rs1555525156

Variant names:

• chr17-7673756-A-ATTCTCTTCCTCTGTGCC
• rs1555525156
• NM_000546.6:c.863_864insGGCACAGAGGAAGAGAA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000546.6(TP53):​c.863_864insGGCACAGAGGAAGAGAA​(p.Asn288LysfsTer63) 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.40

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 Pathogenic. Variant got 12 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 17-7673756-A-ATTCTCTTCCTCTGTGCC is Pathogenic according to our data. Variant chr17-7673756-A-ATTCTCTTCCTCTGTGCC is described in ClinVar as [Pathogenic]. Clinvar id is 485041.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.863_864insGGCACAGAGGAAGAGAA	p.Asn288LysfsTer63	frameshift_variant	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.863_864insGGCACAGAGGAAGAGAA	p.Asn288LysfsTer63	frameshift_variant	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: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 10, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.863_864ins17 pathogenic mutation (also known as p.N288KFS*63), located in coding exon 7 of the TP53 gene, results from an insertion of 17 nucleotides at position 863, causing a translational frameshift with a predicted alternate stop codon. Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of TP53, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 106 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time; however, this change will result in the loss of the tetramerization and regulatory domains of the protein (Soussi T. Human Mutation 2003 Mar;21(3):176-81). As such, this alteration is interpreted as a disease-causing mutation. -

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: rs1555525156; hg19: chr17-7577074;