rs730882019

Variant names:

• chr17-7675156-CGGG-C
• rs730882019
• NM_000546.6:c.453_455delCCC

Your query was ambiguous. Multiple possible variants found:

• chr17-7675156-CGGG-C
• chr17-7675156-CGGG-CGG
• chr17-7675156-CGGG-CGGGG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PM4_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 (★★). Synonymous variant affecting the same amino acid position (i.e. P151P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 10.0
• Publications: 98 publications found

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 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 33 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 46 uncertain 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 rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.453_455delCCC	p.Pro152del	disruptive_inframe_deletion	Exon 5 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.453_455delCCC	p.Pro152del	disruptive_inframe_deletion	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:2

Jan 10, 2020

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)]. -

Jul 17, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in an individual affected with Li-Fraumeni syndrome (PMID: 25047674). 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 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. -

Hereditary cancer-predisposing syndrome Uncertain:2

Jun 18, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 18, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730882019; hg19: chr17-7578474; COSMIC: COSV52826848;