17-7676096-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000546.6(TP53):​c.273G>A​(p.Trp91*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

TP53
NM_000546.6 stop_gained

Scores

4
1
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 1.14
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 17-7676096-C-T is Pathogenic according to our data. Variant chr17-7676096-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 233650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TP53NM_000546.6 linkc.273G>A p.Trp91* stop_gained Exon 4 of 11 ENST00000269305.9 NP_000537.3 P04637-1K7PPA8Q53GA5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TP53ENST00000269305.9 linkc.273G>A p.Trp91* stop_gained Exon 4 of 11 1 NM_000546.6 ENSP00000269305.4 P04637-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:4
Dec 15, 2020
Department of Pediatrics, Memorial Sloan Kettering Cancer Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Jun 18, 2022
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 05, 2020
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 12, 2024
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

not provided Pathogenic:2
Oct 26, 2016
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is denoted TP53 c.273G>A at the cDNA level and p.Trp91Ter (W91X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. TP53 Trp91Ter has been reported in two individuals with breast cancer diagnosed at age 30 or younger, one of whom also had a family history of early onset breast cancer, pancreatic cancer, and astrocytoma (Lalloo 2003). This variant is considered pathogenic. -

Dec 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2
Oct 14, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.W91* pathogenic mutation (also known as c.273G>A) located in coding exon 3 of the TP53 gene, results from a G to A substitution at nucleotide position 273. This changes the amino acid from a tryptophan to a stop codon within coding exon 3. This alteration has been identified in a female patient with breast cancer at the age of 28 and 30, and a clear-cell renal cell carcinoma at age 31 (Lalloo F et al. Eur. J. Cancer 2006 May; 42(8):1143-50). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Jun 18, 2022
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Li-Fraumeni syndrome Pathogenic:1
Sep 11, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp91*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 233650). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 12672316, 31060593). This variant is not present in population databases (gnomAD no frequency). -

Ovarian neoplasm Pathogenic:1
Dec 01, 2018
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
41
DANN
Uncertain
1.0
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Benign
0.56
D
Vest4
0.84
GERP RS
4.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.50
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.50
Position offset: -28

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs876660548; hg19: chr17-7579414; COSMIC: COSV52673580; COSMIC: COSV52673580; API