NM_000546.6(TP53):c.1046_1055del (p.Glu349fs) AND Li-Fraumeni syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 12, 2021
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:: RCV002004183.5

Allele description [Variation Report for NM_000546.6(TP53):c.1046_1055del (p.Glu349fs)]

NM_000546.6(TP53):c.1046_1055del (p.Glu349fs)

Gene:

TP53:tumor protein p53 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000546.6(TP53):c.1046_1055del (p.Glu349fs)

HGVS:

NC_000017.11:g.7670654_7670663del
NG_017013.2:g.21888_21897del
NM_000546.6:c.1046_1055delMANE SELECT
NM_001126112.3:c.1046_1055del
NM_001126113.3:c.*65_*74del
NM_001126114.3:c.*153_*162del
NM_001126115.2:c.650_659del
NM_001126116.2:c.*153_*162del
NM_001126117.2:c.*65_*74del
NM_001126118.2:c.929_938del
NM_001276695.3:c.*65_*74del
NM_001276696.3:c.*153_*162del
NM_001276697.3:c.569_578del
NM_001276698.3:c.*153_*162del
NM_001276699.3:c.*65_*74del
NM_001276760.3:c.929_938del
NM_001276761.3:c.929_938del
NP_000537.3:p.Glu349fs
NP_001119584.1:p.Glu349fs
NP_001119587.1:p.Glu217fs
NP_001119590.1:p.Glu310fs
NP_001263626.1:p.Glu190fs
NP_001263689.1:p.Glu310fs
NP_001263690.1:p.Glu310fs
LRG_321:g.21888_21897del
NC_000017.10:g.7573972_7573981del

Protein change:

E190fs

Links:

dbSNP: rs2150994409

NCBI 1000 Genomes Browser:

rs2150994409

Molecular consequence:

NM_001126113.3:c.*65_*74del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126114.3:c.*153_*162del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126116.2:c.*153_*162del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126117.2:c.*65_*74del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276695.3:c.*65_*74del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276696.3:c.*153_*162del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276698.3:c.*153_*162del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276699.3:c.*65_*74del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000546.6:c.1046_1055del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001126112.3:c.1046_1055del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001126115.2:c.650_659del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001126118.2:c.929_938del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001276697.3:c.569_578del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001276760.3:c.929_938del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001276761.3:c.929_938del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV002291639	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 12, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22178617, 25794615, 26205489, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002291639

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Apr 12, 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

p53 requires an intact C-terminal domain for DNA binding and transactivation.

Kim H, Kim K, Choi J, Heo K, Baek HJ, Roeder RG, An W.

J Mol Biol. 2012 Feb 3;415(5):843-54. doi: 10.1016/j.jmb.2011.12.001. Epub 2011 Dec 9.

PubMed [citation]

PMID:: 22178617
PMCID:: PMC3267882

The p53 C terminus controls site-specific DNA binding and promotes structural changes within the central DNA binding domain.

Laptenko O, Shiff I, Freed-Pastor W, Zupnick A, Mattia M, Freulich E, Shamir I, Kadouri N, Kahan T, Manfredi J, Simon I, Prives C.

Mol Cell. 2015 Mar 19;57(6):1034-1046. doi: 10.1016/j.molcel.2015.02.015.

PubMed [citation]

PMID:: 25794615
PMCID:: PMC6221458

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV002291639.3

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the C-terminal domain of the TP53 protein, which is required for full DNA binding and transactivation activity (PMID: 22178617, 25794615, 26205489). ‚ÄãWhile functional studies have not been performed to directly test the effect of this variant on TP53 protein function, this suggests that disruption of this region of the protein is causative of disease. This variant has not been reported in the literature in individuals with TP53-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu349Valfs*18) in the TP53 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the TP53 protein.

#	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: Mar 5, 2024

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