chr11-108268393-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
ataxia telangiectasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
prostate cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
familial ovarian cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
gastric carcinoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ATM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.2639-17G>T		intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.2639-17G>T		intron	N/A	NP_001338763.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ATM	ENST00000675843.1	MANE Select	c.2639-17G>T	intron	N/A	ENSP00000501606.1
ATM	ENST00000452508.7	TSL:1	c.2639-17G>T	intron	N/A	ENSP00000388058.2
ATM	ENST00000531525.3	TSL:1	c.2639-17G>T	intron	N/A	ENSP00000434327.3

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

GnomAD2 exomes

AF:

0.0123

AC:

3094

AN:

250648

AF XY:

0.0126

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 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

African (AFR)

AF:

0.0714

AC:

2388

AN:

33444

American (AMR)

AF:

0.00394

AC:

176

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00145

AC:

AN:

26132

East Asian (EAS)

AF:

0.0275

AC:

1091

AN:

39638

South Asian (SAS)

AF:

0.0468

AC:

4032

AN:

86138

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52402

Middle Eastern (MID)

AF:

0.00244

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.000199

AC:

221

AN:

1110858

Other (OTH)

AF:

0.00824

AC:

497

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

394

788

1183

1577

1971

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

264

396

528

660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0214

AC:

3255

AN:

152146

Hom.:

Cov.:

AF XY:

0.0216

AC XY:

1606

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0670

AC:

2781

AN:

41480

American (AMR)

AF:

0.00719

AC:

110

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.0148

AC:

AN:

5186

South Asian (SAS)

AF:

0.0462

AC:

223

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68012

Other (OTH)

AF:

0.0137

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

164

328

492

656

820

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00404

Hom.:

Bravo

AF:

0.0230

Asia WGS

AF:

0.0340

AC:

119

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Hereditary cancer-predisposing syndrome (3)

not provided (3)

Familial cancer of breast (2)

Ataxia-telangiectasia syndrome (1)

ATM-related cancer predisposition (1)

Breast and/or ovarian cancer (1)

Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.86

(source)

DANN

Benign

0.56

PhyloP100

0.21

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over