NM_000546.6(TP53):c.527G>A (p.Cys176Tyr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 23, 2023
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:: RCV000166045.10

Allele description [Variation Report for NM_000546.6(TP53):c.527G>A (p.Cys176Tyr)]

NM_000546.6(TP53):c.527G>A (p.Cys176Tyr)

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.527G>A (p.Cys176Tyr)

HGVS:

NC_000017.11:g.7675085C>T
NG_017013.2:g.17466G>A
NM_000546.6:c.527G>AMANE SELECT
NM_001126112.3:c.527G>A
NM_001126113.3:c.527G>A
NM_001126114.3:c.527G>A
NM_001126115.2:c.131G>A
NM_001126116.2:c.131G>A
NM_001126117.2:c.131G>A
NM_001126118.2:c.410G>A
NM_001276695.3:c.410G>A
NM_001276696.3:c.410G>A
NM_001276697.3:c.50G>A
NM_001276698.3:c.50G>A
NM_001276699.3:c.50G>A
NM_001276760.3:c.410G>A
NM_001276761.3:c.410G>A
NP_000537.3:p.Cys176Tyr
NP_000537.3:p.Cys176Tyr
NP_001119584.1:p.Cys176Tyr
NP_001119585.1:p.Cys176Tyr
NP_001119586.1:p.Cys176Tyr
NP_001119587.1:p.Cys44Tyr
NP_001119588.1:p.Cys44Tyr
NP_001119589.1:p.Cys44Tyr
NP_001119590.1:p.Cys137Tyr
NP_001263624.1:p.Cys137Tyr
NP_001263625.1:p.Cys137Tyr
NP_001263626.1:p.Cys17Tyr
NP_001263627.1:p.Cys17Tyr
NP_001263628.1:p.Cys17Tyr
NP_001263689.1:p.Cys137Tyr
NP_001263690.1:p.Cys137Tyr
LRG_321t1:c.527G>A
LRG_321:g.17466G>A
LRG_321p1:p.Cys176Tyr
NC_000017.10:g.7578403C>T
NM_000546.4:c.527G>A
NM_000546.5:c.527G>A
P04637:p.Cys176Tyr
p.C176Y

Protein change:

C137Y

Links:

UniProtKB: P04637#VAR_044921; dbSNP: rs786202962

NCBI 1000 Genomes Browser:

rs786202962

Molecular consequence:

NM_000546.6:c.527G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.527G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.527G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.527G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.131G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.131G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.131G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.410G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.410G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.410G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.50G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.50G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.50G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.410G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.410G>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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NADH dehydrogenase subunit 1, partial (mitochondrion) [Parnassius acco]
NADH dehydrogenase subunit 1, partial (mitochondrion) [Parnassius acco]
gi|1691428524|gb|QDE56604.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000216806	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 23, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11793474, 18555592, 26619011, 29070607, 30720243, 30840781, 9572492 Citation Link,
SCV002582492	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000216806

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 23, 2023)

germline

clinical testing

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

Citation Link,

SCV002582492

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 18, 2022)

germline

clinical testing

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

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
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Integrating mutation data and structural analysis of the TP53 tumor-suppressor protein.

Martin AC, Facchiano AM, Cuff AL, Hernandez-Boussard T, Olivier M, Hainaut P, Thornton JM.

Hum Mutat. 2002 Feb;19(2):149-64.

PubMed [citation]

PMID:: 11793474

Presence of dominant negative mutation of TP53 is a risk of early recurrence in oral cancer.

Hassan NM, Tada M, Hamada J, Kashiwazaki H, Kameyama T, Akhter R, Yamazaki Y, Yano M, Inoue N, Moriuchi T.

Cancer Lett. 2008 Oct 18;270(1):108-19. doi: 10.1016/j.canlet.2008.04.052. Epub 2008 Jun 13.

PubMed [citation]

PMID:: 18555592

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000216806.9

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

Description

The p.C176Y pathogenic mutation (also known as c.527G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 527. The cysteine at codon 176 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration is located in the highly conserved domain IV of the DNA binding domain, and is one of four residues necessary to bind the zinc molecule that stabilizes the beta sheet structure of the protein (Martin AC et al. Hum Mutat. 2002 Feb;19(2):149-64). Multiple yeast-based functional studies have demonstrated a loss of transactivation capability for this variant (Epstein CB et al. Oncogene 1998 Apr;16(16):2115-22; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Hassan NM et al. Cancer Lett. 2008 Oct; 270(1):108-19). 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). This alteration has been detected in at least one individual with classic Li-Fraumeni syndrome (LFS) tested by our laboratory (Ambry internal data), and was reported as a de novo alteration in an individual diagnosed with adrenocortical carcinoma at age 5 (Renaux-Petel M et al. J. Med. Genet. 2018 03;55(3):173-180). 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.

#	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 Genome-Nilou Lab, SCV002582492.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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