NM_000546.6(TP53):c.701A>G (p.Tyr234Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 18, 2022
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:: RCV000492245.10

Allele description [Variation Report for NM_000546.6(TP53):c.701A>G (p.Tyr234Cys)]

NM_000546.6(TP53):c.701A>G (p.Tyr234Cys)

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.701A>G (p.Tyr234Cys)

Other names:

p.Y234C:TAC>TGC

HGVS:

NC_000017.11:g.7674262T>C
NG_017013.2:g.18289A>G
NM_000546.6:c.701A>GMANE SELECT
NM_001126112.3:c.701A>G
NM_001126113.3:c.701A>G
NM_001126114.3:c.701A>G
NM_001126115.2:c.305A>G
NM_001126116.2:c.305A>G
NM_001126117.2:c.305A>G
NM_001126118.2:c.584A>G
NM_001276695.3:c.584A>G
NM_001276696.3:c.584A>G
NM_001276697.3:c.224A>G
NM_001276698.3:c.224A>G
NM_001276699.3:c.224A>G
NM_001276760.3:c.584A>G
NM_001276761.3:c.584A>G
NP_000537.3:p.Tyr234Cys
NP_000537.3:p.Tyr234Cys
NP_001119584.1:p.Tyr234Cys
NP_001119585.1:p.Tyr234Cys
NP_001119586.1:p.Tyr234Cys
NP_001119587.1:p.Tyr102Cys
NP_001119588.1:p.Tyr102Cys
NP_001119589.1:p.Tyr102Cys
NP_001119590.1:p.Tyr195Cys
NP_001263624.1:p.Tyr195Cys
NP_001263625.1:p.Tyr195Cys
NP_001263626.1:p.Tyr75Cys
NP_001263627.1:p.Tyr75Cys
NP_001263628.1:p.Tyr75Cys
NP_001263689.1:p.Tyr195Cys
NP_001263690.1:p.Tyr195Cys
LRG_321t1:c.701A>G
LRG_321:g.18289A>G
LRG_321p1:p.Tyr234Cys
NC_000017.10:g.7577580T>C
NM_000546.4:c.701A>G
NM_000546.5:c.701A>G
P04637:p.Tyr234Cys

Protein change:

Y102C

Links:

UniProtKB: P04637#VAR_005963; dbSNP: rs587780073

NCBI 1000 Genomes Browser:

rs587780073

Molecular consequence:

NM_000546.6:c.701A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.701A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.701A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.701A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.305A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.305A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.305A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.584A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.584A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.584A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.224A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.224A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.224A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.584A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.584A>G - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000581157	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jul 14, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16861262, 28724667 Citation Link,
SCV002582370	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely 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

SCV000581157

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jul 14, 2020)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV002582370

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely 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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients.

Sun J, Meng H, Yao L, Lv M, Bai J, Zhang J, Wang L, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Xie Y.

Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. doi: 10.1158/1078-0432.CCR-16-3227. Epub 2017 Jul 19.

PubMed [citation]

PMID:: 28724667

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000581157.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Y234C pathogenic mutation (also known as c.701A>G), located in coding exon 6 of the TP53 gene, results from an A to G substitution at nucleotide position 701. The tyrosine at codon 234 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in an individual with a personal history of B-CLL and leiomyosarcoma, and a family history of sarcoma, breast cancer, and leukemia (Pepper C et al. Cell Cycle. 2003 Jan-Feb;2(1):53-8). This alteration was also detected in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). This alteration has been shown to be deficient in transactivation and exhibits dominant negative properties in studies conducted in both yeast and mammalian cells (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Dearth LR et al. Carcinogenesis. 2007 Feb;28:289-98). 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, two other alterations at this position (p.Y234D, p.Y234H) have been identified in patients meeting criteria for Li-Fraumeni syndrome (Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science. 1994 Jul; 265(5170):346-55). This amino acid position is well 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.

#	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, SCV002582370.1

#	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: Nov 10, 2024

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