11-108250683-CTTTTTTT-CTTTTTTTTT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PVS1_ModerateBP6_Very_Strong

The NM_000051.4(ATM):c.1236-4_1236-3dupTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0067 ( 0 hom. )

Consequence

ATM
NM_000051.4 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.510

Publications

10 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):

hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
ataxia telangiectasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
prostate cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
familial ovarian cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
gastric carcinoma
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: Likely_benign. The variant received -6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.040562645 fraction of the gene. Cryptic splice site detected, with MaxEntScore 12, offset of 0 (no position change), new splice context is: ctttttttttttttttttAGgct. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant 11-108250683-C-CTT is Benign according to our data. Variant chr11-108250683-C-CTT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1328273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.1236-4_1236-3dupTT		splice_acceptor_variant, intron_variant	Intron 9 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.1236-18_1236-17insTT		intron_variant	Intron 9 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes

AF:

0.000548

AC:

AN:

142248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000285

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000421

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000408

Gnomad SAS

AF:

0.000442

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000626

Gnomad OTH

AF:

0.000514

GnomAD2 exomes

AF:

0.0119

AC:

1939

AN:

163404

AF XY:

0.0122

show subpopulations

Gnomad AFR exome

AF:

0.00886

Gnomad AMR exome

AF:

0.0139

Gnomad ASJ exome

AF:

0.0103

Gnomad EAS exome

AF:

0.0101

Gnomad FIN exome

AF:

0.0118

Gnomad NFE exome

AF:

0.0121

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.00670

AC:

9083

AN:

1356150

Hom.:

Cov.:

AF XY:

0.00662

AC XY:

4477

AN XY:

675808

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00448

AC:

138

AN:

30780

American (AMR)

AF:

0.00956

AC:

371

AN:

38806

Ashkenazi Jewish (ASJ)

AF:

0.00670

AC:

163

AN:

24326

East Asian (EAS)

AF:

0.00390

AC:

149

AN:

38230

South Asian (SAS)

AF:

0.00827

AC:

650

AN:

78550

European-Finnish (FIN)

AF:

0.00439

AC:

169

AN:

38460

Middle Eastern (MID)

AF:

0.00777

AC:

AN:

4632

European-Non Finnish (NFE)

AF:

0.00676

AC:

7070

AN:

1045958

Other (OTH)

AF:

0.00597

AC:

337

AN:

56408

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.283

Heterozygous variant carriers

757

1514

2271

3028

3785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

306

612

918

1224

1530

<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:

0.000548

AC:

AN:

142266

Hom.:

Cov.:

AF XY:

0.000540

AC XY:

AN XY:

68566

show subpopulations

African (AFR)

AF:

0.000285

AC:

AN:

38612

American (AMR)

AF:

0.000420

AC:

AN:

14270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3394

East Asian (EAS)

AF:

0.000409

AC:

AN:

4890

South Asian (SAS)

AF:

0.000444

AC:

AN:

4508

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

7974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.000626

AC:

AN:

65502

Other (OTH)

AF:

0.000512

AC:

AN:

1952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

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:

0.00836

Hom.:

575

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Aug 26, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1236-3_1236-2insTT variant in ATM is classified as benign because it has not been reported in individuals with disease, is located in the 3' splice region but computational tools do not predict a splicing impact and affects a multiallelic stretch of Ts. ACMG/AMP criteria applied: BA1 -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

ATM-related cancer predisposition

Benign:1

Sep 17, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.51

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over