dbSNP rs730882001: TP53:p.Gln165* (chr17-7675119-G-A) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000546.6(TP53):c.493C>T(p.Gln165*) variant causes a stop gained change. 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: 𝑓 0.0 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TP53
NM_000546.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 6.28

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]

TP53 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 17-7675119-G-A is Pathogenic according to our data. Variant chr17-7675119-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 182930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675119-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.493C>T	p.Gln165*	stop_gained	Exon 5 of 11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.493C>T	p.Gln165*	stop_gained	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152214

Hom.:

Cov.:

FAILED QC

Gnomad AFR

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0.00

Gnomad AMI

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Gnomad AMR

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0.00

Gnomad ASJ

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Gnomad EAS

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0.00

Gnomad FIN

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Gnomad MID

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0.00

Gnomad NFE

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0.00

Gnomad OTH

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0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

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AN:

1461886

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

Gnomad4 AFR exome

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0.00

Gnomad4 AMR exome

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Gnomad4 FIN exome

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Gnomad4 NFE exome

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0.00

Gnomad4 OTH exome

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0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

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AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

Gnomad4 AFR

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0.00

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0.00

Gnomad4 ASJ

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0.00

Gnomad4 EAS

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0.00

Gnomad4 SAS

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0.00

Gnomad4 FIN

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0.00

Gnomad4 NFE

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0.00

Gnomad4 OTH

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0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:3

Jun 18, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q165* pathogenic mutation (also known as c.493C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 493. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This variant has been reported in an eleven year old boy diagnosed with medulloblastoma (Waszak SM et al. Lancet Oncol, 2018 06;19:785-798). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Mar 15, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 5 of the TP53 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Experimental studies have shown that this variant results in protein that is non-functional in a human cell proliferation assay (PMID: 29979965). This variant has been reported in individuals affected with breast cancer and medulloblastoma (PMID: 26681312, 29753700, 30287823). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Li-Fraumeni syndrome 1

Pathogenic:2

Jun 18, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 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. -

Li-Fraumeni syndrome

Pathogenic:1

Feb 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 182930). This premature translational stop signal has been observed in individual(s) with breast cancer and medulloblastoma (PMID: 26681312, 29753700). This sequence change creates a premature translational stop signal (p.Gln165*) 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). -

not provided

Pathogenic:1

May 21, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31105275, 29452859, 26681312, 29753700, 30824994, 26425688, 30816478, 30720243, 22866089, 29979965) -

Familial cancer of breast

Pathogenic:1

May 09, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Lip and oral cavity carcinoma

Pathogenic:1

Apr 30, 2019

Institute of Medical Sciences, Banaras Hindu University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Squamous cell carcinoma of the head and neck

Pathogenic:1

Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

Vest4

0.88

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over