rs1555525040

chr17-7673690-TGCTTGCTTACCTC-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000546.6(TP53):c.917_919+10del variant causes a splice donor, splice donor 5th base, coding sequence, intron change. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R306R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.80

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 16 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 17-7673690-TGCTTGCTTACCTC-T is Pathogenic according to our data. Variant chr17-7673690-TGCTTGCTTACCTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 528253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.917_919+10del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	8/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.917_919+10del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	8/11	1	NM_000546.6	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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 01, 2017

Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant has not been reported in the literature in individuals with TP53-related disease. This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. This sequence change removes the last 3 nucleotides of exon 8, and affects a donor splice site in intron 8 of the TP53 gene. It is expected to disrupt RNA splicing and/or create a premature translational stop signal, and likely results in an absent or disrupted protein product. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2019

The c.917_919+10DEL13 alteration is a deletion beginning in exon 8 of the TP53 gene and extending 10 nucleotides into intron 8. This results in the deletion of a total of 13 nucleotides, including the last 3 nucleotides of exon 8 and the first ten nucleotides of the splice donor site of intron 8. This deletion may cause a disruption of normal RNA splicing; however, direct evidence is unavailable. 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: rs1555525040; hg19: chr17-7577008;