NM_000546.6(TP53):c.404G>T (p.Cys135Phe) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 31, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000492398.7

Allele description [Variation Report for NM_000546.6(TP53):c.404G>T (p.Cys135Phe)]

NM_000546.6(TP53):c.404G>T (p.Cys135Phe)

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.404G>T (p.Cys135Phe)
HGVS:
  • NC_000017.11:g.7675208C>A
  • NG_017013.2:g.17343G>T
  • NM_000546.6:c.404G>TMANE SELECT
  • NM_001126112.3:c.404G>T
  • NM_001126113.3:c.404G>T
  • NM_001126114.3:c.404G>T
  • NM_001126115.2:c.8G>T
  • NM_001126116.2:c.8G>T
  • NM_001126117.2:c.8G>T
  • NM_001126118.2:c.287G>T
  • NM_001276695.3:c.287G>T
  • NM_001276696.3:c.287G>T
  • NM_001276697.3:c.-74G>T
  • NM_001276698.3:c.-74G>T
  • NM_001276699.3:c.-74G>T
  • NM_001276760.3:c.287G>T
  • NM_001276761.3:c.287G>T
  • NP_000537.3:p.Cys135Phe
  • NP_000537.3:p.Cys135Phe
  • NP_001119584.1:p.Cys135Phe
  • NP_001119585.1:p.Cys135Phe
  • NP_001119586.1:p.Cys135Phe
  • NP_001119587.1:p.Cys3Phe
  • NP_001119588.1:p.Cys3Phe
  • NP_001119589.1:p.Cys3Phe
  • NP_001119590.1:p.Cys96Phe
  • NP_001263624.1:p.Cys96Phe
  • NP_001263625.1:p.Cys96Phe
  • NP_001263689.1:p.Cys96Phe
  • NP_001263690.1:p.Cys96Phe
  • LRG_321t1:c.404G>T
  • LRG_321:g.17343G>T
  • LRG_321p1:p.Cys135Phe
  • NC_000017.10:g.7578526C>A
  • NM_000546.4:c.404G>T
  • NM_000546.5:c.404G>T
Protein change:
C135F
Links:
dbSNP: rs587781991
Molecular consequence:
  • NM_001276697.3:c.-74G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001276698.3:c.-74G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001276699.3:c.-74G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000546.6:c.404G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.3:c.404G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.3:c.404G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.3:c.404G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.2:c.8G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.2:c.8G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.2:c.8G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.2:c.287G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.3:c.287G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.3:c.287G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.3:c.287G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.3:c.287G>T - 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
SCV000581086Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(May 31, 2024) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Correction: Novel Insight into Mutational Landscape of Head and Neck Squamous Cell Carcinoma.

Gaykalova DA, Mambo E, Choudhary A, Houghton J, Buddavarapu K, Sanford T, Darden W, Adai A, Hadd A, Latham G, Danilova LV, Bishop J, Li RJ, Westra WH, Hennessey P, Koch WM, Ochs MF, Califano JA, Sun W.

PLoS One. 2020;15(5):e0233409. doi: 10.1371/journal.pone.0233409.

PubMed [citation]
PMID:
32401780
PMCID:
PMC7219749

Details of each submission

From Ambry Genetics, SCV000581086.7

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

Description

The p.C135F pathogenic mutation (also known as c.404G>T), located in coding exon 4 of the TP53 gene, results from a G to T substitution at nucleotide position 404. The cysteine at codon 135 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant has been reported as a somatic mutation 64 times in various tumors, but not as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). This variant is located in the highly-conserved DNA binding domain of the p53 protein and is reported to have loss of transactivation capacity in yeast based assays (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). 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). In addition, structural analysis suggests this variant, which is a buried residue in the secondary shell of the DNA binding surface, is structurally destabilizing (Cho Y et al. Science. 1994 Jul 15;265(5170):346-55). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Last Updated: Apr 12, 2026

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