chr17-7675076-T-A

Position:

chr17-7675076-T-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The ENST00000269305.9(TP53):c.536A>T(p.His179Leu) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H179Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

TP53
ENST00000269305.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 13 uncertain in ENST00000269305.9

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7675075-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 406578.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 17-7675076-T-A is Pathogenic according to our data. Variant chr17-7675076-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376608.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1}. Variant chr17-7675076-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.536A>T	p.His179Leu	missense_variant	5/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.536A>T	p.His179Leu	missense_variant	5/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 14, 2024

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9049183, 9049184, 23713777]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Adrenocortical carcinoma, hereditary

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 07, 2022

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 04, 2024

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15510160, 30224644, 16861262, 30661751, 9546439, 12124823, 11590071, 22114072, 29979965, 9049183, 12826609, 23713777, 16633321, 18511570, 19556618, 25433984) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2023

The p.H179L variant (also known as c.536A>T), located in coding exon 4 of the TP53 gene, results from an A to T substitution at nucleotide position 536. The histidine at codon 179 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). Cells carrying this variant were shown to induce tumor formation when transplanted into mice (Cardinali M et al. Mol Carcinog, 1997 Feb;18:78-88). Two other alterations at the same codon, p.H179Q and p.H179R have been described in individuals with TP53-related disease (Petitjean A et al. IARC TP53 database [version R19, August 2018]. Hum Mutat. 2007 Jun;28(6):622-9;Gonzalez KD et al. J. Med. Genet. 2009 Oct; 46(10):689-93). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Li-Fraumeni syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 08, 2021

This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with leucine at codon 179 of the TP53 protein (p.His179Leu). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and leucine. This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 376608). Experimental studies have shown that this missense change impairs¬†transcriptional transactivation activity¬†of the TP53 protein,¬†reduces apoptosis activity and¬†confers cisplatin-sensitivity and increased cell mobility to cells carrying this variant, and acts in a dominant-negative fashion to inhibit function of wild-type protein¬†(PMID: 12826609, 16861262,¬†22114072, 23713777). In addition, cells carrying this variant transplanted in mice¬†induce tumor formation more rapidly than cells carrying wild-type TP53 (PMID: 9049183). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the 179 amino acid residue in TP53 have been observed in affected individuals (PMID:¬†19556618,¬†16633321, 18511570, 25433984). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.84

D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.64

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

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.6

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

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-11

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

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0070

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.22

B;.;.;.;.;.;.;.;.;B;.;P;B;P;.;.;B;.;.;.;D

Vest4

0.68

MutPred

0.93

Loss of disorder (P = 0.0367);Loss of disorder (P = 0.0367);.;.;.;.;.;.;.;Loss of disorder (P = 0.0367);.;Loss of disorder (P = 0.0367);Loss of disorder (P = 0.0367);Loss of disorder (P = 0.0367);.;.;Loss of disorder (P = 0.0367);.;.;.;.;

MVP

0.95

MPC

1.8

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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