17-7675074-C-T

Position:

chr17-7675074-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS3_ModeratePM2_SupportingPP3PS4

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.538G>A variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 180 (p.Glu180Lys). This variant has been reported in 12 unrelated families meeting Revised Chompret criteria and reported in 1 individual with a HER2+ breast cancer. Based on this evidence, this variant scores 7 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 35974385, 33178583, 25584008, 8118819; Internal lab contributors: SCV000629836.7, SCV000581143.5, SCV000292772.10). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3_Moderate; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.262; Align GVGD = Class C55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4; PM2_Supporting, PS3_Moderate; PP3. (Bayesian Points: 8; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584590/MONDO:0018875/009

Frequency

Genomes: not found (cov: 33)

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 5.03

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.538G>A	p.Glu180Lys	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.538G>A	p.Glu180Lys	missense_variant	5/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Aug 05, 2024	The NM_000546.6: c.538G>A variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 180 (p.Glu180Lys). This variant has been reported in 12 unrelated families meeting Revised Chompret criteria and reported in 1 individual with a HER2+ breast cancer. Based on this evidence, this variant scores 7 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 35974385, 33178583, 25584008, 8118819; Internal lab contributors: SCV000629836.7, SCV000581143.5, SCV000292772.10). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3_Moderate; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.262; Align GVGD = Class C55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4; PM2_Supporting, PS3_Moderate; PP3. (Bayesian Points: 8; VCEP specifications version 2.0; 7/24/2024) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 180 of the TP53 protein (p.Glu180Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TP53-related conditions (PMID: 8118819, 25584008; Invitae). ClinVar contains an entry for this variant (Variation ID: 245711). 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, 20128691, 20471942, 21343334). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate partially functional transactivation and conflicting results with respect to apoptosis and growth suppression abilities (PMID: 20128691, 11429705, 10206274, 21343334, 24814347, 30224644, 29979965, 12826609); Identified in several children with adrenocortical carcinoma and other individuals with early-onset breast cancer, but also in unaffected adults, suggesting that this variant may confer reduced penetrance and may not result in classic Li-Fraumeni syndrome (PMID: 33178583, 35974385, 31081129, 9242456, 25584008, 8118819); This variant is associated with the following publications: (PMID: 8118819, 11948487, 10607740, 11044641, 23665223, 20128691, 11896595, 11429705, 17606709, 11429700, 15308588, 10206274, 17947339, 20471942, 16983711, 21343334, 15538112, 29058986, 12082526, 24814347, 25584008, 16035029, 15221755, 9242456, 29979965, 31081129, 30720243, 30840781, 31105275, 33300245, 30224644, 34273903, 12826609, 15510160, 12067251, 22768918, 33178583, 35974385) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2021

The p.E180K variant (also known as c.538G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 538. The glutamic acid at codon 180 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in patients with pediatric adrenocortical carcinoma (Birch JM et al. Cancer Res. 1994 Mar;54:1298-304; Wasserman JD et al. J Clin Oncol, 2015 Feb;33:602-9; Miele E et al. Front Oncol, 2020 Oct;10:554388). This alteration has also been reported in a a high-risk breast cancer proband from Sweden (Kharaziha P et al. Clin Genet, 2019 09;96:216-225). This variant is in the DNA binding domain of the TP53 protein and its position is involved in a dimer-stabilizing salt-bridge (Kitayner M et al. Mol. Cell. 2006 Jun;22:741-53). Multiple functional assays in yeast have shown this variant leads to at least partial deficiency in transactivation activity compared to wild type (Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul 8;100(14):8424-9; Campomenosi P et al. Oncogene. 2001 Jun;20:3573-9). This alteration also demonstrated a reduced ability to bind DNA in functional protein microarray studies (Malcikova J et al. Biol. Chem. 391:197-205; Boutell JM et al. Proteomics. 2004 Jul;4:1950-8). Additional studies in human cell lines show this alteration is deficient in cell growth suppression (Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-138). An in vivo assay in mice showed that a functionally equivalent variant (E180R) leads to a reduction in dimerization and DNA binding, and an inability to induce apoptosis (Timofeev O et al. Cell Rep. 2013 May;3:1512-25). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

TP53-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Oct 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

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

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.97

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

2.0

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

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.0

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

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0050

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

Sift4G

Uncertain

0.0030

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

Polyphen

1.0

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

Vest4

0.87

MutPred

0.90

Gain of ubiquitination at E180 (P = 0.0104);Gain of ubiquitination at E180 (P = 0.0104);.;.;.;.;.;.;.;Gain of ubiquitination at E180 (P = 0.0104);.;Gain of ubiquitination at E180 (P = 0.0104);Gain of ubiquitination at E180 (P = 0.0104);Gain of ubiquitination at E180 (P = 0.0104);.;.;Gain of ubiquitination at E180 (P = 0.0104);.;.;.;.;

MVP

0.94

MPC

1.8

ClinPred

0.97

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.95

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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