NM_000546.6(TP53):c.797G>A (p.Gly266Glu) AND Li-Fraumeni syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 18, 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:: RCV000709403.15

Allele description

NM_000546.6(TP53):c.797G>A (p.Gly266Glu)

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.797G>A (p.Gly266Glu)

HGVS:

NC_000017.11:g.7673823C>T
NG_017013.2:g.18728G>A
NM_000546.6:c.797G>AMANE SELECT
NM_001126112.3:c.797G>A
NM_001126113.3:c.797G>A
NM_001126114.3:c.797G>A
NM_001126115.2:c.401G>A
NM_001126116.2:c.401G>A
NM_001126117.2:c.401G>A
NM_001126118.2:c.680G>A
NM_001276695.3:c.680G>A
NM_001276696.3:c.680G>A
NM_001276697.3:c.320G>A
NM_001276698.3:c.320G>A
NM_001276699.3:c.320G>A
NM_001276760.3:c.680G>A
NM_001276761.3:c.680G>A
NP_000537.3:p.Gly266Glu
NP_000537.3:p.Gly266Glu
NP_001119584.1:p.Gly266Glu
NP_001119585.1:p.Gly266Glu
NP_001119586.1:p.Gly266Glu
NP_001119587.1:p.Gly134Glu
NP_001119587.1:p.Gly134Glu
NP_001119588.1:p.Gly134Glu
NP_001119589.1:p.Gly134Glu
NP_001119590.1:p.Gly227Glu
NP_001263624.1:p.Gly227Glu
NP_001263625.1:p.Gly227Glu
NP_001263626.1:p.Gly107Glu
NP_001263627.1:p.Gly107Glu
NP_001263628.1:p.Gly107Glu
NP_001263689.1:p.Gly227Glu
NP_001263690.1:p.Gly227Glu
LRG_321t1:c.797G>A
LRG_321t5:c.401G>A
LRG_321:g.18728G>A
LRG_321p1:p.Gly266Glu
LRG_321p5:p.Gly134Glu
NC_000017.10:g.7577141C>T
NM_000546.4:c.797G>A
NM_000546.5:c.797G>A
NM_001126115.1:c.401G>A

Protein change:

G107E

Links:

dbSNP: rs193920774

NCBI 1000 Genomes Browser:

rs193920774

Molecular consequence:

NM_000546.6:c.797G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.797G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.797G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.797G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.401G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.401G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.401G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.680G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.680G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.680G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.320G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.320G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.320G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.680G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.680G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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PIK3CD phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [H...
PIK3CD phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [Homo sapiens]
Gene ID:5293

Gene
Gene Links for GEO Profiles (Select 125831627) (1)
Gene
ZCCHC24 zinc finger CCHC-type containing 24 [Homo sapiens]
ZCCHC24 zinc finger CCHC-type containing 24 [Homo sapiens]
Gene ID:219654

Gene
Gene Links for GEO Profiles (Select 25675747) (1)
Gene
Assembly for Nucleotide (Select 2735962100) (1)
Assembly

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000931773	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 22, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 18511570, 24651015, 11429705, 12917626, 17724467, 20505364, 12826609, 16827139, 20407015, 27523101, 29979965, 30224644, 28492532
SCV004840289	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 12826609, 18511570, 22265402, 24651015, 26580448, 29979965, 30224644, 32371905, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000931773

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 22, 2023)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV004840289

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Dec 18, 2023)

germline

clinical testing

PubMed (9)
[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	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

p53 mutants can often transactivate promoters containing a p21 but not Bax or PIG3 responsive elements.

Campomenosi P, Monti P, Aprile A, Abbondandolo A, Frebourg T, Gold B, Crook T, Inga A, Resnick MA, Iggo R, Fronza G.

Oncogene. 2001 Jun 14;20(27):3573-9.

PubMed [citation]

PMID:: 11429705

Characterization of the p53 mutants ability to inhibit p73 beta transactivation using a yeast-based functional assay.

Monti P, Campomenosi P, Ciribilli Y, Iannone R, Aprile A, Inga A, Tada M, Menichini P, Abbondandolo A, Fronza G.

Oncogene. 2003 Aug 14;22(34):5252-60.

PubMed [citation]

PMID:: 12917626

See all PubMed Citations (17)

Details of each submission

From Invitae, SCV000931773.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 266 of the TP53 protein (p.Gly266Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 18511570, 24651015; external communication). ClinVar contains an entry for this variant (Variation ID: 161516). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 11429705, 12826609, 12917626, 17724467, 20505364, 29979965, 30224644). This variant disrupts the p.Gly266 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 16827139, 20407015, 27523101, 29979965, 30224644; externalcommunication). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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 All of Us Research Program, National Institutes of Health, SCV004840289.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

Description

This missense variant replaces glycine with glutamic acid at codon 266 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 studies have reported this variant as defective in yeast based transcriptional activation assays, and human cell growth suppression and proliferation assays (PMID: 12826609, 29979965, 30224644). This variant has been reported in individuals affected with childhood-onset medulloblastoma (PMID: 22265402, 24651015), adrenocortical carcinoma (PMID: 26580448, 32371905), and in an individual with a personal and/or family history suggestive of Li Fraumeni syndrome (PMID: 18511570). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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