NM_000546.6(TP53):c.1024C>T (p.Arg342Ter) AND Li-Fraumeni syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 6, 2024
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:: RCV000549233.18

Allele description [Variation Report for NM_000546.6(TP53):c.1024C>T (p.Arg342Ter)]

NM_000546.6(TP53):c.1024C>T (p.Arg342Ter)

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.1024C>T (p.Arg342Ter)

Other names:

p.R342*:CGA>TGA

HGVS:

NC_000017.11:g.7670685G>A
NG_017013.2:g.21866C>T
NM_000546.6:c.1024C>TMANE SELECT
NM_001126112.3:c.1024C>T
NM_001126113.3:c.*43C>T
NM_001126114.3:c.*131C>T
NM_001126115.2:c.628C>T
NM_001126116.2:c.*131C>T
NM_001126117.2:c.*43C>T
NM_001126118.2:c.907C>T
NM_001276695.3:c.*43C>T
NM_001276696.3:c.*131C>T
NM_001276697.3:c.547C>T
NM_001276698.3:c.*131C>T
NM_001276699.3:c.*43C>T
NM_001276760.3:c.907C>T
NM_001276761.3:c.907C>T
NP_000537.3:p.Arg342Ter
NP_000537.3:p.Arg342Ter
NP_001119584.1:p.Arg342Ter
NP_001119587.1:p.Arg210Ter
NP_001119587.1:p.Arg210Ter
NP_001119590.1:p.Arg303Ter
NP_001263626.1:p.Arg183Ter
NP_001263689.1:p.Arg303Ter
NP_001263690.1:p.Arg303Ter
LRG_321t1:c.1024C>T
LRG_321t5:c.628C>T
LRG_321t7:c.*43C>T
LRG_321:g.21866C>T
LRG_321p1:p.Arg342Ter
LRG_321p5:p.Arg210Ter
NC_000017.10:g.7574003G>A
NM_000546.4:c.1024C>T
NM_000546.5:c.1024C>T
NM_001126115.1:c.628C>T
NM_001126117.1:c.*43C>T
p.Arg210*
p.Arg342X
p.R342*

Protein change:

R183*

Links:

dbSNP: rs730882029

NCBI 1000 Genomes Browser:

rs730882029

Molecular consequence:

NM_001126113.3:c.*43C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126114.3:c.*131C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126116.2:c.*131C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126117.2:c.*43C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276695.3:c.*43C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276696.3:c.*131C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276698.3:c.*131C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276699.3:c.*43C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000546.6:c.1024C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001126112.3:c.1024C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001126115.2:c.628C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001126118.2:c.907C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001276697.3:c.547C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001276760.3:c.907C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001276761.3:c.907C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000629765	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 6, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20522432, 17567834, 19714490, 21761402, 24382691, 26911350, 28492532
SCV000966989	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Apr 20, 2018)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 19714490, 16969106, 26911350, 20436704, 26718964, 26425688, 24382691, 21761402, 21665182, 19711436, 24033266
SCV001363226	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 22, 2019)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 21761402, 26911350, 23484829, 26230955, 21519010, 27463065, 25952993, 22186996, 27680515, 27959731, 25516983, 27895058, 19714490, 24382691, 16969106 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000629765

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 6, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV000966989

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Apr 20, 2018)

germline

clinical testing

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

SCV001363226

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 22, 2019)

germline

clinical testing

PubMed (15)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

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

Telomere length in peripheral blood cells of germline TP53 mutation carriers is shorter than that of normal individuals of corresponding age.

Trkova M, Prochazkova K, Krutilkova V, Sumerauer D, Sedlacek Z.

Cancer. 2007 Aug 1;110(3):694-702.

PubMed [citation]

PMID:: 17567834

See all PubMed Citations (24)

Details of each submission

From Invitae, SCV000629765.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change creates a premature translational stop signal (p.Arg342*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 17567834, 19714490, 21761402, 24382691, 26911350). ClinVar contains an entry for this variant (Variation ID: 182970). 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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000966989.1

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

Description

The p.Arg342X variant in TP53 has been reported as a germline variant in more th an 15 individuals with TP53-associated cancers and as a somatic variant in more than 100 individuals (Fiszer-Maliszewska 2009, Schniederjan 2009, Lee 2010, Melh em-Bertrandt 2012, Hettmer 2014, Kandioler 2015, Mannan 2016, Smardova 2016, IAR C TP53 database [http://p53.iarc.fr/], COSMIC database). This variant has also b een reported in ClinVar (Variation ID# 182970) and was absent from large populat ion studies. In vitro functional studies provide some evidence that the p.Arg342 X variant may impact protein function by resulting in abnormal nuclear localizat ion (Trostel 2006). This nonsense variant leads to a premature termination codon at position 342 which is predicted to lead to a truncated or absent protein. He terozygous loss of function of the TP53 gene is an established disease mechanism in Li-Fraumeni syndrome. In summary, this variant meets criteria to be classifi ed as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner based upon frequency in affected individuals, absence from controls, and the predicted impact to the protein. ACMG/AMP Criteria applied: PVS1; PS4; PM2; PS3_Supportin g.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363226.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

Variant summary: TP53 c.1024C>T (p.Arg342X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251350 control chromosomes (gnomAD) but has been reported in the literature in multiple individuals affected with features of Li-Fraunemia syndrome such as breast and/or ovarian cancer, osteosarcoma, adenocarcinoma, adrenocortical carcinoma, foot fibrosarcoma and prostate cancer (Mannan_2016, Hettmer_2014, Fiszer-Maliszewska_2009, Wang_2013). These data indicate that the variant is very likely to be associated with disease. An experimental study using a cell system reports that this truncation impaired association with dynein motor complex and prevented p53 nuclear translocation (Trostel_2006). However, this does not allow convincing conclusions about the variant effect. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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: May 1, 2024

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