rs794727846

Positions:

• chr17-7674253-ATGTAGT-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP3 PP5

The ENST00000269305.9(TP53):​c.704_709del​(p.Asn235_Tyr236del) 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N235N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: TP53 ENST00000269305.9 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3
• Conservation: PhyloP100: 9.31

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 8 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in ENST00000269305.9
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000269305.9.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 17-7674253-ATGTAGT-A is Pathogenic according to our data. Variant chr17-7674253-ATGTAGT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198431.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.704_709del	p.Asn235_Tyr236del	inframe_deletion	7/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.704_709del	p.Asn235_Tyr236del	inframe_deletion	7/11	1	NM_000546.6	ENSP00000269305	P1

Frequencies

GnomAD3 genomes Cov.: 30

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

GnomAD4 genome Cov.: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 16, 2024	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [Myriad internal data]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 28, 2022	The c.704_709delACTACA variant (also known as p.N235_Y236del) is located in coding exon 6 of the TP53 gene. This variant results from an in-frame ACTACA deletion at nucleotide positions 704 to 709. This results in the in-frame deletion of 2 amino acids at codons 235 and 236. This specific alteration, as well as another in-frame deletion within the same region (c.706_708delTAC) have been identified in patients with Li Fraumeni syndrome (LFS) or meeting Chompret criteria (Ambry internal data; Lübbe J et al. Brain Pathol., 1995 Jan;5:15-23). In addition, three missense alteration at codon 236 (p.Y236C, p.Y236D, p.Y236H) have been reported in families with LFS or in individuals with confirmed de novo mutations at these positions and LFS spectrum tumors (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9, Rines R et al., Carcinogenesis 1998 Jun; 19(6):979-84; Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al., Science 1994 Jul; 265(5170):346-55). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Li-Fraumeni syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2023

This variant, c.704_709del, results in the deletion of 2 amino acid(s) of the TP53 protein (p.Asn235_Tyr236del), but otherwise preserves the integrity of the reading frame. 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. This variant disrupts a region of the TP53 protein in which other variant(s) (p.Tyr236His) have been determined to be pathogenic (PMID: 12826609, 29979965; external communication). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 20, 2015

- -

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: rs794727846; hg19: chr17-7577571;