rs1057519625

chr17-7670657-TTGAGTTCC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_000546.6(TP53):c.1044_1051del(p.Glu349GlyfsTer30) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as drug response (no stars). Synonymous variant affecting the same amino acid position (i.e. L348L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 frameshift
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 7.03

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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.1044_1051del	p.Glu349GlyfsTer30	frameshift_variant	10/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.1044_1051del	p.Glu349GlyfsTer30	frameshift_variant	10/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Poly (ADP-Ribose) polymerase inhibitor response Other:1

drug response, no assertion criteria provided

clinical testing

Oxford Haemato-Oncology Service, Oxford University Hospitals NHS Foundation Trust

Nov 27, 2017

- Loss of TP53 usually associated with poor prognosis. Associated with a somatic copy number loss, so double hit and therefore possibly responsive to PARP inhibitors.

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: rs1057519625; hg19: chr17-7573975;