rs1555525902

Positions:

• chr17-7674956-TGAG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_000546.6(TP53):​c.572_574del​(p.Pro191del) variant causes a inframe deletion change. 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. P191P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.43

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 6 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 14 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.
• PP5: Variant 17-7674956-TGAG-T is Pathogenic according to our data. Variant chr17-7674956-TGAG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458551.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.572_574del	p.Pro191del	inframe_deletion	6/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.572_574del	p.Pro191del	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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

This variant, c.572_574del, results in the deletion of 1 amino acid(s) of the TP53 protein (p.Pro191del), 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 individuals with clinical features of Li-Fraumeni syndrome (PMID: 33245408; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 458551). 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: 33116240). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 01, 2021

Published functional studies demonstrate a damaging effect: loss of transactivation activity (Monti 2020); Not observed in large population cohorts (Lek 2016); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33116240, 28522256, 30185652, 29805648, 29489027, 30041611, 27407063, 25313908, 22983585, 21483000, 26425688, 26205736, 27045317, 27586204, 11454518, 31317311) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2022

The c.572_574delCTC variant (also known as p.P191del) is located in coding exon 5 of the TP53 gene. This variant results from an in-frame CTC deletion at nucleotide positions 572 to 574. This results in the in-frame deletion of a proline at codon 191. This alteration has been reported in an individual meeting Chompret criteria (Grill S et al. Arch Gynecol Obstet, 2020 Nov) and has also been observed in at least one individual with a personal and/or family history that is consistent with TP53-related disease (Ambry internal data, personal communication). This alteration has also been reported in the tumor of an individual with adrenocortical carcinoma (Barzon L et al. Eur. J. Endocrinol., 2001 Aug;145:207-12). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation in yeast and human cell assays (Monti P et al. Sci Rep, 2020 10;10:18427). Based on internal structural assessment, this alteration results in disruption of the DNA-binding domain (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Aug 13, 2024

According to the ClinGen ACMG TP53 v1.4.0 criteria we chose these criteria: PS4 (supporting pathogenic): Multiple Individuals meeting chompret criteria, PM2 (supporting pathogenic): not in gnomAD -

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: rs1555525902; hg19: chr17-7578274;