chr11-108268393-G-T

Position:

chr11-108268393-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP2_StrongBP4BA1

This summary comes from the ClinGen Evidence Repository: The ATM c.2639-17G>T variant has a gnomAD v2.1.1 filtering allele frequency of 6.505% (African/African-American; exomes) which exceeds the ATM BA1 threshold of 0.50% (BA1). This variant has been observed in a homozygous state in multiple individuals without biallelic disease (BP2_Strong; GTR Lab ID: 61756). In silico splicing predictors (SpliceAI: AL 0.00/DL 0.00/AG 0.01/DG 0.00; MaxEntScan: +1.92% (wild type = 9.90, variant = 10.09)) find that this variant is unlikely to affect splicing (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA163513/MONDO:0016419/020

Frequency

Genomes: 𝑓 0.021 ( 87 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 233 hom. )

Consequence

ATM
NM_000051.4 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:18

Conservation

PhyloP100: 0.209

Variant links:

Genes affected

ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

ATM links:

ATM (HGNC:):

ATM links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP2

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

BP4

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

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.2639-17G>T		intron_variant		ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.2639-17G>T		intron_variant			NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0214

AC:

3254

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0672

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00720

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.0150

Gnomad SAS

AF:

0.0464

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.0123

AC:

3094

AN:

250648

Hom.:

AF XY:

0.0126

AC XY:

1704

AN XY:

135596

show subpopulations

Gnomad AFR exome

AF:

0.0684

Gnomad AMR exome

AF:

0.00370

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.0148

Gnomad SAS exome

AF:

0.0483

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000449

Gnomad OTH exome

AF:

0.00671

GnomAD4 exome

AF:

0.00580

AC:

8458

AN:

1459386

Hom.:

233

Cov.:

AF XY:

0.00687

AC XY:

4987

AN XY:

726186

show subpopulations

Gnomad4 AFR exome

AF:

0.0714

Gnomad4 AMR exome

AF:

0.00394

Gnomad4 ASJ exome

AF:

0.00145

Gnomad4 EAS exome

AF:

0.0275

Gnomad4 SAS exome

AF:

0.0468

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.000199

Gnomad4 OTH exome

AF:

0.00824

GnomAD4 genome

AF:

0.0214

AC:

3255

AN:

152146

Hom.:

Cov.:

AF XY:

0.0216

AC XY:

1606

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0670

Gnomad4 AMR

AF:

0.00719

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.0148

Gnomad4 SAS

AF:

0.0462

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.00413

Hom.:

Bravo

AF:

0.0230

Asia WGS

AF:

0.0340

AC:

119

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic 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, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial cancer of breast

Benign:3

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 10, 2024	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Benign, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Mar 09, 2022	The ATM c.2639-17G>T variant has a gnomAD v2.1.1 filtering allele frequency of 6.505% (African/African-American; exomes) which exceeds the ATM BA1 threshold of 0.50% (BA1). This variant has been observed in a homozygous state in multiple individuals without biallelic disease (BP2_Strong; GTR Lab ID: 61756). In silico splicing predictors (SpliceAI: AL 0.00/DL 0.00/AG 0.01/DG 0.00; MaxEntScan: +1.92% (wild type = 9.90, variant = 10.09)) find that this variant is unlikely to affect splicing (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Feb 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 06, 2012	This alteration is classified as benign based on a combination of the following: 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	Apr 13, 2015	- -

Ataxia-telangiectasia syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Breast and/or ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Dec 07, 2021

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.86

DANN

Benign

0.56

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