rs2234997

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000051.4(ATM):c.378T>A(p.Asp126Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,612,140 control chromosomes in the GnomAD database, including 1,546 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.058 ( 813 hom., cov: 32)

Exomes 𝑓: 0.0066 ( 733 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24O:1

Conservation

PhyloP100: -0.695

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011576712).

BP6

Variant 11-108235716-T-A is Benign according to our data. Variant chr11-108235716-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 128455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108235716-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.378T>A	p.Asp126Glu	missense_variant	Exon 5 of 63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.378T>A	p.Asp126Glu	missense_variant	Exon 5 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0574

AC:

8734

AN:

152182

Hom.:

810

Cov.:

show subpopulations

Gnomad AFR

AF:

0.196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0255

Gnomad ASJ

AF:

0.0132

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00125

Gnomad OTH

AF:

0.0378

GnomAD3 exomes

AF:

0.0161

AC:

4046

AN:

251232

Hom.:

342

AF XY:

0.0116

AC XY:

1580

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.202

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0145

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00124

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00126

Gnomad OTH exome

AF:

0.00996

GnomAD4 exome

AF:

0.00660

AC:

9635

AN:

1459840

Hom.:

733

Cov.:

AF XY:

0.00570

AC XY:

4143

AN XY:

726396

show subpopulations

Gnomad4 AFR exome

AF:

0.202

Gnomad4 AMR exome

AF:

0.0135

Gnomad4 ASJ exome

AF:

0.0142

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00165

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000707

Gnomad4 OTH exome

AF:

0.0153

GnomAD4 genome

AF:

0.0575

AC:

8760

AN:

152300

Hom.:

813

Cov.:

AF XY:

0.0552

AC XY:

4114

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.196

Gnomad4 AMR

AF:

0.0255

Gnomad4 ASJ

AF:

0.0132

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000827

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00125

Gnomad4 OTH

AF:

0.0374

Alfa

AF:

0.0102

Hom.:

Bravo

AF:

0.0651

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.193

AC:

848

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.0190

AC:

2305

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:24Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8Other:1

Feb 16, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: 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

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:4

Sep 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18502988, 24728327, 27153395, 17333338, 17517479, 22529920, 12552566, 22071889) -

Jul 17, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

May 23, 2018

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Nov 12, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast

Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Breast and/or ovarian cancer

Benign:1

May 26, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Benign:1

Sep 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM p.Asp126Glu variant was identified in 15 of 1440 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer (Broeks 2008, Gonzalez-Hormazabal 2008, Mangone 2015, Petereit 2013, Thorstenson 2001) and was present in 1 of 200 control chromosomes (frequency: 0.005) from healthy individuals (Mangone 2015). The variant was also identified in dbSNP (ID: rs2234997) as With other allele, ClinVar (classified as benign by Ambry Genetics, Emory Genetics, Prevention Genetics, Invitae; classified as likely benign by Illumina, IBRMDL, GSLUC), Cosmic (classified as neutral), MutDB (classified as Polymorphism), ATM-LOVD, databases. The variant was not identified in LOVD 3.0, databases. The variant was identified in control databases in 5588 (478 homozygous) of 276988 chromosomes at a frequency of 0.02 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 4785 of 24012 chromosomes (freq: 0.199), Ashkenazi Jewish* in 143 of 10146 chromosomes (freq: 0.014), Latino in 396 of 34384 chromosomes (freq: 0.012), Other in 71 of 6456 chromosomes (freq: 0.011). The p.Asp126 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant is located with the Telomere-length maintenance and DNA damage repair functional domain increasing the likelihood that it may have clinical significance. ATM D126E genotypes, had a mild effect on survival, but the differences did not reach the level of statistical significance (Li 2006). In addition, the variant lead to decreased DDR response and efficiency, which is associated with increased risk of developing lung cancer in African American women (Wallace 2014). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary breast ovarian cancer syndrome

Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

4.4

DANN

Benign

0.96

DEOGEN2

Benign

0.035

.;T;.;T;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.56

T;T;T;.;T

MetaRNN

Benign

0.0012

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.58

.;N;.;N;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.17

N;N;.;N;.

REVEL

Benign

0.16

Sift

Benign

0.55

T;T;.;T;.

Sift4G

Benign

0.48

T;T;T;T;T

Polyphen

0.0010

.;B;.;B;.

Vest4

0.053, 0.012, 0.034

MutPred

0.087

Loss of ubiquitination at K129 (P = 0.0787);Loss of ubiquitination at K129 (P = 0.0787);Loss of ubiquitination at K129 (P = 0.0787);Loss of ubiquitination at K129 (P = 0.0787);Loss of ubiquitination at K129 (P = 0.0787);

MPC

0.12

ClinPred

0.0061

GERP RS

-2.6

Varity_R

0.049

gMVP

0.080

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over