NM_000546.6(TP53):c.993G>A (p.Gln331=) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Jun 18, 2022
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:: RCV000492456.7

Allele description [Variation Report for NM_000546.6(TP53):c.993G>A (p.Gln331=)]

NM_000546.6(TP53):c.993G>A (p.Gln331=)

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.993G>A (p.Gln331=)

HGVS:

NC_000017.11:g.7673535C>T
NG_017013.2:g.19016G>A
NM_000546.6:c.993G>AMANE SELECT
NM_001126112.3:c.993G>A
NM_001126113.3:c.993G>A
NM_001126114.3:c.993G>A
NM_001126115.2:c.597G>A
NM_001126116.2:c.597G>A
NM_001126117.2:c.597G>A
NM_001126118.2:c.876G>A
NM_001276695.3:c.876G>A
NM_001276696.3:c.876G>A
NM_001276697.3:c.516G>A
NM_001276698.3:c.516G>A
NM_001276699.3:c.516G>A
NM_001276760.3:c.876G>A
NM_001276761.3:c.876G>A
NP_000537.3:p.Gln331=
NP_000537.3:p.Gln331=
NP_001119584.1:p.Gln331=
NP_001119585.1:p.Gln331=
NP_001119586.1:p.Gln331=
NP_001119587.1:p.Gln199=
NP_001119588.1:p.Gln199=
NP_001119589.1:p.Gln199=
NP_001119590.1:p.Gln292=
NP_001263624.1:p.Gln292=
NP_001263625.1:p.Gln292=
NP_001263626.1:p.Gln172=
NP_001263627.1:p.Gln172=
NP_001263628.1:p.Gln172=
NP_001263689.1:p.Gln292=
NP_001263690.1:p.Gln292=
LRG_321t1:c.993G>A
LRG_321:g.19016G>A
LRG_321p1:p.Gln331=
NC_000017.10:g.7576853C>T
NM_000546.4:c.993G>A
NM_000546.5:c.993G>A

Links:

dbSNP: rs11575996

NCBI 1000 Genomes Browser:

rs11575996

Molecular consequence:

NM_000546.6:c.993G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001126112.3:c.993G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001126113.3:c.993G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001126114.3:c.993G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001126115.2:c.597G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001126116.2:c.597G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001126117.2:c.597G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001126118.2:c.876G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001276695.3:c.876G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001276696.3:c.876G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001276697.3:c.516G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001276698.3:c.516G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001276699.3:c.516G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001276760.3:c.876G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001276761.3:c.876G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Functional consequence:

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

Observations:

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

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hypothetical protein Syn7803C45_62 [Synechococcus phage ACG-2014d]
hypothetical protein Syn7803C45_62 [Synechococcus phage ACG-2014d]
gi|723010667|gb|AIX14673.1|

Protein
Homo sapiens frizzled class receptor 8 (FZD8), RefSeqGene on chromosome 10
Homo sapiens frizzled class receptor 8 (FZD8), RefSeqGene on chromosome 10
gi|345842516|ref|NG_029968.1|

Nucleotide
unnamed protein product, partial [Homo sapiens]
unnamed protein product, partial [Homo sapiens]
gi|29960|emb|CAA24757.1|

Protein
Homo sapiens isolate 4N-7 actin-like protein (ACT) gene, partial cds
Homo sapiens isolate 4N-7 actin-like protein (ACT) gene, partial cds
gi|62421119|gb|AY970471.1|

Nucleotide
Chemokine (C-C motif) receptor 5 [Mus musculus]
Chemokine (C-C motif) receptor 5 [Mus musculus]
gi|73695319|gb|AAI03575.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000581098	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Feb 24, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22653678, 29324801 Citation Link,
SCV002582338	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002589038	BRCAlab, Lund University	no assertion criteria provided	Pathogenic (Aug 26, 2022)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000581098

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Feb 24, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV002582338

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 18, 2022)

germline

clinical testing

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

SCV002589038

BRCAlab, Lund University

no assertion criteria provided

Pathogenic
(Aug 26, 2022)

germline

clinical testing

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	yes	not provided	1	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

Prevalence of germline TP53 mutations and history of Li-Fraumeni syndrome in families with childhood adrenocortical tumors, choroid plexus tumors, and rhabdomyosarcoma: a population-based survey.

Magnusson S, Gisselsson D, Wiebe T, Kristoffersson U, Borg Å, Olsson H.

Pediatr Blood Cancer. 2012 Nov;59(5):846-53. doi: 10.1002/pbc.24223. Epub 2012 May 31.

PubMed [citation]

PMID:: 22653678

Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark.

Stoltze U, Skytte AB, Roed H, Hasle H, Ejlertsen B, Overeem Hansen TV, Schmiegelow K, Gerdes AM, Wadt K.

PLoS One. 2018;13(1):e0190050. doi: 10.1371/journal.pone.0190050.

PubMed [citation]

PMID:: 29324801
PMCID:: PMC5764253

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000581098.6

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

Description

The c.993G>A variant (also known as p.Q331Q) is located in coding exon 8 of the TP53 gene. This variant results from a G to A substitution at nucleotide position 993. This nucleotide substitution does not change the glutamine at amino acid 331. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This variant was detected in a child with adrenocortical carcinoma at age six whose mother was diagnosed with breast cancer at age 37. Sequence analysis of cDNA showed expression of the wild type allele only, indicating that the alteration may lead to unstable mRNA transcript that is subject to nonsense mediated decay (Magnusson S et al. Pediatr Blood Cancer. 2012 Nov;59(5):846-53). The c.933G>A variant has also been reported in a female diagnosed with breast cancer at age 35 (Stoltze U et al. PLoS One. 2018 Jan;13:e0190050). This variant was not reported in population-based 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 may weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be 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 Genome-Nilou Lab, SCV002582338.1

#	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 BRCAlab, Lund University, SCV002589038.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

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

Last Updated: Aug 11, 2024

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