rs587781564

Positions:

• chr17-7673771-GCGCCGGTCTCT-GTG

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM4 PP3 PP5_Moderate

The NM_000546.6(TP53):​c.838_848delinsCA​(p.Arg280_Arg283delinsHis) variant causes a protein altering 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: 31)
• Consequence: TP53 NM_000546.6 protein_altering
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

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 9 ACMG points.

• PM1: In a region_of_interest Interaction with DNA (size 7) in uniprot entity P53_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 17-7673772-CGCCGGTCTCT-TG is Pathogenic according to our data. Variant chr17-7673772-CGCCGGTCTCT-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141193.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.838_848delinsCA	p.Arg280_Arg283delinsHis	protein_altering_variant	8/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.838_848delinsCA	p.Arg280_Arg283delinsHis	protein_altering_variant	8/11	1	NM_000546.6	ENSP00000269305	P1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2013

​The c.838_848del11insCA variant, located in coding exon 7 of the TP53 gene, results from the deletion of 11 nucleotides at position 838 to 848 and the insertion of 2 nucleotides (C and A) in the deleted region. The result of this deletion and insertion is the loss of four amino acids at codon 280 to 283 (arginine, aspartic acid, arginine, and arginine) and the insertion of one different amino acid, histidine, at the new codon 280. This is not a frameshift mutation, but the result of this variant is predicted to be a protein that is three amino acids shorter than the wild-type.Alterations in one of the deleted codons, codon 282, are among the most common TP53 mutations found in both sporadic tumors and in the germline (Malkin, D. Genes Cancer. 2011 Apr;2(4):475-84).In addition, this variant is located in a DNA-binding domain, and mutations in this region are known to cause a more highly penetrate cancer phenotype than mutations in other regions (Silva, AG. Orphanet J Rare Dis. 2012 Dec 21;7:101; Birch, JM. Oncogene.1998 Sep 3;17(9):1061-8). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 10700 alleles tested) in our clinical cohort (includes this individual). There are no available functional studies to aid in predicting the impact of this variant on the TP53 protein, but based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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: rs587781564; hg19: chr17-7577090;