NM_000546.6(TP53):c.225del (p.Ala76fs) AND Li-Fraumeni syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 13, 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:: RCV003510960.2

Allele description [Variation Report for NM_000546.6(TP53):c.225del (p.Ala76fs)]

NM_000546.6(TP53):c.225del (p.Ala76fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000546.6(TP53):c.225del (p.Ala76fs)

HGVS:

NC_000017.11:g.7676144del
NG_017013.2:g.16407del
NM_000546.6:c.225delMANE SELECT
NM_001126112.3:c.225del
NM_001126113.3:c.225del
NM_001126114.3:c.225del
NM_001126118.2:c.108del
NM_001276695.3:c.108del
NM_001276696.3:c.108del
NM_001276760.3:c.108del
NM_001276761.3:c.108del
NM_001407262.1:c.225del
NM_001407263.1:c.108del
NM_001407264.1:c.225del
NM_001407265.1:c.108del
NM_001407266.1:c.225del
NM_001407267.1:c.108del
NM_001407268.1:c.225del
NM_001407269.1:c.108del
NM_001407270.1:c.225del
NM_001407271.1:c.108del
NP_000537.3:p.Ala76Hisfs
NP_000537.3:p.Ala76fs
NP_001119584.1:p.Ala76Hisfs
NP_001119584.1:p.Ala76fs
NP_001119585.1:p.Ala76Hisfs
NP_001119585.1:p.Ala76fs
NP_001119586.1:p.Ala76Hisfs
NP_001119586.1:p.Ala76fs
NP_001119590.1:p.Ala37Hisfs
NP_001119590.1:p.Ala37fs
NP_001263624.1:p.Ala37fs
NP_001263625.1:p.Ala37fs
NP_001263689.1:p.Ala37fs
NP_001263690.1:p.Ala37fs
NP_001394191.1:p.Ala76fs
NP_001394192.1:p.Ala37fs
NP_001394193.1:p.Ala76fs
NP_001394194.1:p.Ala37fs
NP_001394195.1:p.Ala76fs
NP_001394196.1:p.Ala37fs
NP_001394197.1:p.Ala76fs
NP_001394198.1:p.Ala37fs
NP_001394199.1:p.Ala76fs
NP_001394200.1:p.Ala37fs
LRG_321t1:c.225del
LRG_321t2:c.225del
LRG_321t3:c.225del
LRG_321t4:c.225del
LRG_321t8:c.108del
LRG_321:g.16407del
LRG_321:p.Ala76Hisfs
LRG_321p1:p.Ala76Hisfs
LRG_321p3:p.Ala76Hisfs
LRG_321p4:p.Ala76Hisfs
LRG_321p8:p.Ala37Hisfs
NC_000017.10:g.7579462del
NM_000546.5:c.225delT
NM_001126112.2:c.225delT
NM_001126113.2:c.225delT
NM_001126114.2:c.225delT
NM_001126118.1:c.108delT
NR_176326.1:n.367del

Protein change:

A37fs

Molecular consequence:

NM_000546.6:c.225del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001126112.3:c.225del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001126113.3:c.225del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001126114.3:c.225del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001126118.2:c.108del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001276695.3:c.108del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001276696.3:c.108del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001276760.3:c.108del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001276761.3:c.108del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407262.1:c.225del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407263.1:c.108del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407264.1:c.225del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407265.1:c.108del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407266.1:c.225del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407267.1:c.108del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407268.1:c.225del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407269.1:c.108del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407270.1:c.225del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407271.1:c.108del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_176326.1:n.367del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV004336894	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 13, 2023)	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

SCV004336894

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 13, 2023)

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004336894.1

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

Description

This sequence change creates a premature translational stop signal (p.Ala76Hisfs*47) 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 variant has not been reported in the literature in individuals affected with TP53-related conditions. 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: Nov 10, 2024

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