NM_000546.6(TP53):c.794T>A (p.Leu265Gln) AND Li-Fraumeni syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Apr 24, 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:: RCV001225765.11

Allele description [Variation Report for NM_000546.6(TP53):c.794T>A (p.Leu265Gln)]

NM_000546.6(TP53):c.794T>A (p.Leu265Gln)

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.794T>A (p.Leu265Gln)

HGVS:

NC_000017.11:g.7673826A>T
NG_017013.2:g.18725T>A
NM_000546.6:c.794T>AMANE SELECT
NM_001126112.3:c.794T>A
NM_001126113.3:c.794T>A
NM_001126114.3:c.794T>A
NM_001126115.2:c.398T>A
NM_001126116.2:c.398T>A
NM_001126117.2:c.398T>A
NM_001126118.2:c.677T>A
NM_001276695.3:c.677T>A
NM_001276696.3:c.677T>A
NM_001276697.3:c.317T>A
NM_001276698.3:c.317T>A
NM_001276699.3:c.317T>A
NM_001276760.3:c.677T>A
NM_001276761.3:c.677T>A
NP_000537.3:p.Leu265Gln
NP_001119584.1:p.Leu265Gln
NP_001119585.1:p.Leu265Gln
NP_001119586.1:p.Leu265Gln
NP_001119587.1:p.Leu133Gln
NP_001119588.1:p.Leu133Gln
NP_001119589.1:p.Leu133Gln
NP_001119590.1:p.Leu226Gln
NP_001263624.1:p.Leu226Gln
NP_001263625.1:p.Leu226Gln
NP_001263626.1:p.Leu106Gln
NP_001263627.1:p.Leu106Gln
NP_001263628.1:p.Leu106Gln
NP_001263689.1:p.Leu226Gln
NP_001263690.1:p.Leu226Gln
LRG_321t1:c.794T>A
LRG_321:g.18725T>A
NC_000017.10:g.7577144A>T
NM_000546.4:c.794T>A
NM_000546.5:c.794T>A

Protein change:

L106Q

Links:

dbSNP: rs879253942

NCBI 1000 Genomes Browser:

rs879253942

Molecular consequence:

NM_000546.6:c.794T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.794T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.794T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.794T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.398T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.398T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.398T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.677T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.677T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.677T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.317T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.317T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.317T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.677T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.677T>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001398055	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 24, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 34240179, 9067756, 16861262, 17606709, 20128691, 20522432, 21343334, 12826609, 29979965, 30224644, 28492532
SCV001429674	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 11, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001398055

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 24, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV001429674

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 11, 2019)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Paired Tumor-Normal Sequencing Provides Insights Into the TP53-Related Cancer Spectrum in Patients With Li-Fraumeni Syndrome.

Ceyhan-Birsoy O, Selenica P, Chui MH, Jayakumaran G, Ptashkin R, Misyura M, Aypar U, Jairam S, Yang C, Li Y, Mehta N, Kemel Y, Salo-Mullen E, Maio A, Sheehan M, Zehir A, Carlo M, Latham A, Stadler Z, Robson M, Offit K, Ladanyi M, et al.

J Natl Cancer Inst. 2021 Nov 29;113(12):1751-1760. doi: 10.1093/jnci/djab117.

PubMed [citation]

PMID:: 34240179
PMCID:: PMC9891110

Three germline mutations in the TP53 gene.

Cornelis RS, van Vliet M, van de Vijver MJ, Vasen HF, Voute PA, Top B, Khan PM, Devilee P, Cornelisse CJ.

Hum Mutat. 1997;9(2):157-63.

PubMed [citation]

PMID:: 9067756

See all PubMed Citations (12)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001398055.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 265 of the TP53 protein (p.Leu265Gln). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 34240179; Invitae). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu265 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9067756, 12826609, 16861262, 17606709, 20128691, 20522432, 21343334). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 953467).

#	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 Cancer Variant Interpretation Group UK, Institute of Cancer Research, London, SCV001429674.1

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

Description

Data included in classification: Absent from gnomAD (PM2_sup). Align GVGD: Class 65, Revel: 0.964. Bayes del: 0.601. TP53 ConSurf plot shows this residue to be 9 on the conservation scale (predicted to be a highly conserved and buried structural residue). (PP3_mod). Kato et al. 2003 (PMID 12826609) Transactivation class: Non functional. Giacomelli et al. 2018 (PMID 30224644) DNE and LOF variant. Fortuno et al, 2018 (PMID: 29775997) Suggested prediction: non-functional. (PS3_strong). Data not included in classification: UK Family 1: Variant identified in a child with adrenocortical cancer (1 proband meeting Chompret criteria). Pathogenic variant that affects same residue with 2* ClinVar status p.Leu265Pro (BLOSUM62: -3 compared to -2 for current variant).

#	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		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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