NM_000546.6(TP53):c.993G>A (p.Gln331=) AND Li-Fraumeni syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 10, 2023
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:: RCV000685844.8

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)

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
SCV000813343	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 10, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 29324801, 33674644, 22653678, 17576681, 9536098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000813343

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 10, 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

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

Prevalence of germline pathogenic variants in 22 cancer susceptibility genes in Swedish pediatric cancer patients.

von Stedingk K, Stjernfelt KJ, Kvist A, Wahlström C, Kristoffersson U, Stenmark-Askmalm M, Wiebe T, Hjorth L, Koster J, Olsson H, Øra I.

Sci Rep. 2021 Mar 5;11(1):5307. doi: 10.1038/s41598-021-84502-4.

PubMed [citation]

PMID:: 33674644
PMCID:: PMC7935871

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000813343.6

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

Description

This sequence change affects codon 331 of the TP53 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TP53 protein. This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of TP53 related conditions (PMID: 22653678, 29324801, 33674644). ClinVar contains an entry for this variant (Variation ID: 428868). Studies have shown that this variant alters TP53 gene expression (PMID: 22653678). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been 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: Sep 29, 2024

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