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

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Jan 1, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001225765.3

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_001126112.2:c.794T>A
  • NM_001126113.2:c.794T>A
  • NM_001126114.2:c.794T>A
  • NM_001126115.1:c.398T>A
  • NM_001126116.1:c.398T>A
  • NM_001126117.1:c.398T>A
  • NM_001126118.1:c.677T>A
  • NM_001276695.2:c.677T>A
  • NM_001276696.2:c.677T>A
  • NM_001276697.2:c.317T>A
  • NM_001276698.2:c.317T>A
  • NM_001276699.2:c.317T>A
  • NM_001276760.2:c.677T>A
  • NM_001276761.2: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_321t2:c.794T>A
  • LRG_321t3:c.794T>A
  • LRG_321t4:c.794T>A
  • LRG_321t5:c.398T>A
  • LRG_321t6:c.398T>A
  • LRG_321t7:c.398T>A
  • LRG_321t8:c.677T>A
  • LRG_321:g.18725T>A
  • LRG_321:p.Leu265Gln
  • LRG_321p3:p.Leu265Gln
  • LRG_321p4:p.Leu265Gln
  • LRG_321p5:p.Leu133Gln
  • LRG_321p6:p.Leu133Gln
  • LRG_321p7:p.Leu133Gln
  • LRG_321p8:p.Leu226Gln
  • NC_000017.10:g.7577144A>T
  • NM_000546.5:c.794T>A
Protein change:
L106Q
Molecular consequence:
  • NM_000546.6:c.794T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.2:c.794T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.2:c.794T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.2:c.794T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.1:c.398T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.1:c.398T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.1:c.398T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.1:c.677T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.2:c.677T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.2:c.677T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.2:c.317T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.2:c.317T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.2:c.317T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.2:c.677T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.2:c.677T>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001398055Invitaecriteria provided, single submitter
Uncertain significance
(Jan 1, 2020)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV001429674Cancer Variant Interpretation Group UK, Institute of Cancer Research, Londoncriteria provided, single submitter
Likely pathogenic
(Oct 11, 2019)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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

TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes.

Ruijs MW, Verhoef S, Rookus MA, Pruntel R, van der Hout AH, Hogervorst FB, Kluijt I, Sijmons RH, Aalfs CM, Wagner A, Ausems MG, Hoogerbrugge N, van Asperen CJ, Gomez Garcia EB, Meijers-Heijboer H, Ten Kate LP, Menko FH, van 't Veer LJ.

J Med Genet. 2010 Jun;47(6):421-8. doi: 10.1136/jmg.2009.073429.

PubMed [citation]
PMID:
20522432
See all PubMed Citations (9)

Details of each submission

From Invitae, SCV001398055.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces leucine with glutamine at codon 265 of the TP53 protein (p.Leu265Gln). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TP53-related conditions. This variant has been reported to affect TP53 protein function (PMID: 12826609). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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, 20522432, 12826609, 16861262, 17606709, 20128691, 21343334). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical 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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Apr 12, 2021

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