NM_000546.6(TP53):c.782+1G>A AND Li-Fraumeni syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 12, 2022
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:: RCV001063778.7

Allele description [Variation Report for NM_000546.6(TP53):c.782+1G>A]

NM_000546.6(TP53):c.782+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.782+1G>A

HGVS:

NC_000017.11:g.7674180C>T
NG_017013.2:g.18371G>A
NM_000546.6:c.782+1G>AMANE SELECT
NM_001126112.3:c.782+1G>A
NM_001126113.3:c.782+1G>A
NM_001126114.3:c.782+1G>A
NM_001126115.2:c.386+1G>A
NM_001126116.2:c.386+1G>A
NM_001126117.2:c.386+1G>A
NM_001126118.2:c.665+1G>A
NM_001276695.3:c.665+1G>A
NM_001276696.3:c.665+1G>A
NM_001276697.3:c.305+1G>A
NM_001276698.3:c.305+1G>A
NM_001276699.3:c.305+1G>A
NM_001276760.3:c.665+1G>A
NM_001276761.3:c.665+1G>A
NM_001407262.1:c.782+1G>A
NM_001407263.1:c.665+1G>A
NM_001407264.1:c.782+1G>A
NM_001407265.1:c.665+1G>A
NM_001407266.1:c.782+1G>A
NM_001407267.1:c.665+1G>A
NM_001407268.1:c.782+1G>A
NM_001407269.1:c.665+1G>A
NM_001407270.1:c.782+1G>A
NM_001407271.1:c.665+1G>A
LRG_321t1:c.782+1G>A
LRG_321:g.18371G>A
NC_000017.10:g.7577498C>T
NM_000546.5:c.782+1G>A

Links:

dbSNP: rs1555525429

NCBI 1000 Genomes Browser:

rs1555525429

Molecular consequence:

NM_000546.6:c.782+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126112.3:c.782+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126113.3:c.782+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126114.3:c.782+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126115.2:c.386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126116.2:c.386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126117.2:c.386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126118.2:c.665+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276695.3:c.665+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276696.3:c.665+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276697.3:c.305+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276698.3:c.305+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276699.3:c.305+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276760.3:c.665+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276761.3:c.665+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407262.1:c.782+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407263.1:c.665+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407264.1:c.782+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407265.1:c.665+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407266.1:c.782+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407267.1:c.665+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407268.1:c.782+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407269.1:c.665+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407270.1:c.782+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407271.1:c.665+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
SCV001228639	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 12, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29070607, 16199547, 20522432, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001228639

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 12, 2022)

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

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

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001228639.5

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

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 634684). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 29070607). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 7 of the TP53 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432).

#	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: Jul 15, 2024

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