NM_000546.6(TP53):c.672+1G>A AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 5, 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:: RCV002288814.5

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:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

Clear Turn Off Turn On

PNMA2 PNMA family member 2 [Homo sapiens]
PNMA2 PNMA family member 2 [Homo sapiens]
Gene ID:10687

Gene
10687[uid] AND (alive[prop]) (1)
Gene
RecName: Full=Paraneoplastic antigen Ma2; AltName: Full=40 kDa neuronal protein;...
RecName: Full=Paraneoplastic antigen Ma2; AltName: Full=40 kDa neuronal protein; AltName: Full=Onconeuronal antigen Ma2; AltName: Full=Paraneoplastic neuronal antigen MM2
gi|37999812|sp|Q9UL42.2|PNMA2_HUMAN

Protein

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
SCV002582476	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003911996	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Feb 16, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22495821, 23409989, 29070607 Citation Link,
SCV004359993	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 5, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22495821, 23409989, 29070607, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002582476

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 18, 2022)

germline

clinical testing

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

SCV003911996

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Feb 16, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004359993

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 5, 2023)

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
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Functional studies of a novel germline p53 splicing mutation identified in a patient with Li-Fraumeni-like syndrome.

Piao J, Sakurai N, Iwamoto S, Nishioka J, Nakatani K, Komada Y, Mizutani S, Takagi M.

Mol Carcinog. 2013 Oct;52(10):770-6. doi: 10.1002/mc.21912. Epub 2012 Apr 11.

PubMed [citation]

PMID:: 22495821

Novel p53 splicing site mutation in Li-Fraumeni-like syndrome with osteosarcoma.

Sakurai N, Iwamoto S, Miura Y, Nakamura T, Matsumine A, Nishioka J, Nakatani K, Komada Y.

Pediatr Int. 2013 Feb;55(1):107-11. doi: 10.1111/j.1442-200X.2012.03641.x.

PubMed [citation]

PMID:: 23409989

See all PubMed Citations (4)

Details of each submission

From Genome-Nilou Lab, SCV002582476.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV003911996.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The c.672+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 5 of the TP53 gene. This alteration has been reported in an individual with osteosarcoma diagnosed at age 15 (Sakurai N et al. Pediatr Int, 2013 Feb;55:107-11). Functional studies performed on this alteration include RNA analysis which identified an 18 nucleotide insertion event and functional studies which demonstrated loss of function (Piao J et al. Mol Carcinog, 2013 Oct;52:770-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely 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 Color Diagnostics, LLC DBA Color Health, SCV004359993.1

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

Description

This variant causes a G>A nucleotide substitution at the +1 position of intron 6 of the TP53 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A functional RNA study has shown that this variant may result in the use of a cryptic donor site 18 base pairs into intron 6, resulting in the insertion of 6 amino acids into the DNA binding domain (PMID: 23409989). Functional studies using this 6 amino acid construct showed impaired TP53 transcriptional transactivation, reduced cell cycle arrest at G0/G1 in response to DNA damage, and impaired ability to inhibit cell growth (PMID: 22495821). This variant has been reported in individuals affected with osteosarcoma and rhabdomyosarcoma, the latter of which was confirmed de novo (PMID: 22495821, 23409989, 29070607). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease. Based on the available evidence, this variant is 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

ClinVar

Relating variation to medicine