17-7675156-CGGG-CGGGG

Position:

• chr17-7675156-CGGG-CGGGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000546.6(TP53):​c.455dupC​(p.Pro153fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,884 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P152P) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (1 hom.)
• Consequence: TP53 NM_000546.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 10.0

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]

TP53 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7675156-C-CG is Pathogenic according to our data. Variant chr17-7675156-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 182958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.455dupC	p.Pro153fs	frameshift_variant	5/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.455dupC	p.Pro153fs	frameshift_variant	5/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461884 Hom.: 1 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 11, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 182958). This premature translational stop signal has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 1565143). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro153Alafs*28) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 29, 2024	This variant inserts 1 nucleotide in exon 5 of the TP53 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has been reported in an individual affected with osteosarcoma in a Li-Fraumeni family (PMID:1565143). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 16, 2019	The c.455dupC variant in the TP53 gene is a duplication of one nucleotide that results in the substitution of an alanine for a proline at residue 153, and a frameshift resulting in a premature stop codon 28 residues downstream. This variant results in a frameshift prior to the last exon and thus is likely to result in loss of function via nonsense-mediated decay. The c.455dupC variant in TP53 has been observed in a family with classical Li-Fraumeni syndrome where the index patient was diagnosed with osteosarcoma at age 19, two siblings had passed away from osteosarcoma at age 18 and breast cancer at age 29, and the father had passed away from osteosarcoma at age 27 (PMID 1565143). This variant has not been observed in general population databases. Therefore, the c.455dupC variant in the TP53 gene is classified as pathogenic. -

Li-Fraumeni syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 14, 1992	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 14, 2023	The c.455dupC pathogenic mutation, located in coding exon 4 of the TP53 gene, results from a duplication of C at nucleotide position 455, causing a translational frameshift with a predicted alternate stop codon (p.P153Afs*28). This alteration was identified in an individual diagnosed with osteosarcoma at age 19 who also had a family history of early onset breast cancer and osteosarcoma (Toguchida J et al. N. Engl. J. Med. 1992 May; 326(20):1301-8). Of note, these authors designated this mutation as a 1bp insertion of C between codons 151-152, causing a premature stop at codon 180. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 25, 2014

This duplication of one nucleotide in TP53 is denoted c.455dupC at the cDNA level and p.Pro153AlafsX28 (P153AfsX28) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is ACCCC[dupC]GCCC. The duplication causes a frameshift, which changes a Proline to an Alanine at codon 153, and creates a premature stop codon at position 28 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. TP53 c.455dupC has been observed in at least one Li-Fraumeni family (Toguchida 1992). we consider this variant to be pathogenic. -

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

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: rs730882019; hg19: chr17-7578474;