Variant rs730882019 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PM4_Supporting

The NM_000546.6(TP53):c.453_455delCCC(p.Pro152del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

TP53
NM_000546.6 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

TP53 links:

TP53 (HGNC:):

TP53 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000546.6. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.453_455delCCC	p.Pro152del	disruptive_inframe_deletion	5/11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.453_455delCCC	p.Pro152del	disruptive_inframe_deletion	5/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 17, 2019	This variant has been reported to affect TP53 protein function (PMID: 9150393, 7669577). 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. This variant has been observed in an individual affected with Li-Fraumeni syndrome¬†(PMID: 25047674). This variant is not present in population databases (ExAC no frequency). This variant, c.453_455del, results in the deletion of 1 amino acid(s) of the TP53 protein (p.Pro153del), but otherwise preserves the integrity of the reading frame. -
Uncertain significance, criteria provided, single submitter	clinical testing	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Jan 10, 2020	Data included in classification: Variant is absent in gnomAD controls (PM2_supp). Data not included in classification: UK family 1: proband with breast ca at ages 24, 26 and 40; sarcoma age 26; and lung adenoca age 51. Family history of oesophageal cancer in mother age 46, breast cancer in maternal grandmother age 60, breast cancer age 38 in maternal aunt and breast cancer age 35 in maternal cousin 1 and brain cancer in maternal cousin 2 age 40. Proband has confirmed BRCA2 pathogenic variant c.5130_5133delTGTA p.(Tyr1710Ter). Bayes Del and AGVGD predictions cannot be generated for an inframe deletion. Note: there are 3 consecutive proline residues at 151,152,153, which historically may have resulted in mis-naming/conflation of variants. [eg UK Family 1 has previously been mentioned in a paper describing p.Pro151del (PMID: 9150393)]. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 01, 2020	The c.453_455delCCC variant (also known as p.P153del) is located in coding exon 4 of the TP53 gene. This variant results from an in-frame CCC deletion at nucleotide positions 453 to 455. This results in the in-frame deletion of a proline at codon 153. This amino acid position is not well conserved in available vertebrate species. This alteration has been reported in a 52 year old Caucasian female, who was treated for breast cancer and later developed epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (Michalarea V et al. Lung Cancer, 2014 Sep;85:485-7). Two separate assays have shown this alteration results in an increase in apoptosis relative to wild type (Camplejohn RS et al. Br J Cancer, 1995 Sep;72:654-62; Lomax ME et al. Oncogene, 1997 Apr;14:1869-74). Of note, this alteration has historically been mis-designated as a deletion of codon 151, due to the presence of three consecutive proline residues at codons 151,152,153. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Li-Fraumeni syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing