NM_000546.6(TP53):c.658T>A (p.Tyr220Asn) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 23, 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:: RCV000570507.4

Allele description [Variation Report for NM_000546.6(TP53):c.658T>A (p.Tyr220Asn)]

NM_000546.6(TP53):c.658T>A (p.Tyr220Asn)

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.658T>A (p.Tyr220Asn)

HGVS:

NC_000017.11:g.7674873A>T
NG_017013.2:g.17678T>A
NM_000546.6:c.658T>AMANE SELECT
NM_001126112.3:c.658T>A
NM_001126113.3:c.658T>A
NM_001126114.3:c.658T>A
NM_001126115.2:c.262T>A
NM_001126116.2:c.262T>A
NM_001126117.2:c.262T>A
NM_001126118.2:c.541T>A
NM_001276695.3:c.541T>A
NM_001276696.3:c.541T>A
NM_001276697.3:c.181T>A
NM_001276698.3:c.181T>A
NM_001276699.3:c.181T>A
NM_001276760.3:c.541T>A
NM_001276761.3:c.541T>A
NP_000537.3:p.Tyr220Asn
NP_001119584.1:p.Tyr220Asn
NP_001119585.1:p.Tyr220Asn
NP_001119586.1:p.Tyr220Asn
NP_001119587.1:p.Tyr88Asn
NP_001119588.1:p.Tyr88Asn
NP_001119589.1:p.Tyr88Asn
NP_001119590.1:p.Tyr181Asn
NP_001263624.1:p.Tyr181Asn
NP_001263625.1:p.Tyr181Asn
NP_001263626.1:p.Tyr61Asn
NP_001263627.1:p.Tyr61Asn
NP_001263628.1:p.Tyr61Asn
NP_001263689.1:p.Tyr181Asn
NP_001263690.1:p.Tyr181Asn
LRG_321:g.17678T>A
NC_000017.10:g.7578191A>T
NM_000546.4:c.658T>A

Protein change:

Y181N

Links:

dbSNP: rs530941076

NCBI 1000 Genomes Browser:

rs530941076

Molecular consequence:

NM_000546.6:c.658T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.658T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.658T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.658T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.262T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.262T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.262T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.541T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.541T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.541T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.181T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.181T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.181T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.541T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.541T>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000675343	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 23, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12826609, 26619011, 8023157 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000675343

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 23, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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

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

Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.

Chang MT, Asthana S, Gao SP, Lee BH, Chapman JS, Kandoth C, Gao J, Socci ND, Solit DB, Olshen AB, Schultz N, Taylor BS.

Nat Biotechnol. 2016 Feb;34(2):155-63. doi: 10.1038/nbt.3391. Epub 2015 Nov 30.

PubMed [citation]

PMID:: 26619011
PMCID:: PMC4744099

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000675343.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.Y220N pathogenic mutation (also known as c.658T>A), located in coding exon 5 of the TP53 gene, results from a T to A substitution at nucleotide position 658. The tyrosine at codon 220 is replaced by asparagine, an amino acid with dissimilar properties. This 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). 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 alteration at the same amino acid position (p.Y220C) has been reported in multiple individuals and families with classic Li-Fraumeni syndrome (Birch et al. Cancer Res. 1994 Mar 1;54(5):1298-304; Monti et al. Clin Cancer Res. 2007 Jul 1;13(13):3789-95; Melham-Bertrand et al. Cancer. 2012 Feb 15;118(4):908-13). Based on internal structural analysis, p.Y220N destabilizes a residue in an indicated functional domain to a greater degree than multiple pathogenic variants in the region (Cho Y et al. Science 1994 Jul;265:346-55). This variant has been 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

Last Updated: Sep 29, 2024

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