17-7676154-G-C

Position:

chr17-7676154-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000546.6(TP53):c.215C>G(p.Pro72Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,613,582 control chromosomes in the GnomAD database, including 411,964 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.63 ( 31776 hom., cov: 31)

Exomes 𝑓: 0.72 ( 380188 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1U:1B:26O:2

Conservation

PhyloP100: 1.44

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.0827485E-6).

BP6

Variant 17-7676154-G-C is Benign according to our data. Variant chr17-7676154-G-C is described in ClinVar as [Benign]. Clinvar id is 12351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676154-G-C is described in Lovd as [Benign]. Variant chr17-7676154-G-C is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.215C>G	p.Pro72Arg	missense_variant	4/11	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.215C>G	p.Pro72Arg	missense_variant	4/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.627

AC:

95293

AN:

151904

Hom.:

31786

Cov.:

show subpopulations

Gnomad AFR

AF:

0.388

Gnomad AMI

AF:

0.670

Gnomad AMR

AF:

0.699

Gnomad ASJ

AF:

0.721

Gnomad EAS

AF:

0.577

Gnomad SAS

AF:

0.521

Gnomad FIN

AF:

0.736

Gnomad MID

AF:

0.662

Gnomad NFE

AF:

0.745

Gnomad OTH

AF:

0.660

GnomAD3 exomes

AF:

0.668

AC:

167398

AN:

250534

Hom.:

57557

AF XY:

0.664

AC XY:

90173

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.380

Gnomad AMR exome

AF:

0.715

Gnomad ASJ exome

AF:

0.715

Gnomad EAS exome

AF:

0.570

Gnomad SAS exome

AF:

0.500

Gnomad FIN exome

AF:

0.730

Gnomad NFE exome

AF:

0.738

Gnomad OTH exome

AF:

0.698

GnomAD4 exome

AF:

0.716

AC:

1046941

AN:

1461558

Hom.:

380188

Cov.:

AF XY:

0.710

AC XY:

516401

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.376

Gnomad4 AMR exome

AF:

0.714

Gnomad4 ASJ exome

AF:

0.719

Gnomad4 EAS exome

AF:

0.605

Gnomad4 SAS exome

AF:

0.507

Gnomad4 FIN exome

AF:

0.733

Gnomad4 NFE exome

AF:

0.748

Gnomad4 OTH exome

AF:

0.695

GnomAD4 genome

AF:

0.627

AC:

95285

AN:

152024

Hom.:

31776

Cov.:

AF XY:

0.625

AC XY:

46413

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.387

Gnomad4 AMR

AF:

0.700

Gnomad4 ASJ

AF:

0.721

Gnomad4 EAS

AF:

0.576

Gnomad4 SAS

AF:

0.523

Gnomad4 FIN

AF:

0.736

Gnomad4 NFE

AF:

0.745

Gnomad4 OTH

AF:

0.652

Alfa

AF:

0.714

Hom.:

27610

Bravo

AF:

0.617

TwinsUK

AF:

0.755

AC:

2801

ALSPAC

AF:

0.750

AC:

2889

ESP6500AA

AF:

0.405

AC:

1784

ESP6500EA

AF:

0.745

AC:

6409

ExAC

AF:

0.659

AC:

79937

Asia WGS

AF:

0.514

AC:

1788

AN:

3476

EpiCase

AF:

0.750

EpiControl

AF:

0.745

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:1Benign:26Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2016	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Li-Fraumeni syndrome 1

Uncertain:1Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	IntelligeneCG	Aug 18, 2017	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 17719241, 22289634, 23729685, 22703879, 18990008, 22524816, 20128691, 12459171, 19657731, 15138483, 21323870, 18426989, 15183530, 20587514, 18256523, 19789321, 15131588, 19837266, 18567547, 23210739, 22189267, 21038427, 20019240, 23073555, 20939739, 19357867, 19521721, 20886596, 21931130, 21454683, 21814224, 22336889, 19542078, 16258005, 11983757, 19657586, 11844595, 22367371, 21245379, 9891044, 17403527, 18583979, 12567188, 19171829, 19165225, 19639206, 21124037, 23207172, 21778786, 24728327, 21283750, 22545084, 24747975, 12826609, 19470478, 8625447, 23793604, 27153395, 25896519, 15609317, 23683469, 9607760) -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2014	- -

Li-Fraumeni syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hereditary breast ovarian cancer syndrome

Benign:2

Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -

Lip and oral cavity carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Medical Sciences, Banaras Hindu University

Apr 30, 2019

- -

Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C0585442:Bone osteosarcoma;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7;C4748488:Bone marrow failure syndrome 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 20, 2021

- -

CODON 72 POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Oct 01, 2009

- -

Acute myeloid leukemia

Benign:1

Benign, no assertion criteria provided

clinical testing

Dr. Afia Zoology Lab, University of Education

- -

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

Benign

0.072

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.57

DEOGEN2

Benign

0.013

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

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.44

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

MetaRNN

Benign

0.0000081

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.4

.;.;.;L;.;L;L;L;.;.;L;.;.;.;.;.

MutationTaster

Benign

1.0

P;P;P;P;P;P

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.29

N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;N

REVEL

Uncertain

0.37

Sift

Benign

0.26

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

Sift4G

Benign

0.57

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

Polyphen

0.74

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

Vest4

0.16

MPC

0.81

ClinPred

0.0069

GERP RS

1.9

Varity_R

0.086

gMVP

0.21

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

Other links and lift over