rs786204061

Variant names:

• chr17-7673771-G-GCGCCGGTCTCTCCCAGGA
• rs786204061
• NM_000546.6:c.831_848dupTCCTGGGAGAGACCGGCG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4

The NM_000546.6(TP53):​c.831_848dupTCCTGGGAGAGACCGGCG​(p.Arg283_Thr284insProGlyArgAspArgArg) variant causes a disruptive inframe insertion 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18

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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.831_848dupTCCTGGGAGAGACCGGCG	p.Arg283_Thr284insProGlyArgAspArgArg	disruptive_inframe_insertion	Exon 8 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.831_848dupTCCTGGGAGAGACCGGCG	p.Arg283_Thr284insProGlyArgAspArgArg	disruptive_inframe_insertion	Exon 8 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Sep 16, 2014

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this is a novel, in-frame duplication with uncertain impact on protein function. While this region of TP53 is important for DNA binding, the evidence is insufficient at this time to prove that this sequence change affects protein function or causes disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change inserts 18 nucleotides in exon 8 of the TP53 mRNA (c.831_848dupTCCTGGGAGAGACCGGCG). This leads to the insertion of 6 amino acid residues in the TP53 protein (p.Pro278_Arg283dup), but otherwise preserves the integrity of the reading frame. This sequence change has not been published in the literature and is not present in population databases. The 6 duplicated amino acid residues Pro278-Arg283 fall in the DNA binding domain of the TP53 protein (amino acids 102-292) (PMID: 8276238). Several missense substitutions at these six codons have been reported in affected patients (PMID: 10864200, 11370630, 15173255, 8688334) and have been shown experimentally to disrupt TP53 protein function (PMID: 17606709, 21343334). -

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: rs786204061; hg19: chr17-7577089;