rs2227922

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000051.4(ATM):c.1810C>T(p.Pro604Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00224 in 1,608,310 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P604R) has been classified as Uncertain significance. The gene ATM is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0041 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 26 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:36O:2

Conservation

PhyloP100: 4.58

Publications

80 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0075432956).

BP6

Variant 11-108252824-C-T is Benign according to our data. Variant chr11-108252824-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127343.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00415 (631/152128) while in subpopulation AFR AF = 0.00701 (291/41520). AF 95% confidence interval is 0.00635. There are 2 homozygotes in GnomAd4. There are 300 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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.1810C>T	p.Pro604Ser	missense	Exon 12 of 63	NP_000042.3
	ATM	NM_001351834.2		c.1810C>T	p.Pro604Ser	missense	Exon 13 of 64	NP_001338763.1	Q13315

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATM	ENST00000675843.1	MANE Select	c.1810C>T	p.Pro604Ser	missense	Exon 12 of 63	ENSP00000501606.1	Q13315
ATM	ENST00000452508.7	TSL:1	c.1810C>T	p.Pro604Ser	missense	Exon 13 of 64	ENSP00000388058.2	Q13315
ATM	ENST00000531525.3	TSL:1	c.1810C>T	p.Pro604Ser	missense	Exon 12 of 30	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes

AF:

0.00415

AC:

631

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00701

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00420

Gnomad ASJ

AF:

0.0366

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00160

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.00319

AC:

799

AN:

250226

AF XY:

0.00306

show subpopulations

Gnomad AFR exome

AF:

0.00649

Gnomad AMR exome

AF:

0.00392

Gnomad ASJ exome

AF:

0.0314

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00159

Gnomad OTH exome

AF:

0.00722

GnomAD4 exome

AF:

0.00205

AC:

2978

AN:

1456182

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

1552

AN XY:

724746

show subpopulations

African (AFR)

AF:

0.00666

AC:

222

AN:

33320

American (AMR)

AF:

0.00428

AC:

191

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.0324

AC:

843

AN:

26042

East Asian (EAS)

AF:

0.00

AC:

AN:

39508

South Asian (SAS)

AF:

0.000663

AC:

AN:

85982

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.0112

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00114

AC:

1260

AN:

1107450

Other (OTH)

AF:

0.00552

AC:

332

AN:

60180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

136

271

407

542

678

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.00415

AC:

631

AN:

152128

Hom.:

Cov.:

AF XY:

0.00403

AC XY:

300

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00701

AC:

291

AN:

41520

American (AMR)

AF:

0.00419

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0366

AC:

127

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00160

AC:

109

AN:

67960

Other (OTH)

AF:

0.0142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

130

163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00367

Hom.:

Bravo

AF:

0.00484

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00614

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00286

AC:

347

Asia WGS

AF:

0.00203

AC:

AN:

3468

EpiCase

AF:

0.00278

EpiControl

AF:

0.00267

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

Ataxia-telangiectasia syndrome (8)

Hereditary cancer-predisposing syndrome (7)

not provided (8)

Familial cancer of breast (3)

Hereditary breast ovarian cancer syndrome (2)

ATM-related disorder (1)

Breast and/or ovarian cancer (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.092

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

M_CAP

Benign

0.081

MetaRNN

Benign

0.0075

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.4

PhyloP100

4.6

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.41

Sift

Benign

0.11

Sift4G

Benign

0.27

Polyphen

0.64

Vest4

0.68

MVP

0.88

MPC

0.33

ClinPred

0.023

GERP RS

5.5

Varity_R

0.40

gMVP

0.53

Mutation Taster

=95/5

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