NM_000546.6(TP53):c.766A>G (p.Thr256Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 4, 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:: RCV000129326.8

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:: 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
SCV000184089	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 4, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29979965, 30224644 Citation Link,
SCV004359984	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 20, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12826609, 16861262, 20127978, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184089

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 4, 2023)

germline

clinical testing

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

Citation Link,

SCV004359984

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 20, 2021)

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

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

Mutational processes shape the landscape of TP53 mutations in human cancer.

Giacomelli AO, Yang X, Lintner RE, McFarland JM, Duby M, Kim J, Howard TP, Takeda DY, Ly SH, Kim E, Gannon HS, Hurhula B, Sharpe T, Goodale A, Fritchman B, Steelman S, Vazquez F, Tsherniak A, Aguirre AJ, Doench JG, Piccioni F, Roberts CWM, et al.

Nat Genet. 2018 Oct;50(10):1381-1387. doi: 10.1038/s41588-018-0204-y. Epub 2018 Sep 17.

PubMed [citation]

PMID:: 30224644
PMCID:: PMC6168352

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000184089.9

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

Description

The p.T256A variant (also known as c.766A>G) is located in coding exon 6 of the TP53 gene. This alteration results from an A to G substitution at nucleotide position 766. The threonine at codon 256 is replaced by alanine, an amino acid with similar properties. This has been identified in a patient reported to have Li-Fraumeni syndrome; however clinical details were not provided (Morgan JE et al. Hum Mutat. 2010 Apr;31(4):484-91). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TP53-related disease; however, it has also been seen in individuals with cancer diagnoses at later age of onset than expected for TP53-related disease (Ambry internal data, personal communication). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). However, studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on current evidence, this alteration may be a moderate risk allele that leads to increased risk of developing a TP53-related cancer; however, since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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 Color Diagnostics, LLC DBA Color Health, SCV004359984.1

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

Description

This missense variant replaces threonine with alanine at codon 256 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional analysis in yeast reported transcriptional activity for this variant (PMID: 16861262) with reduced activity in one study (PMID: 12826609). This variant has been reported in an individual affected with Li-Fraumeni syndrome (PMID: 20127978). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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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