17-7675089-G-A

Position:

chr17-7675089-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. BS3_SupportingPP3_ModeratePM1BS2_SupportingPS4_Supporting

This summary comes from the ClinGen Evidence Repository: This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). This variant is within a codon that is an established hotspot in the TP53 gene (PM1). This variant has been reported in 2 probands meeting Revised Chompret criteria (PS4_Supporting; PMID:31119730, internal laboratory contributor(SCV000903055.2)). Transactivation assays show partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID:12826609, 30224644). This variant has been observed in 5 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor, SCV000833097.4). In summary, the clinical significance of TP53 c.523C>T (p.Arg175Cys) is uncertain for Li-Fraumeni Syndrome. ACMG/AMP criteria applied, as specified by the TP53 Expert Panel: PP3_Moderate; PM1; PS4_Supporting; BS3_Supporting; BS2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA002442/MONDO:0018875/009

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:24U:7

Conservation

PhyloP100: 4.04

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 Uncertain_significance. Variant got 3 ACMG points.

PS4

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

PM1

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

PP3

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

BS2

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

BS3

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.523C>T	p.Arg175Cys	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.523C>T	p.Arg175Cys	missense_variant	5/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251284

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135826

show subpopulations

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 SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:24Uncertain:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 13, 2023	Variant summary: TP53 c.523C>T (p.Arg175Cys) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251284 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.523C>T has been reported in the literature in individuals affected with breast, ovarian and other cancers ((example, Walsh_2011, Sun_2017, Weber-Lassalle_2018, Sheng_2020)) but to our knowledge, it has not been reported in individuals affected with Li-Fraumeni Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least two publication reports experimental evidence evaluating an impact on protein function. These results showed similar levels of cell cyle arrest and apoptotic functions to wild type (e.g. Ryan_1998), and partially functional transcriptional activity as measured in a yeast-based assay (Kato_2003). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Li-Fraumeni syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 175 of the TP53 protein (p.Arg175Cys). This variant is present in population databases (rs138729528, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 22006311, 25503501, 28724667, 31119730). ClinVar contains an entry for this variant (Variation ID: 245851). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644, 33245408). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. -
Uncertain significance, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Jun 27, 2022	This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). This variant is within a codon that is an established hotspot in the TP53 gene (PM1). This variant has been reported in 2 probands meeting Revised Chompret criteria (PS4_Supporting; PMID: 31119730, internal laboratory contributor(SCV000903055.2)). Transactivation assays show partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). This variant has been observed in 5 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor, SCV000833097.4). In summary, the clinical significance of TP53 c.523C>T (p.Arg175Cys) is uncertain for Li-Fraumeni Syndrome. ACMG/AMP criteria applied, as specified by the TP53 Expert Panel: PP3_Moderate; PM1; PS4_Supporting; BS3_Supporting; BS2_Supporting. -

Glioblastoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Prostate adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Carcinoma of esophagus

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gastric adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell lung carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

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

- -

Brainstem glioma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Li-Fraumeni syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Feb 23, 2023

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 30224644). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TP53 -related disorder (PMID: 22006311). However, the evidence of pathogenicity is insufficient at this time. Different missense changes at the same codon (p.Arg175Gly, p.Arg175His, p.Arg175Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012374, VCV000182963, VCV000376649). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

Nasopharyngeal neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of brain

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Hepatocellular carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of the large intestine

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Medulloblastoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Ovarian serous cystadenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Uterine carcinosarcoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

B-cell chronic lymphocytic leukemia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant neoplasm of body of uterus

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Pancreatic adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gallbladder carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Transitional cell carcinoma of the bladder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 17, 2024

Published functional studies demonstrate no damaging effect: retained apoptosis and growth suppression activities, partially functional transactivation per IARC, and intact transactivation of typical p53 targets (PMID: 30224644, 29979965, 12826609, 8062826, 9546439, 9632751, 11375890); Observed in individuals with a personal history of breast or ovarian cancer (PMID: 22006311, 30216591, 28724667, 31119730, 35820297, 38814507); 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; This variant is associated with the following publications: (PMID: 22006311, 26619011, 23792586, 29979965, 30216591, 25927356, 30720243, 31016814, 30352134, 31119730, 30089713, 21343334, 12826609, 8825920, 8164043, 30224644, 8062826, 11375890, 9546439, 9632751, 28861920, 28724667, 11370630, 30840781, 21761402, 26556035, 27323394, 30741375, 30979843, 33257846, 33245408, 35820297, 34863587, 38814507, 15510160) -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

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

Oct 12, 2023

PM1, PP3_mod, PS4_sup, BS2sup, BS3sup, See ClinVar ClinGen TP53 Variant Curation Expert Panel classification (Class 3). According to the ACMG gene specific: TP53 criteria we chose these criteria: PS4 (supporting pathogenic): This variant has been reported in 2 probands meeting Revised Chompret criteria (PS4_Supporting; PMID: 31119730, internal laboratory contributor(SCV000903055.2, PM1 (medium pathogenic): This variant is within a codon that is an established hotspot in the TP53 gene (PM1), PP3 (medium pathogenic): BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65, BS2 (supporting benign): This variant has been observed in 5 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor, SCV000833097.4). , BS3 (supporting benign): Transactivation assays show partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting) -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2024

The p.R175C variant (also known as c.523C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 523. The arginine at codon 175 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in a patient diagnosed with breast cancer at age 30 (Guo Y et al. Breast, 2022 Oct;65:55-60). This variant is in the DNA binding domain of the TP53 protein and has shown a partial decrease in transactivation capacity for some, but not all downstream targets in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. U.S.A. 2003 Jul;100:8424-9). However, studies conducted in human cell lines indicate this alteration remains proficient at growth suppression and has no 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). Additional functional studies in mammalian cells have also shown this variant to behave similarly to wild type in terms of protein conformation, transactivation, growth suppression, apoptotic activities, and protein level regulation (Ory K et al. EMBO J. 1994 Aug;13:3496-504; Ryan K et al. Mol. Cell. Biol. 1998 Jul;18:3692-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

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

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.88

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

1.1

MutationAssessor

Pathogenic

2.9

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

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-7.7

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

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.96

MutPred

0.99

Loss of disorder (P = 0.0217);Loss of disorder (P = 0.0217);.;.;.;.;.;.;.;Loss of disorder (P = 0.0217);.;Loss of disorder (P = 0.0217);Loss of disorder (P = 0.0217);Loss of disorder (P = 0.0217);.;.;Loss of disorder (P = 0.0217);.;.;.;.;

MVP

1.0

MPC

1.9

ClinPred

1.0

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.95

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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