NM_000546.6(TP53):c.758C>A (p.Thr253Asn) AND Li-Fraumeni syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 9, 2022
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:: RCV002531153.3

Allele description [Variation Report for NM_000546.6(TP53):c.758C>A (p.Thr253Asn)]

NM_000546.6(TP53):c.758C>A (p.Thr253Asn)

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.758C>A (p.Thr253Asn)

HGVS:

NC_000017.11:g.7674205G>T
NG_017013.2:g.18346C>A
NM_000546.6:c.758C>AMANE SELECT
NM_001126112.3:c.758C>A
NM_001126113.3:c.758C>A
NM_001126114.3:c.758C>A
NM_001126115.2:c.362C>A
NM_001126116.2:c.362C>A
NM_001126117.2:c.362C>A
NM_001126118.2:c.641C>A
NM_001276695.3:c.641C>A
NM_001276696.3:c.641C>A
NM_001276697.3:c.281C>A
NM_001276698.3:c.281C>A
NM_001276699.3:c.281C>A
NM_001276760.3:c.641C>A
NM_001276761.3:c.641C>A
NP_000537.3:p.Thr253Asn
NP_000537.3:p.Thr253Asn
NP_001119584.1:p.Thr253Asn
NP_001119585.1:p.Thr253Asn
NP_001119586.1:p.Thr253Asn
NP_001119587.1:p.Thr121Asn
NP_001119588.1:p.Thr121Asn
NP_001119589.1:p.Thr121Asn
NP_001119590.1:p.Thr214Asn
NP_001263624.1:p.Thr214Asn
NP_001263625.1:p.Thr214Asn
NP_001263626.1:p.Thr94Asn
NP_001263627.1:p.Thr94Asn
NP_001263628.1:p.Thr94Asn
NP_001263689.1:p.Thr214Asn
NP_001263690.1:p.Thr214Asn
LRG_321t1:c.758C>A
LRG_321:g.18346C>A
LRG_321p1:p.Thr253Asn
NC_000017.10:g.7577523G>T
NM_000546.5:c.758C>A

Protein change:

T121N

Links:

dbSNP: rs1555525465

NCBI 1000 Genomes Browser:

rs1555525465

Molecular consequence:

NM_000546.6:c.758C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.758C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.758C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.758C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.362C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.362C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.362C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.641C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.641C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.641C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.281C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.281C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.281C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.641C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.641C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Li-Fraumeni syndrome (LFS)
Synonyms:: Sarcoma family syndrome of Li and Fraumeni
Identifiers:: MONDO: MONDO:0018875; MedGen: C0085390; OMIM: PS151623

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003198826	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 9, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12826609, 29979965, 30224644, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003198826

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 9, 2022)

germline

clinical testing

PubMed (4)
[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

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

A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.

Kotler E, Shani O, Goldfeld G, Lotan-Pompan M, Tarcic O, Gershoni A, Hopf TA, Marks DS, Oren M, Segal E.

Mol Cell. 2018 Jul 5;71(1):178-190.e8. doi: 10.1016/j.molcel.2018.06.012. Erratum in: Mol Cell. 2018 Sep 6;71(5):873. doi: 10.1016/j.molcel.2018.08.013.

PubMed [citation]

PMID:: 29979965

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003198826.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant has not been reported in the literature in individuals affected with TP53-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 29979965, 30224644). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 505571). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 253 of the TP53 protein (p.Thr253Asn).

#	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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