17-7675113-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000546.6(TP53):c.499C>T(p.Gln167*) variant causes a stop gained change. 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q167Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

TP53
NM_000546.6 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 6.49

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

breast cancer
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
Li-Fraumeni syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
Li-Fraumeni syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
adrenocortical carcinoma, hereditary
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
sarcoma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
bone marrow failure syndrome 5
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
colorectal cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
choroid plexus carcinoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TP53 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 17-7675113-G-A is Pathogenic according to our data. Variant chr17-7675113-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 528250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TP53	NM_000546.6	MANE Select	c.499C>T	p.Gln167*	stop_gained	Exon 5 of 11	NP_000537.3
TP53	NM_001126112.3		c.499C>T	p.Gln167*	stop_gained	Exon 5 of 11	NP_001119584.1
TP53	NM_001407262.1		c.499C>T	p.Gln167*	stop_gained	Exon 6 of 12	NP_001394191.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TP53	ENST00000269305.9	TSL:1 MANE Select	c.499C>T	p.Gln167*	stop_gained	Exon 5 of 11	ENSP00000269305.4
TP53	ENST00000445888.6	TSL:1	c.499C>T	p.Gln167*	stop_gained	Exon 5 of 11	ENSP00000391478.2
TP53	ENST00000610292.4	TSL:1	c.382C>T	p.Gln128*	stop_gained	Exon 4 of 10	ENSP00000478219.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

251344

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome 1

Pathogenic:3

Jun 18, 2022

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 11, 2023

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.

Apr 06, 2018

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

not provided

Pathogenic:3

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 05, 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 at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 18555592, 10519380, 29979965, 11051239, 30886117, 12067251, 22768918)

Hereditary cancer-predisposing syndrome

Pathogenic:3

Hauer Lab, Department Of Pediatric Oncology, Technical University Munich

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

ACMG/AMP, PVS1, PM2, PP5

Jun 18, 2022

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 13, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Q167* pathogenic mutation (also known as c.499C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 499. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This alteration was identified as a somatic alteration in AML and MDS tumors, and found to have between 0-10% of wildtype transactivation activity across multiple response elements tested (Lodé L et al. Haematologica, 2018 Jan;103:e13-e16). 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.

Li-Fraumeni syndrome

Pathogenic:1

Sep 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 528250). This sequence change creates a premature translational stop signal (p.Gln167*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with gastric carcinoma or myelodysplastic syndromes (PMID: 21080251, 27741277). For these reasons, this variant has been classified as Pathogenic.

Adrenocortical carcinoma, hereditary

Pathogenic:1

Aug 22, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.96

PhyloP100

6.5

Vest4

0.86

GERP RS

4.6

PromoterAI

-0.0078

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over