  • NM_000546.4:c.892G>A
  • NM_000546.5(TP53):c.892G>A
  • NM_000546.5:c.892G>A
  • P04637:p.Glu298Lys
  • p.E298K
Protein change:
E139K
Links:
UniProtKB: P04637#VAR_045448; dbSNP: rs201744589
NCBI 1000 Genomes Browser:
rs201744589
Molecular consequence:
  • NM_000546.6:c.892G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.3:c.892G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.3:c.892G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.3:c.892G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.2:c.496G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.2:c.496G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.2:c.496G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.2:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.3:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.3:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.3:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.3:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.3:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.3:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.3:c.775G>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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000184859Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely benign
(Apr 25, 2018) 		germlineclinical testing

Citation Link,

SCV001342499Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Dec 15, 2022) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Mutations and deletions of the TP53 gene predict nonresponse to treatment and poor outcome in first relapse of childhood acute lymphoblastic leukemia.

Hof J, Krentz S, van Schewick C, Körner G, Shalapour S, Rhein P, Karawajew L, Ludwig WD, Seeger K, Henze G, von Stackelberg A, Hagemeier C, Eckert C, Kirschner-Schwabe R.

J Clin Oncol. 2011 Aug 10;29(23):3185-93. doi: 10.1200/JCO.2011.34.8144. Epub 2011 Jul 11.

PubMed [citation]
PMID:
21747090
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000184859.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Color Diagnostics, LLC DBA Color Health, SCV001342499.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This missense variant replaces glutamic acid with lysine at codon 298 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies have shown this variant to be functional in transcriptional transactivation and cell growth suppression assays (PMID: 12826609, 30224644). This variant has been reported in individuals affected with gastric cancer and acute lymphocytic leukemia in the literature (PMID: 21747090, 31949278). In a large international case-control study, this variant was reported in 1/60465 breast cancer cases and 2/53459 controls (OR=0.442, 95%CI 0.04 to 4.876, p-value=0.603; PMID: 33471991). This variant has been identified in 3/251492 chromosomes 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 20, 2024