Genetic Variant ATM:p.Pro1054Arg (chr11-108272729-C-G) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000051.4(ATM):c.3161C>G(p.Pro1054Arg) variant causes a missense change. The variant allele was found at a frequency of 0.022 in 1,613,692 control chromosomes in the GnomAD database, including 492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1054T) has been classified as Likely benign. The gene ATM is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.017 ( 30 hom., cov: 32)

Exomes 𝑓: 0.023 ( 462 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21O:1

Conservation

PhyloP100: 6.36

Publications

147 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

Specifications for ATM are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 42 uncertain in NM_000051.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0074827075).

BP6

Variant 11-108272729-C-G is Benign according to our data. Variant chr11-108272729-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 132695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0165 (2517/152258) while in subpopulation NFE AF = 0.0269 (1829/68022). AF 95% confidence interval is 0.0259. There are 30 homozygotes in GnomAd4. There are 1134 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 30 AR,AD gene

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.3161C>G	p.Pro1054Arg	missense	Exon 22 of 63	NP_000042.3
	ATM	NM_001351834.2		c.3161C>G	p.Pro1054Arg	missense	Exon 23 of 64	NP_001338763.1	Q13315

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATM	ENST00000675843.1	MANE Select	c.3161C>G	p.Pro1054Arg	missense	Exon 22 of 63	ENSP00000501606.1	Q13315
ATM	ENST00000452508.7	TSL:1	c.3161C>G	p.Pro1054Arg	missense	Exon 23 of 64	ENSP00000388058.2	Q13315
ATM	ENST00000531525.3	TSL:1	c.3161C>G	p.Pro1054Arg	missense	Exon 22 of 30	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes

AF:

0.0166

AC:

2521

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0189

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.00782

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0269

Gnomad OTH

AF:

0.0230

GnomAD2 exomes

AF:

0.0166

AC:

4160

AN:

251228

AF XY:

0.0169

show subpopulations

Gnomad AFR exome

AF:

0.00425

Gnomad AMR exome

AF:

0.0108

Gnomad ASJ exome

AF:

0.0215

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00801

Gnomad NFE exome

AF:

0.0267

Gnomad OTH exome

AF:

0.0232

GnomAD4 exome

AF:

0.0226

AC:

33044

AN:

1461434

Hom.:

462

Cov.:

AF XY:

0.0224

AC XY:

16284

AN XY:

727028

show subpopulations

African (AFR)

AF:

0.00370

AC:

124

AN:

33480

American (AMR)

AF:

0.0115

AC:

516

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0198

AC:

517

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39668

South Asian (SAS)

AF:

0.00550

AC:

474

AN:

86254

European-Finnish (FIN)

AF:

0.00787

AC:

420

AN:

53354

Middle Eastern (MID)

AF:

0.0323

AC:

186

AN:

5766

European-Non Finnish (NFE)

AF:

0.0266

AC:

29607

AN:

1111676

Other (OTH)

AF:

0.0199

AC:

1199

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

1726

3452

5179

6905

8631

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1070

2140

3210

4280

5350

<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:

0.0165

AC:

2517

AN:

152258

Hom.:

Cov.:

AF XY:

0.0152

AC XY:

1134

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00409

AC:

170

AN:

41550

American (AMR)

AF:

0.0188

AC:

288

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00782

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0269

AC:

1829

AN:

68022

Other (OTH)

AF:

0.0223

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

129

258

386

515

644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0218

Hom.:

Bravo

AF:

0.0171

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0330

AC:

127

ESP6500AA

AF:

0.00591

AC:

ESP6500EA

AF:

0.0228

AC:

196

ExAC

AF:

0.0169

AC:

2046

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0267

EpiControl

AF:

0.0280

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ataxia-telangiectasia syndrome (5)

not specified (6)

Hereditary cancer-predisposing syndrome (4)

not provided (3)

Familial cancer of breast (2)

Carcinoma of colon (1)

Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.86

MetaRNN

Benign

0.0075

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.9

PhyloP100

6.4

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-5.5

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MPC

0.59

ClinPred

0.022

GERP RS

5.6

Varity_R

0.47

gMVP

0.66

Mutation Taster

=77/23

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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