NM_000546.6(TP53):c.766A>G (p.Thr256Ala) AND Li-Fraumeni syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 14, 2023
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:: RCV000688741.9

Allele description [Variation Report for NM_000546.6(TP53):c.766A>G (p.Thr256Ala)]

NM_000546.6(TP53):c.766A>G (p.Thr256Ala)

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.766A>G (p.Thr256Ala)

HGVS:

NC_000017.11:g.7674197T>C
NG_017013.2:g.18354A>G
NM_000546.6:c.766A>GMANE SELECT
NM_001126112.3:c.766A>G
NM_001126113.3:c.766A>G
NM_001126114.3:c.766A>G
NM_001126115.2:c.370A>G
NM_001126116.2:c.370A>G
NM_001126117.2:c.370A>G
NM_001126118.2:c.649A>G
NM_001276695.3:c.649A>G
NM_001276696.3:c.649A>G
NM_001276697.3:c.289A>G
NM_001276698.3:c.289A>G
NM_001276699.3:c.289A>G
NM_001276760.3:c.649A>G
NM_001276761.3:c.649A>G
NP_000537.3:p.Thr256Ala
NP_000537.3:p.Thr256Ala
NP_001119584.1:p.Thr256Ala
NP_001119585.1:p.Thr256Ala
NP_001119586.1:p.Thr256Ala
NP_001119587.1:p.Thr124Ala
NP_001119588.1:p.Thr124Ala
NP_001119589.1:p.Thr124Ala
NP_001119590.1:p.Thr217Ala
NP_001263624.1:p.Thr217Ala
NP_001263625.1:p.Thr217Ala
NP_001263626.1:p.Thr97Ala
NP_001263627.1:p.Thr97Ala
NP_001263628.1:p.Thr97Ala
NP_001263689.1:p.Thr217Ala
NP_001263690.1:p.Thr217Ala
LRG_321t1:c.766A>G
LRG_321:g.18354A>G
LRG_321p1:p.Thr256Ala
NC_000017.10:g.7577515T>C
NM_000546.4:c.766A>G
NM_000546.5:c.766A>G
p.T256A

Protein change:

T124A

Links:

dbSNP: rs587781433

NCBI 1000 Genomes Browser:

rs587781433

Molecular consequence:

NM_000546.6:c.766A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.766A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.766A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.766A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.370A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.370A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.370A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.649A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.649A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.649A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.289A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.289A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.289A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.649A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.649A>G - 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
SCV000816364	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 14, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16861262, 12826609, 29979965, 30224644, 20127978, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000816364

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 14, 2023)

germline

clinical testing

PubMed (6)
[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

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

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 (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000816364.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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 have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 16861262, 29979965, 30224644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 141011). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 20127978). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 256 of the TP53 protein (p.Thr256Ala).

#	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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