rs1555524108

chr17-7669650-TA-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_000546.6(TP53):c.1140del(p.His380GlnfsTer42) variant causes a frameshift change involving the alteration of a non-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).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 1.22

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0355 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7669650-TA-T is Pathogenic according to our data. Variant chr17-7669650-TA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458520.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.1140del	p.His380GlnfsTer42	frameshift_variant	11/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.1140del	p.His380GlnfsTer42	frameshift_variant	11/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Choroid plexus papilloma;C0346629:Colorectal cancer;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2750850:Glioma susceptibility 1;C3553606:Basal cell carcinoma, susceptibility to, 7;C4748488:Bone marrow failure syndrome 5 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Jan 23, 2024

The c.1140del variant is not present in 1000 Genomes, EVS, ExAC, gnomAD, Indian Exome Database or our in-house exome database. This variant has not been reported in the literature in individuals affected with TP53-related conditions. It has been previously reported to the ClinVar database (Accession: VCV000458520.6) as ‘Uncertain significance’ by a single submitter. In-silico pathogenicity prediction programs like MutationTaster2, CADD, Varsome, Franklin etc predicted this variant to be likely deleterious, however these predictions were not confirmed by published functional studies. This variant is located at the last exon of the gene that causes frameshift at the 380th amino acid position of the wild-type transcript which disrupts the last 14 amino acids of the TP53 protein and extends the protein by 27 additional amino acid residues, however not predicted to cause nonsense mediated decay of the mRNA. This region is critical to the protein function and several other pathogenic variants in this region have been reported to the clinical databases. -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 03, 2017

In summary, this variant is a novel frameshift in the final exon of TP53 with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TP53-related disease. This variant disrupts a portion of the C-terminal regulatory domain (residues 363-393) of TP53 that is necessary for full TP53 DNA binding and transactivation activity (PMID: 22178617, 25794615, 26205489). However, this particular variant has not been tested, and the clinical significance of this disruption is unknown. This sequence change deletes 1 nucleotide from exon 11 of the TP53 mRNA (c.1140delT), causing a frameshift at codon 380 (p.His380Glnfs*42). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acids of the TP53 protein, and to extend the protein by an additional 27 amino acids. -

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: rs1555524108; hg19: chr17-7572968; COSMIC: COSV52672952; COSMIC: COSV52672952;