11-108227849-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP2_StrongBA1

This summary comes from the ClinGen Evidence Repository: The ATM c.146C>G (p.Ser49Cys) variant has a GnomAD (v2.1.1) filtering allele frequency of 1.208% (NFE) which is above the ATM BA1 threshold of .5% (BA1). This variant has been observed in a homozygous and/or compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (Laboratory data) (BP2_Strong). 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/CA202190/MONDO:0016419/020

Frequency

Genomes: 𝑓 0.0072 ( 6 hom., cov: 33)

Exomes 𝑓: 0.011 ( 126 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:34O:1

Conservation

PhyloP100: 2.00

Publications

101 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):

ATM-related cancer predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
ataxia telangiectasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine
prostate cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
gastric carcinoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary nonpolyposis colon cancer
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 -12 ACMG points.

BP2

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATM	NM_000051.4	MANE Select	c.146C>G	p.Ser49Cys	missense	Exon 3 of 63	NP_000042.3
ATM	NM_001351834.2		c.146C>G	p.Ser49Cys	missense	Exon 4 of 64	NP_001338763.1	Q13315
ATM	NM_001351835.2		c.146C>G	p.Ser49Cys	missense	Exon 3 of 4	NP_001338764.1	Q6P7P1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATM	ENST00000675843.1	MANE Select	c.146C>G	p.Ser49Cys	missense	Exon 3 of 63	ENSP00000501606.1	Q13315
ATM	ENST00000452508.7	TSL:1	c.146C>G	p.Ser49Cys	missense	Exon 4 of 64	ENSP00000388058.2	Q13315
ATM	ENST00000531525.3	TSL:1	c.146C>G	p.Ser49Cys	missense	Exon 3 of 30	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes

AF:

0.00727

AC:

1105

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00180

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0131

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00712

AC:

1789

AN:

251092

AF XY:

0.00716

show subpopulations

Gnomad AFR exome

AF:

0.00210

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00259

Gnomad NFE exome

AF:

0.0126

Gnomad OTH exome

AF:

0.00686

GnomAD4 exome

AF:

0.0114

AC:

16678

AN:

1461052

Hom.:

126

Cov.:

AF XY:

0.0111

AC XY:

8053

AN XY:

726760

show subpopulations

African (AFR)

AF:

0.00194

AC:

AN:

33456

American (AMR)

AF:

0.00293

AC:

131

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000651

AC:

AN:

26118

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39594

South Asian (SAS)

AF:

0.00399

AC:

343

AN:

86040

European-Finnish (FIN)

AF:

0.00272

AC:

145

AN:

53398

Middle Eastern (MID)

AF:

0.00406

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.0138

AC:

15387

AN:

1111718

Other (OTH)

AF:

0.00938

AC:

566

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

786

1572

2359

3145

3931

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

614

1228

1842

2456

3070

<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:

0.00724

AC:

1102

AN:

152206

Hom.:

Cov.:

AF XY:

0.00640

AC XY:

476

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00270

AC:

112

AN:

41554

American (AMR)

AF:

0.00379

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00311

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00180

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0131

AC:

888

AN:

67986

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

112

168

224

280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00847

Hom.:

Bravo

AF:

0.00734

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00273

AC:

ESP6500EA

AF:

0.0136

AC:

117

ExAC

AF:

0.00736

AC:

894

Asia WGS

AF:

0.00115

AC:

AN:

3476

EpiCase

AF:

0.0109

EpiControl

AF:

0.0125

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

Hereditary cancer-predisposing syndrome (7)

Ataxia-telangiectasia syndrome (6)

not provided (6)

Familial cancer of breast (2)

ATM-related cancer predisposition (1)

Hereditary breast ovarian cancer syndrome (1)

Malignant tumor of breast (1)

Tip-toe gait (1)

Breast cancer, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.071

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.3

PhyloP100

2.0

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.060

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0060

Polyphen

0.98

Vest4

0.42

MVP

0.85

MPC

0.48

ClinPred

0.032

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.23

Mutation Taster

=94/6

polymorphism

(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