NM_000546.6(TP53):c.324_331delinsAAA (p.Phe109fs) AND Li-Fraumeni syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Feb 2, 2021
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:: RCV001293594.3

Allele description [Variation Report for NM_000546.6(TP53):c.324_331delinsAAA (p.Phe109fs)]

NM_000546.6(TP53):c.324_331delinsAAA (p.Phe109fs)

Gene:

TP53:tumor protein p53 [Gene - OMIM - HGNC]

Variant type:

Indel

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000546.6(TP53):c.324_331delinsAAA (p.Phe109fs)

HGVS:

NC_000017.11:g.7676038_7676045delinsTTT
NG_017013.2:g.16506_16513delinsAAA
NM_000546.6:c.324_331delinsAAAMANE SELECT
NM_001126112.3:c.324_331delinsAAA
NM_001126113.3:c.324_331delinsAAA
NM_001126114.3:c.324_331delinsAAA
NM_001126118.2:c.207_214delinsAAA
NM_001276695.3:c.207_214delinsAAA
NM_001276696.3:c.207_214delinsAAA
NM_001276760.3:c.207_214delinsAAA
NM_001276761.3:c.207_214delinsAAA
NP_000537.3:p.Phe109fs
NP_001119584.1:p.Phe109fs
NP_001119585.1:p.Phe109fs
NP_001119586.1:p.Phe109fs
NP_001119590.1:p.Phe70fs
NP_001263624.1:p.Phe70fs
NP_001263625.1:p.Phe70fs
NP_001263689.1:p.Phe70fs
NP_001263690.1:p.Phe70fs
LRG_321t1:c.324_331delinsAAA
LRG_321:g.16506_16513delinsAAA
NC_000017.10:g.7579356_7579363delinsTTT
NM_000546.5:c.324_331delinsAAA

Protein change:

F109fs

Links:

dbSNP: rs2073455679

NCBI 1000 Genomes Browser:

rs2073455679

Molecular consequence:

NM_000546.6:c.324_331delinsAAA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001126112.3:c.324_331delinsAAA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001126113.3:c.324_331delinsAAA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001126114.3:c.324_331delinsAAA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001126118.2:c.207_214delinsAAA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001276695.3:c.207_214delinsAAA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001276696.3:c.207_214delinsAAA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001276760.3:c.207_214delinsAAA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001276761.3:c.207_214delinsAAA - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV001482210	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Feb 2, 2021)	germline	clinical testing	Citation Link,
SCV004672367	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 12, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20522432, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001482210

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Feb 2, 2021)

germline

clinical testing

Citation Link,

SCV004672367

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 12, 2020)

germline

clinical testing

PubMed (2)
[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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001482210.1

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

Description

Variant summary: TP53 c.324_331delinsAAA (p.Phe109AsnfsX38) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251288 control chromosomes. To our knowledge, no occurrence of c.324_331delinsAAA in individuals affected with Li-Fraumeni Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004672367.1

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

Description

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant has not been reported in the literature in individuals with TP53-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Phe109Asnfs*38) in the TP53 gene. It is expected to result in an absent or disrupted protein product.

#	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: Nov 10, 2024

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