rs1800059

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000051.4(ATM):c.5071A>C(p.Ser1691Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 1,614,054 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1691T) has been classified as Uncertain significance. The gene ATM is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 5 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:31O:1

Conservation

PhyloP100: 1.22

Publications

46 publications found

Variant links:

COSMIC-nc: COSV53724445

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=0.008389473).

BP6

Variant 11-108299779-A-C is Benign according to our data. Variant chr11-108299779-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127399.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0016 (244/152324) while in subpopulation NFE AF = 0.00238 (162/68032). AF 95% confidence interval is 0.00208. There are 1 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 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.5071A>C	p.Ser1691Arg	missense	Exon 34 of 63	NP_000042.3
	ATM	NM_001351834.2		c.5071A>C	p.Ser1691Arg	missense	Exon 35 of 64	NP_001338763.1	Q13315

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATM	ENST00000675843.1	MANE Select	c.5071A>C	p.Ser1691Arg	missense	Exon 34 of 63	ENSP00000501606.1	Q13315
ATM	ENST00000452508.7	TSL:1	c.5071A>C	p.Ser1691Arg	missense	Exon 35 of 64	ENSP00000388058.2	Q13315
ATM	ENST00000527805.6	TSL:1	n.*135A>C		non_coding_transcript_exon	Exon 32 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

244

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00238

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00176

AC:

442

AN:

251232

AF XY:

0.00163

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00296

Gnomad NFE exome

AF:

0.00292

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00205

AC:

2996

AN:

1461730

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

1407

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33474

American (AMR)

AF:

0.000671

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00275

AC:

147

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00244

AC:

2716

AN:

1111912

Other (OTH)

AF:

0.00152

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

164

327

491

654

818

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.00160

AC:

244

AN:

152324

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

109

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000577

AC:

AN:

41578

American (AMR)

AF:

0.00157

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00273

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00238

AC:

162

AN:

68032

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00241

Hom.:

Bravo

AF:

0.00156

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00202

AC:

245

EpiCase

AF:

0.00218

EpiControl

AF:

0.00184

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ataxia-telangiectasia syndrome (10)

not provided (8)

not specified (7)

Hereditary cancer-predisposing syndrome (5)

Breast and/or ovarian cancer (1)

Familial cancer of breast (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.081

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.66

M_CAP

Benign

0.015

MetaRNN

Benign

0.0084

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

1.2

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.69

REVEL

Uncertain

0.34

Sift

Benign

0.50

Sift4G

Benign

0.45

Polyphen

0.0010

Vest4

0.23

MutPred

0.72

Gain of helix (P = 0.0425)

MVP

0.75

MPC

0.14

ClinPred

0.0040

GERP RS

2.6

Varity_R

0.13

gMVP

0.14

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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