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NM_000546.6(TP53):c.853G>A (p.Glu285Lys) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Jan 25, 2025
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000492206.14

Allele description [Variation Report for NM_000546.6(TP53):c.853G>A (p.Glu285Lys)]

NM_000546.6(TP53):c.853G>A (p.Glu285Lys)

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.853G>A (p.Glu285Lys)
HGVS:
  • NC_000017.11:g.7673767C>T
  • NG_017013.2:g.18784G>A
  • NM_000546.6:c.853G>AMANE SELECT
  • NM_001126112.3:c.853G>A
  • NM_001126113.3:c.853G>A
  • NM_001126114.3:c.853G>A
  • NM_001126115.2:c.457G>A
  • NM_001126116.2:c.457G>A
  • NM_001126117.2:c.457G>A
  • NM_001126118.2:c.736G>A
  • NM_001276695.3:c.736G>A
  • NM_001276696.3:c.736G>A
  • NM_001276697.3:c.376G>A
  • NM_001276698.3:c.376G>A
  • NM_001276699.3:c.376G>A
  • NM_001276760.3:c.736G>A
  • NM_001276761.3:c.736G>A
  • NP_000537.3:p.Glu285Lys
  • NP_000537.3:p.Glu285Lys
  • NP_001119584.1:p.Glu285Lys
  • NP_001119585.1:p.Glu285Lys
  • NP_001119586.1:p.Glu285Lys
  • NP_001119587.1:p.Glu153Lys
  • NP_001119588.1:p.Glu153Lys
  • NP_001119589.1:p.Glu153Lys
  • NP_001119590.1:p.Glu246Lys
  • NP_001263624.1:p.Glu246Lys
  • NP_001263625.1:p.Glu246Lys
  • NP_001263626.1:p.Glu126Lys
  • NP_001263627.1:p.Glu126Lys
  • NP_001263628.1:p.Glu126Lys
  • NP_001263689.1:p.Glu246Lys
  • NP_001263690.1:p.Glu246Lys
  • LRG_321t1:c.853G>A
  • LRG_321:g.18784G>A
  • LRG_321p1:p.Glu285Lys
  • NC_000017.10:g.7577085C>T
  • NM_000546.4:c.853G>A
  • NM_000546.5:c.853G>A
  • NM_001126114.1:c.853G>A
Protein change:
E126K
Links:
dbSNP: rs112431538
NCBI 1000 Genomes Browser:
rs112431538
Molecular consequence:
  • NM_000546.6:c.853G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.3:c.853G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.3:c.853G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.3:c.853G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.2:c.457G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.2:c.457G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.2:c.457G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.2:c.736G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.3:c.736G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.3:c.736G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.3:c.376G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.3:c.376G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.3:c.376G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.3:c.736G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.3:c.736G>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000581131Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jan 25, 2025) 		germlineclinical testing

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

Citation Link,

SCV002582343Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Jun 18, 2022) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Isolation of temperature-sensitive p53 mutations from a comprehensive missense mutation library.

Shiraishi K, Kato S, Han SY, Liu W, Otsuka K, Sakayori M, Ishida T, Takeda M, Kanamaru R, Ohuchi N, Ishioka C.

J Biol Chem. 2004 Jan 2;279(1):348-55. Epub 2003 Oct 13.

PubMed [citation]
PMID:
14559903

Inactive full-length p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers.

Dearth LR, Qian H, Wang T, Baroni TE, Zeng J, Chen SW, Yi SY, Brachmann RK.

Carcinogenesis. 2007 Feb;28(2):289-98. Epub 2006 Jul 21.

PubMed [citation]
PMID:
16861262
See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000581131.7

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

Description

The p.E285K (also known as c.853G>A) pathogenic mutation, located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 853. The glutamic acid at codon 285 is replaced by lysine, an amino acid with similar properties. The p.E285K variant has been identified in two Chinese families meeting Chompret critera. Both families have a proband with early onset breast cancers and family history of other TP53-related cancers (Lee DS et al. Breast Cancer Res. 2012; 14(2):R66). In addition, this alteration was identified in an individual with three primaries including breast cancer at 38, a leiomyosarcoma at 45, and thyroid cancer at 46 (Mitchell G et al. PLoS ONE. 2013 ; 8(7):e69026). The p.E285K variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Functional studies have indicated that this is a temperature sensitive alteration that has moderate activity at lower temperatures, and loses transactivation capability at 35 degrees in yeast and 37 degrees in mammalian cells (Grochova D et al. Oncogene 2008 Feb; 27(9):1243-52; Dearth LR et al. Carcinogenesis 2007 Feb; 28(2):289-98; Shiraishi K et al. J. Biol. Chem. 2004 Jan; 279(1):348-55). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). Another variant at the same position, p.E285V, was also identified as a de novo alteration in a child with both choriod plexus carcinoma and adrenocortical carcinoma by 1.5 years of age (Russell-Swetek A et al. J. Med. Genet. 2008 Sep; 45(9):603-6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

From Genome-Nilou Lab, SCV002582343.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 16, 2025