NM_000546.5(TP53):c.892G>A (p.Glu298Lys) AND Li-Fraumeni syndrome

Clinical significance:Likely benign (Last evaluated: Aug 28, 2019)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000206802.10

Allele description [Variation Report for NM_000546.5(TP53):c.892G>A (p.Glu298Lys)]

NM_000546.5(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_000546.5(TP53):c.892G>A (p.Glu298Lys)
HGVS:
  • NC_000017.11:g.7673728C>T
  • NG_017013.2:g.18823G>A
  • NM_000546.5:c.892G>A
  • NM_001126112.2:c.892G>A
  • NM_001126113.2:c.892G>A
  • NM_001126114.2:c.892G>A
  • NM_001126115.1:c.496G>A
  • NM_001126116.1:c.496G>A
  • NM_001126117.1:c.496G>A
  • NM_001126118.1:c.775G>A
  • NM_001276695.2:c.775G>A
  • NM_001276696.2:c.775G>A
  • NM_001276697.2:c.415G>A
  • NM_001276698.2:c.415G>A
  • NM_001276699.2:c.415G>A
  • NM_001276760.2:c.775G>A
  • NM_001276761.2:c.775G>A
  • 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_321t2:c.892G>A
  • LRG_321t3:c.892G>A
  • LRG_321t4:c.892G>A
  • LRG_321t5:c.496G>A
  • LRG_321t6:c.496G>A
  • LRG_321t7:c.496G>A
  • LRG_321t8:c.775G>A
  • LRG_321:g.18823G>A
  • LRG_321:p.Glu298Lys
  • LRG_321p1:p.Glu298Lys
  • LRG_321p3:p.Glu298Lys
  • LRG_321p4:p.Glu298Lys
  • LRG_321p5:p.Glu166Lys
  • LRG_321p6:p.Glu166Lys
  • LRG_321p7:p.Glu166Lys
  • LRG_321p8:p.Glu259Lys
  • NC_000017.10:g.7577046C>T
  • NM_000546.4:c.892G>A
  • NM_000546.5(TP53):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_000546.5:c.892G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.2:c.892G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.2:c.892G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.2:c.892G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.1:c.496G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.1:c.496G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.1:c.496G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.1:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.2:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.2:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.2:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.2:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Li-Fraumeni syndrome (LFS)
Synonyms:
Sarcoma family syndrome of Li and Fraumeni
Identifiers:
MONDO: MONDO:0018875; MedGen: C0085390; OMIM: PS151623

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000260657Invitaecriteria provided, single submitter
Uncertain significance
(Oct 18, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001142530ClinGen TP53 Variant Curation Expert Panel,ClinGenreviewed by expert panel
Likely benign
(Aug 28, 2019)
germlinecuration

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Citations

PubMed

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, K├Ârner 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

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
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000260657.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces glutamic acid with lysine at codon 298 of the TP53 protein (p.Glu298Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs201744589, ExAC 0.009%). This variant has been observed in individual(s) affected with leukemia (PMID: 21747090). However, it is unclear if this variant emerged at relapse diagnosis or not. ClinVar contains an entry for this variant (Variation ID: 141483). This variant has been reported not to substantially affect TP53 protein function (PMID: 12826609, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From ClinGen TP53 Variant Curation Expert Panel,ClinGen, SCV001142530.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). In summary, TP53 c.892G>A; p.Glu298Lys meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4 and BS3.

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

Last Updated: Aug 27, 2021

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