NM_000546.6(TP53):c.404G>A (p.Cys135Tyr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 22, 2024
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:: RCV000130396.16

Allele description [Variation Report for NM_000546.6(TP53):c.404G>A (p.Cys135Tyr)]

NM_000546.6(TP53):c.404G>A (p.Cys135Tyr)

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>A (p.Cys135Tyr)

HGVS:

NC_000017.11:g.7675208C>T
NG_017013.2:g.17343G>A
NM_000546.6:c.404G>AMANE SELECT
NM_001126112.3:c.404G>A
NM_001126113.3:c.404G>A
NM_001126114.3:c.404G>A
NM_001126115.2:c.8G>A
NM_001126116.2:c.8G>A
NM_001126117.2:c.8G>A
NM_001126118.2:c.287G>A
NM_001276695.3:c.287G>A
NM_001276696.3:c.287G>A
NM_001276697.3:c.-74G>A
NM_001276698.3:c.-74G>A
NM_001276699.3:c.-74G>A
NM_001276760.3:c.287G>A
NM_001276761.3:c.287G>A
NP_000537.3:p.Cys135Tyr
NP_000537.3:p.Cys135Tyr
NP_001119584.1:p.Cys135Tyr
NP_001119585.1:p.Cys135Tyr
NP_001119586.1:p.Cys135Tyr
NP_001119587.1:p.Cys3Tyr
NP_001119588.1:p.Cys3Tyr
NP_001119589.1:p.Cys3Tyr
NP_001119590.1:p.Cys96Tyr
NP_001263624.1:p.Cys96Tyr
NP_001263625.1:p.Cys96Tyr
NP_001263689.1:p.Cys96Tyr
NP_001263690.1:p.Cys96Tyr
LRG_321t1:c.404G>A
LRG_321:g.17343G>A
LRG_321p1:p.Cys135Tyr
NC_000017.10:g.7578526C>T
NM_000546.4:c.404G>A
NM_000546.5:c.404G>A
P04637:p.Cys135Tyr
p.C135Y

Protein change:

C135Y

Links:

UniProtKB: P04637#VAR_044756; dbSNP: rs587781991

Molecular consequence:

NM_001276697.3:c.-74G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276698.3:c.-74G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276699.3:c.-74G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000546.6:c.404G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.404G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.404G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.404G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.8G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.8G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.8G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.287G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.287G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.287G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.287G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.287G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000185255	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Nov 22, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12826609, 16861262, 20407015, 29979965, 30224644, 30630526, 30840781 Citation Link,
SCV000686738	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 14, 2022)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 12826609, 15017592, 16247456, 16861262, 20407015, 21080251, 29979965, 30224644, 30630526, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185255

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Nov 22, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV000686738

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 14, 2022)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A quantitative model to predict pathogenicity of missense variants in the TP53 gene.

Fortuno C, Cipponi A, Ballinger ML, Tavtigian SV, Olivier M, Ruparel V, Haupt Y, Haupt S, Study ISK, Tucker K, Spurdle AB, Thomas DM, James PA.

Hum Mutat. 2019 Jun;40(6):788-800. doi: 10.1002/humu.23739. Epub 2019 Mar 18.

PubMed [citation]

PMID:: 30840781

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 (11)

Details of each submission

From Ambry Genetics, SCV000185255.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The p.C135Y pathogenic mutation (also known as c.404G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 404. The cysteine at codon 135 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been reported in one Chinese patient diagnosed with sporadic triple negative breast cancer; this individual also carried a likely pathogenic variant in the MSH6 gene (Yi D et al. Hum. Genomics. 2019 01;13:4). This variant has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant was detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Dearth LR et al. Carcinogenesis. 2007 Feb; 28(2):289-98; Jordan JJ et al. Mol. Cancer Res. 2010 May;8(5):701-16). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Internal 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; Ambry internal data). 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 variant is interpreted as a disease-causing mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000686738.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This missense variant replaces cysteine with tyrosine at codon 135 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies have shown that this variant yields protein that is non-functional in yeast transactivation assays (PMID: 12826609, 15017592, 16861262, 20407015), human cell proliferation assays (PMID: 29979965), and human cell growth suppression assays (PMID: 16247456, 30224644). This variant has been reported in a Chinese individual affected with gastric cancer (PMID: 21080251) and in a Chinese individual with sporadic triple-negative breast cancer carrying a second variant in MSH6 (PMID: 30630526). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	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: Jul 27, 2026

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