rs786204061

chr17-7673771-G-GCGCCGGTCTCTCCCAGGA

Variant summary

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

The NM_000546.6(TP53):c.848_849insTCCTGGGAGAGACCGGCG(p.Pro278_Arg283dup) variant causes a 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 (★). Synonymous variant affecting the same amino acid position (i.e. R283R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 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 hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.848_849insTCCTGGGAGAGACCGGCG	p.Pro278_Arg283dup	inframe_insertion	8/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.848_849insTCCTGGGAGAGACCGGCG	p.Pro278_Arg283dup	inframe_insertion	8/11	1	NM_000546.6	P1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 16, 2014

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. 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). This sequence change has not been published in the literature and is not present in population databases. 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. -

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;