17-7675190-C-T

Position:

chr17-7675190-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000546.6(TP53):c.422G>A(p.Cys141Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 6.14

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]

TP53 links:

TP53 (HGNC:):

TP53 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 17-7675190-C-T is Pathogenic according to our data. Variant chr17-7675190-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.422G>A	p.Cys141Tyr	missense_variant	5/11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.422G>A	p.Cys141Tyr	missense_variant	5/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 13, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8816796, 9418900]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11370630, 20522432]. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 28, 2023	The p.C141Y pathogenic mutation (also known as c.422G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 422. The cysteine at codon 141 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been reported several times in families either meeting diagnostic criteria for Li-Fraumeni syndrome (LFS) or in families with features suggestive of LFS (Zhou XP et al. Ann Neurol. 1999 Dec;46(6):913-6; Monti P et al. Clin Cancer Res. 2007 Jul 1;13(13):3789-95; Bougeard G et al. J Med Genet. 2008 Aug;45(8):535-8; Ruijs MW et al. J Med Genet. 2010 Jun;47(6):421-8). This mutation is located in the DNA binding domain of the p53 protein and is reported to have loss of transactivation capacity and reduced DNA-binding in yeast-based assays compared to wildtype p53 protein (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Malcikova J et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient at growth suppression (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Li-Fraumeni syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 141 of the TP53 protein (p.Cys141Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with breast cancer, Li-Fraumeni syndrome (LFS)-related cancers (liposarcoma, astrocytoma, Hodgkin lymphoma), and in families with a strong history of LFS-related cancers (PMID: 10589545, 11370630, 20522432, 21232794; Invitae). ClinVar contains an entry for this variant (Variation ID: 140801). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16861262, 20128691, 21343334, 24256616). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 18, 2020

Published functional studies demonstrate a damaging effect: loss of transactivation and cell growth suppression abilities (Kato 2003, Dearth 2007, Monti 2011, Malcikova 2010, Kotler 2018); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33138793, 31105275, 10589545, 31206626, 18511570, 26619011, 24256616, 21232794, 20522432, 11370630, 30840781, 30720243, 28975465, 28152038, 29979965, 17606709, 20128691, 16861262, 12826609, 21343334) -

Ovarian neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Neoplasm

Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.87

D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D;D

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;T;T

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.2

.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-8.1

D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.;D

Polyphen

1.0

D;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D;.;.

Vest4

0.93

MutPred

0.95

Loss of methylation at K139 (P = 0.0558);Loss of methylation at K139 (P = 0.0558);.;.;.;.;Loss of methylation at K139 (P = 0.0558);.;Loss of methylation at K139 (P = 0.0558);Loss of methylation at K139 (P = 0.0558);Loss of methylation at K139 (P = 0.0558);.;.;Loss of methylation at K139 (P = 0.0558);.;.;.;.;Loss of methylation at K139 (P = 0.0558);.;

MVP

0.99

MPC

2.1

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.77

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

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