NM_000546.6(TP53):c.920-2A>G AND Li-Fraumeni syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 15, 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:: RCV000036537.21

Allele description [Variation Report for NM_000546.6(TP53):c.920-2A>G]

NM_000546.6(TP53):c.920-2A>G

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.920-2A>G

HGVS:

NC_000017.11:g.7673610T>C
NG_017013.2:g.18941A>G
NM_000546.6:c.920-2A>GMANE SELECT
NM_001126112.3:c.920-2A>G
NM_001126113.3:c.920-2A>G
NM_001126114.3:c.920-2A>G
NM_001126115.2:c.524-2A>G
NM_001126116.2:c.524-2A>G
NM_001126117.2:c.524-2A>G
NM_001126118.2:c.803-2A>G
NM_001276695.3:c.803-2A>G
NM_001276696.3:c.803-2A>G
NM_001276697.3:c.443-2A>G
NM_001276698.3:c.443-2A>G
NM_001276699.3:c.443-2A>G
NM_001276760.3:c.803-2A>G
NM_001276761.3:c.803-2A>G
NM_001407262.1:c.920-2A>G
NM_001407263.1:c.803-2A>G
NM_001407264.1:c.920-2A>G
NM_001407265.1:c.803-2A>G
NM_001407266.1:c.920-2A>G
NM_001407267.1:c.803-2A>G
NM_001407268.1:c.920-2A>G
NM_001407269.1:c.803-2A>G
NM_001407270.1:c.920-2A>G
NM_001407271.1:c.803-2A>G
LRG_321t1:c.920-2A>G
LRG_321:g.18941A>G
NC_000017.10:g.7576928T>C
NM_000546.4:c.920-2A>G
NM_000546.5:c.920-2A>G
c.920-2A>G

Links:

dbSNP: rs397516439

NCBI 1000 Genomes Browser:

rs397516439

Molecular consequence:

NM_000546.6:c.920-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001126112.3:c.920-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001126113.3:c.920-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001126114.3:c.920-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001126115.2:c.524-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001126116.2:c.524-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001126117.2:c.524-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001126118.2:c.803-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001276695.3:c.803-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001276696.3:c.803-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001276697.3:c.443-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001276698.3:c.443-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001276699.3:c.443-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001276760.3:c.803-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001276761.3:c.803-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407262.1:c.920-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407263.1:c.803-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407264.1:c.920-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407265.1:c.803-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407266.1:c.920-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407267.1:c.803-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407268.1:c.920-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407269.1:c.803-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407270.1:c.920-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407271.1:c.803-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Functional consequence:

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

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000060192	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	no assertion criteria provided	Likely pathogenic (Aug 1, 2008)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001224140	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 15, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19556618, 21305319, 32817165, 16199547, 20522432, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000060192

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

no assertion criteria provided

Likely pathogenic
(Aug 1, 2008)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001224140

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 15, 2022)

germline

clinical testing

PubMed (6)
[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
not provided	germline	not provided	2	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Characterization of germline TP53 splicing mutations and their genetic and functional analysis.

Varley JM, Attwooll C, White G, McGown G, Thorncroft M, Kelsey AM, Greaves M, Boyle J, Birch JM.

Oncogene. 2001 May 10;20(21):2647-54.

PubMed [citation]

PMID:: 11420676

High frequency of de novo mutations in Li-Fraumeni syndrome.

Gonzalez KD, Buzin CH, Noltner KA, Gu D, Li W, Malkin D, Sommer SS.

J Med Genet. 2009 Oct;46(10):689-93. doi: 10.1136/jmg.2008.058958. Epub 2009 Jun 25.

PubMed [citation]

PMID:: 19556618

See all PubMed Citations (7)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000060192.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	1	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001224140.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

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: 43595). This variant is also known as IVS8-2A>G. Disruption of this splice site has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 19556618, 21305319, 32817165; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 8 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: Nov 10, 2024

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