NM_000546.6(TP53):c.672+1G>A AND Li-Fraumeni syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 26, 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:: RCV000200333.10

Allele description [Variation Report for NM_000546.6(TP53):c.672+1G>A]

NM_000546.6(TP53):c.672+1G>A

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.672+1G>A

HGVS:

NC_000017.11:g.7674858C>T
NG_017013.2:g.17693G>A
NM_000546.6:c.672+1G>AMANE SELECT
NM_001126112.3:c.672+1G>A
NM_001126113.3:c.672+1G>A
NM_001126114.3:c.672+1G>A
NM_001126115.2:c.276+1G>A
NM_001126116.2:c.276+1G>A
NM_001126117.2:c.276+1G>A
NM_001126118.2:c.555+1G>A
NM_001276695.3:c.555+1G>A
NM_001276696.3:c.555+1G>A
NM_001276697.3:c.195+1G>A
NM_001276698.3:c.195+1G>A
NM_001276699.3:c.195+1G>A
NM_001276760.3:c.555+1G>A
NM_001276761.3:c.555+1G>A
NM_001407262.1:c.672+1G>A
NM_001407263.1:c.555+1G>A
NM_001407264.1:c.672+1G>A
NM_001407265.1:c.555+1G>A
NM_001407266.1:c.672+1G>A
NM_001407267.1:c.555+1G>A
NM_001407268.1:c.672+1G>A
NM_001407269.1:c.555+1G>A
NM_001407270.1:c.672+1G>A
NM_001407271.1:c.555+1G>A
LRG_321t1:c.672+1G>A
LRG_321:g.17693G>A
NC_000017.10:g.7578176C>T
NM_000546.4:c.672+1G>A
NM_000546.5:c.672+1G>A

Links:

dbSNP: rs863224499

NCBI 1000 Genomes Browser:

rs863224499

Molecular consequence:

NM_000546.6:c.672+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126112.3:c.672+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126113.3:c.672+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126114.3:c.672+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126115.2:c.276+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126116.2:c.276+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126117.2:c.276+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126118.2:c.555+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276695.3:c.555+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276696.3:c.555+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276697.3:c.195+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276698.3:c.195+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276699.3:c.195+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276760.3:c.555+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276761.3:c.555+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407262.1:c.672+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407263.1:c.555+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407264.1:c.672+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407265.1:c.555+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407266.1:c.672+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407267.1:c.555+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407268.1:c.672+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407269.1:c.555+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407270.1:c.672+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407271.1:c.555+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Functional consequence:

sequence_variant_affecting_splicing [Sequence Ontology: SO:1000071] - Comment(s)

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
SCV000253850	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 26, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16494995, 29070607, 22495821, 23409989, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000253850

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 26, 2023)

germline

clinical testing

PubMed (5)
[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

The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families.

Achatz MI, Olivier M, Le Calvez F, Martel-Planche G, Lopes A, Rossi BM, Ashton-Prolla P, Giugliani R, Palmero EI, Vargas FR, Da Rocha JC, Vettore AL, Hainaut P.

Cancer Lett. 2007 Jan 8;245(1-2):96-102. Epub 2006 Feb 21.

PubMed [citation]

PMID:: 16494995

Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome.

Renaux-Petel M, Charbonnier F, Théry JC, Fermey P, Lienard G, Bou J, Coutant S, Vezain M, Kasper E, Fourneaux S, Manase S, Blanluet M, Leheup B, Mansuy L, Champigneulle J, Chappé C, Longy M, Sévenet N, Paillerets BB, Guerrini-Rousseau L, Brugières L, Caron O, et al.

J Med Genet. 2018 Mar;55(3):173-180. doi: 10.1136/jmedgenet-2017-104976. Epub 2017 Oct 25.

PubMed [citation]

PMID:: 29070607

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000253850.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change affects a donor splice site in intron 6 of the TP53 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the gain of 6 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 16494995, 23409989, 29070607; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 216078). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects TP53 function (PMID: 22495821). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in intron 6 (PMID: 22495821, 23409989). 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

Last Updated: Aug 11, 2024

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