rs1800056

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000051.4(ATM):c.2572T>C(p.Phe858Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,614,054 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F858S) has been classified as Likely benign. The gene ATM is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0084 ( 7 hom., cov: 32)

Exomes 𝑓: 0.012 ( 126 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:32O:1

Conservation

PhyloP100: 2.94

Publications

135 publications found

Variant links:

COSMIC-nc: COSV53728338

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0052860677).

BP6

Variant 11-108267276-T-C is Benign according to our data. Variant chr11-108267276-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 132736.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 = 0.00836 (1273/152228) while in subpopulation NFE AF = 0.0141 (962/68002). AF 95% confidence interval is 0.0134. There are 7 homozygotes in GnomAd4. There are 560 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 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.2572T>C	p.Phe858Leu	missense	Exon 17 of 63	NP_000042.3
	ATM	NM_001351834.2		c.2572T>C	p.Phe858Leu	missense	Exon 18 of 64	NP_001338763.1	Q13315

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATM	ENST00000675843.1	MANE Select	c.2572T>C	p.Phe858Leu	missense	Exon 17 of 63	ENSP00000501606.1	Q13315
ATM	ENST00000452508.7	TSL:1	c.2572T>C	p.Phe858Leu	missense	Exon 18 of 64	ENSP00000388058.2	Q13315
ATM	ENST00000531525.3	TSL:1	c.2572T>C	p.Phe858Leu	missense	Exon 17 of 30	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes

AF:

0.00838

AC:

1274

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00720

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00377

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0141

Gnomad OTH

AF:

0.00907

GnomAD2 exomes

AF:

0.00865

AC:

2175

AN:

251440

AF XY:

0.00878

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.00454

Gnomad ASJ exome

AF:

0.0129

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00462

Gnomad NFE exome

AF:

0.0145

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0115

AC:

16837

AN:

1461826

Hom.:

126

Cov.:

AF XY:

0.0113

AC XY:

8222

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00194

AC:

AN:

33480

American (AMR)

AF:

0.00512

AC:

229

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0125

AC:

326

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000777

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00457

AC:

244

AN:

53416

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0137

AC:

15235

AN:

1111958

Other (OTH)

AF:

0.00950

AC:

574

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

863

1726

2588

3451

4314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

548

1096

1644

2192

2740

<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:

0.00836

AC:

1273

AN:

152228

Hom.:

Cov.:

AF XY:

0.00752

AC XY:

560

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00217

AC:

AN:

41542

American (AMR)

AF:

0.00719

AC:

110

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000830

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00377

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0141

AC:

962

AN:

68002

Other (OTH)

AF:

0.00898

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

138

206

275

344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.0125

Hom.:

Bravo

AF:

0.00832

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0182

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0120

AC:

103

ExAC

AF:

0.00914

AC:

1110

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0126

EpiControl

AF:

0.0128

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (12)

Ataxia-telangiectasia syndrome (7)

Hereditary cancer-predisposing syndrome (5)

not provided (4)

Breast and/or ovarian cancer (1)

Carcinoma of colon (1)

Familial cancer of breast (1)

Hereditary breast ovarian cancer syndrome (1)

Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0053

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.3

PhyloP100

2.9

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.12

Sift

Benign

0.035

Sift4G

Uncertain

0.032

Polyphen

0.73

Vest4

0.24

MutPred

0.083

Loss of stability (P = 0.0937)

MVP

0.98

MPC

0.15

ClinPred

0.042

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.33

Mutation Taster

=98/2

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