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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 3, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001269151.5

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

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

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>T

HGVS:

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

Links:

dbSNP: rs863224499

NCBI 1000 Genomes Browser:

rs863224499

Molecular consequence:

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001448415	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 5, 2020)	germline	clinical testing	PubMed (24) [See all records that cite these PMIDs] 17606709, 21343334, 20407015, 26681682, 20805372, 26230955, 21519010, 27463065, 25952993, 22186996, 27680515, 27959731, 16818505, 27895058, 30327374, 11782540, 23246812, 22915647, 26585234, 27276561, 16494995, 25564201, 32658383, 29070607 Citation Link,
SCV002243941	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 3, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16494995, 23409989, 29070607, 16199547, 20522432, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001448415

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Nov 5, 2020)

germline

clinical testing

PubMed (24)
[See all records that cite these PMIDs]

Citation Link,

SCV002243941

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 3, 2023)

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

Citations

PubMed

Transcriptional functionality of germ line p53 mutants influences cancer phenotype.

Monti P, Ciribilli Y, Jordan J, Menichini P, Umbach DM, Resnick MA, Luzzatto L, Inga A, Fronza G.

Clin Cancer Res. 2007 Jul 1;13(13):3789-95.

PubMed [citation]

PMID:: 17606709
PMCID:: PMC2128783

Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes.

Monti P, Perfumo C, Bisio A, Ciribilli Y, Menichini P, Russo D, Umbach DM, Resnick MA, Inga A, Fronza G.

Mol Cancer Res. 2011 Mar;9(3):271-9. doi: 10.1158/1541-7786.MCR-10-0496. Epub 2011 Feb 22.

PubMed [citation]

PMID:: 21343334
PMCID:: PMC3077904

See all PubMed Citations (28)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001448415.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (24)

Description

Variant summary: TP53 c.672+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251208 control chromosomes (gnomAD). c.672+1G>T has been reported in the literature in multiple individuals affected with primary tumors belonging to the Li-Fraumeni Syndrome (LFS) spectrum (e.g. Achatz_2006, Fitarelli-Kiehl_2015, Eccles_2016, Wilson_2010, Renaux-Petel_2017, Pondrom_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant in the germline state to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was 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

From Invitae, SCV002243941.3

#	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: 630765). This variant is also known as IVS6 +1G>T. 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. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 6 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

ClinVar

Relating variation to medicine