NM_000546.6(TP53):c.993+2T>C AND Li-Fraumeni syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 23, 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:: RCV003621596.2

Allele description [Variation Report for NM_000546.6(TP53):c.993+2T>C]

NM_000546.6(TP53):c.993+2T>C

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.993+2T>C

HGVS:

NC_000017.11:g.7673533A>G
NG_017013.2:g.19018T>C
NM_000546.6:c.993+2T>CMANE SELECT
NM_001126112.3:c.993+2T>C
NM_001126113.3:c.993+2T>C
NM_001126114.3:c.993+2T>C
NM_001126115.2:c.597+2T>C
NM_001126116.2:c.597+2T>C
NM_001126117.2:c.597+2T>C
NM_001126118.2:c.876+2T>C
NM_001276695.3:c.876+2T>C
NM_001276696.3:c.876+2T>C
NM_001276697.3:c.516+2T>C
NM_001276698.3:c.516+2T>C
NM_001276699.3:c.516+2T>C
NM_001276760.3:c.876+2T>C
NM_001276761.3:c.876+2T>C
NM_001407262.1:c.993+2T>C
NM_001407263.1:c.876+2T>C
NM_001407264.1:c.993+2T>C
NM_001407265.1:c.876+2T>C
NM_001407266.1:c.993+2T>C
NM_001407267.1:c.876+2T>C
NM_001407268.1:c.993+2T>C
NM_001407269.1:c.876+2T>C
NM_001407270.1:c.993+2T>C
NM_001407271.1:c.876+2T>C
LRG_321:g.19018T>C
NC_000017.10:g.7576851A>G

Links:

dbSNP: rs1597359053

NCBI 1000 Genomes Browser:

rs1597359053

Molecular consequence:

NM_000546.6:c.993+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126112.3:c.993+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126113.3:c.993+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126114.3:c.993+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126115.2:c.597+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126116.2:c.597+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126117.2:c.597+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126118.2:c.876+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276695.3:c.876+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276696.3:c.876+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276697.3:c.516+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276698.3:c.516+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276699.3:c.516+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276760.3:c.876+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001276761.3:c.876+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407262.1:c.993+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407263.1:c.876+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407264.1:c.993+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407265.1:c.876+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407266.1:c.993+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407267.1:c.876+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407268.1:c.993+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407269.1:c.876+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407270.1:c.993+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407271.1:c.876+2T>C - 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
SCV004412215	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 23, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10980596, 16199547, 20522432, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004412215

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 23, 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

Novel p53 splice site mutations in three families with Li-Fraumeni syndrome.

Verselis SJ, Rheinwald JG, Fraumeni JF Jr, Li FP.

Oncogene. 2000 Aug 31;19(37):4230-5.

PubMed [citation]

PMID:: 10980596

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004412215.1

#	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. Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (Invitae). ClinVar contains an entry for this variant (Variation ID: 1192295). Disruption of this splice site has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 10980596). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 9 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: Sep 29, 2024

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