rs1064794309

Variant names:

• chr17-7674196-GTGA-G
• rs1064794309
• NM_000546.6:c.764_766delTCA

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000546.6(TP53):​c.764_766delTCA​(p.Ile255del) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: TP53 NM_000546.6 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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 Pathogenic. Variant got 13 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.
• PP5: Variant 17-7674196-GTGA-G is Pathogenic according to our data. Variant chr17-7674196-GTGA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7674196-GTGA-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.764_766delTCA	p.Ile255del	disruptive_inframe_deletion	Exon 7 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.764_766delTCA	p.Ile255del	disruptive_inframe_deletion	Exon 7 of 11	1	NM_000546.6	ENSP00000269305.4

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:2

Feb 16, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Sep 17, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.764_766delTCA variant (also known as p.I255del) is located in coding exon 6 of the TP53 gene. This variant results from an in-frame TCA deletion at nucleotide positions 764 to 766. This results in the in-frame deletion of an isoleucine at codon 255. This alteration has been reported as de novo in a proband with bilateral breast cancer at age 32, and also in this individual's child with a high-grade brain tumor diagnosed at age 2 (Quinn E et al. Cold Spring Harb Mol Case Stud 2019 08;5(4)). This alteration has also been identified in an individual with both early-onset breast cancer and astrocytoma (Melhem-Bertrandt A et al. Cancer 2012 Feb;118(4):908-13). Based on internal structural analysis, p.I255del is considered deleterious to protein structure (Ambry internal data; Golovenko D et al. Structure 2018 09;26(9):1237-1250.e6). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome Pathogenic:1

Jan 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.764_766del, results in the deletion of 1 amino acid(s) of the TP53 protein (p.Ile255del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with TP53-related conditions (PMID: 21761402, 30886117; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as c.763delATC. ClinVar contains an entry for this variant (Variation ID: 420134). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TP53 function (PMID: 30886117). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Sep 20, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.764_766delTCA variant in TP53 gene has previously been reported in at least one individual suspicious for Li-Fraumeni syndrome (Melhem-Bertrandt et al., 2012). The c.764_766delTCA variant is an in-frame deletion that results in the loss of a single Isoleucine residue, denoted p.I255del within the DNA binding domain (Bode et al., 2004). The residue removed by this deletion occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. Based on currently available evidence, c.764_766delTCA is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064794309; hg19: chr17-7577514;