rs876658144

Positions:

• chr17-7674865-CGGCTCATAG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM4 PP3 PP5_Moderate

The NM_000546.6(TP53):​c.657_665del​(p.Tyr220_Pro222del) variant causes a 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P219P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 13 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.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 17-7674865-CGGCTCATAG-C is Pathogenic according to our data. Variant chr17-7674865-CGGCTCATAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 229689.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.657_665del	p.Tyr220_Pro222del	inframe_deletion	6/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.657_665del	p.Tyr220_Pro222del	inframe_deletion	6/11	1	NM_000546.6	P1

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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2016

The c.657_665delCTATGAGCC variant is located in coding exon 5 of the TP53 gene. This variant results from an in-frame nine base pair deletion from nucleotide positions 657 to 665, which causes a deletion of 3 amino acid residues (P219, Y220, and E221). This deletion removes residue Y220, a well-characterized mutation hot spot involved in stabilizing the folding of the p53 beta sheet (Bullock AN et al.Oncogene 2000 Mar; 19(10):1245-56). This deletion results in a gap in the structure that when minimized is filled with buried solvent, which would result in a energetically unstable region (internal analysis). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0005% (greater than 200000 alleles tested) in our clinical cohort. In addition, this alteration is predicted to be deleterious by PROVEAN (Protein Variation Effect Analyzer) in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876658144; hg19: chr17-7578183;