11-108365359-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 3 ACMG points: 3P and 0B. PM3PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.9022C>T variant in ATM is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 3008 (p.Arg3008Cys). This variant has been detected in at least 5 individuals with Ataxia-Telangiectasia (PMID:12552566, 18573109, 25122203, 26896183, 30549301). Additionally, experimental studies showed that this variant impacts ATM kinase activity and radiosensitivity compared to wild type (PMID:19431188). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PM3_Very Strong, PS3_Supporting) LINK:https://erepo.genome.network/evrepo/ui/classification/CA294307/MONDO:0700270/020

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:19

Conservation

PhyloP100: 5.75

Publications

75 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 links:

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

C11orf65 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 3 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.9022C>T	p.Arg3008Cys	missense_variant	Exon 63 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.9022C>T	p.Arg3008Cys	missense_variant	Exon 63 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251428

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727228

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111986

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000224691), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.365

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

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:

0.0000109

Hom.:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:19

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:7

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3008 of the ATM protein (p.Arg3008Cys). This variant is present in population databases (rs587782292, gnomAD 0.007%). This missense change has been observed in individual(s) with ataxia-telangiectasia (A-T) and/or breast cancer (PMID: 9872980, 10817650, 12552566, 30549301). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 142187). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATM protein function. Experimental studies have shown that this missense change affects ATM function (PMID: 12552566, 15101044, 18573109). For these reasons, this variant has been classified as Pathogenic. -

Sep 01, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12552566 , 15101044 , 18573109). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.52; 3Cnet: 0.86). It has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 12552566 , 30549301 , 9872980). Different missense changes at the same codon (p.Arg3008His, p.Arg3008Leu, p.Arg3008Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000141634 , VCV000806734 , VCV000822905). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jul 02, 2018

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 31, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (MIM#208900). (I) 0106 - This gene is associated with autosomal recessive disease. Carriers of ATM pathogenic variants are at increased risk of developing cancer (mainly breast cancer) (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 4 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple homozygotes and compound heterozygotes individuals with ataxia-telangiectasia as well as cancer (ClinVar, PMIDs: 30549301, 9334731, 22649200; 32918381). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Western blot in patients' blood did not detect residual activity (PMID: 22649200). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Aug 06, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 13, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:4

Sep 20, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect showing loss of ATM kinase activity (Angele et al., 2003; Austen et al., 2008; Barone et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in the heterozygous state in individuals with breast or prostate cancer in published literature (Aloraifi et al., 2015; Matejcic et al., 2020; Darst et al., 2021); This variant is associated with the following publications: (PMID: 26354930, 29117359, 28580595, 29038235, 29625052, 19431188, 21792198, 21933854, 15101044, 22529920, 16014569, 23585524, 18573109, 16189143, 10817650, 22649200, 27479817, 27542854, 21459046, 25480502, 9872980, 26681312, 29482223, 28767289, 30549301, 32866655, 23532176, 34687117, 32980694, 32853339, 32832836, 26094658, 26896183, 29922827, 12552566) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 04, 2020

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant abolishes the protein's kinase activity (PMID: 19431188, 18573109). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure. -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ATM p.Arg3008Cys variant was identified in 3 of 1508 proband chromosomes (frequency: 0.002) from individuals or families with AtaxiaTelangiectasia and CLL (Navrkalova 2013, Reiman 2011, Skowronska 2012). The variant was also identified in ClinVar (classified as pathogenic by Ambry genetics, GeneDx, Invitae; classified as likely pathogenic by Counsyl), Cosmic (classified as pathogenic), MutDB, and ATM-LOVD databases. The variant was not identified in Genesight-COGR, and LOVD 3.0 databases. The variant was identified in control databases in 4 of 246188 chromosomes at a frequency of 0.000016 in the following populations: African in 1 of 15304 chromosomes (freq. 0.00006), East Asian in 1 of 17244 chromosomes (freq. 0.00006), European (Non-Finnish) in 2 of 111646 chromosomes (freq. 0.00002), but not seen in Ashkenazi Jewish, European (Finnish), Latino, South Asian or other populations increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017)". The p.Arg3008 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Phosphatidylinositol 3-/4-kinase, catalytic functional domain increasing the likelihood that it may have clinical significance. In addition, several studies reported the expressed R3008C mutant ATM protein showed absence of ATM kinase activity, and strongly suggest that the 9022C>T (R3008C) missense mutation is the disease causing mutation (Angele 2003, Austen 2008,). The Taylor (2005) identified this variant in homozygous state with total absence of ATM kinase activity, although the amount of ATM protein expressed was about half that of normal cells. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Nov 19, 2020

Sema4, Sema4

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Apr 11, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R3008C pathogenic mutation (also known as c.9022C>T) is located in coding exon 62 of the ATM gene. This alteration results from a C to T substitution at nucleotide position 9022. The arginine at codon 3008 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported both in trans with pathogenic splice site mutations and also homozygous in a patient with classic ataxia-telangiectasia (Hacia J et al. Genome Res. 1998 Dec; 8(12):1245-58; Li A and Swift M. Am J Hum Genet. 2000 May 29; 92(3):170-7; Angele S et al. Hum Mutat. 2003 Feb; 21(2):169-70). A study of 104 Irish cases of hereditary breast cancer identified this alteration in one case (Aloraifi F et al., FEBS J. 2015 Sep; 282(17):3424-37). This alteration was also identified in one individual diagnosed with breast cancer in a study of 10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 Aug;18:823-32). This alteration impacts a highly-conserved residue in the ATM kinase domain and functional studies of this alteration have demonstrated complete loss of kinase activity both in vitro and in vivo (Angele S et al. Hum Mutat. 2003 Feb; 21(2):169-70). In addition, p.R3008C has been associated with reduced ATM protein levels, radiosensitivity levels similar to truncating mutations, and interference with endogenous ATM protein (Gutierrez-Enriquez S et al. Genes Chromosomes Cancer. 2004 Jun; 40(2):109-19; Barone G et al. Hum Mutat. 2009 Aug; 30(8):1222-30). Another missense alteration at this codon (p.R3008H) has been described as a likely deleterious allele detected in 1/122 familial breast cancer cases, 0/186 healthy control samples (Paglia L et al. Breast Cancer Res Treat. 2010 Jan; 119(2):443-52). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Feb 12, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with cysteine at codon 3008 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have reported the variant protein to be defective in ATM kinase activity and cellular response to ionizing radiation exposure (PMID: 12552566, 18573109, 19431188). This variant has been observed in homozygous and compound heterozygous state in multiple individuals affected with ataxia-telangiectasia (PMID: 9872980, 10817650, 12552566, 18573109, 21459046, 21792198). This variant also has been observed in three individuals affected with breast cancer (PMID: 26681312, 30128536) and another individual at high-risk for breast and ovarian cancer (PMID: 26094658). This variant has been identified in 4/251428 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Familial cancer of breast

Pathogenic:2

Oct 28, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 06, 2024

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 12552566, 18573109, 23585524]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9872980, 12552566, 22649200]. -

ATM-related cancer predisposition

Pathogenic:1

Nov 26, 2024

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.9022C>T variant in ATM is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 3008 (p.Arg3008Cys). This variant has been detected in at least 5 individuals with Ataxia-Telangiectasia (PMID: 12552566, 18573109, 25122203, 26896183, 30549301). Additionally, experimental studies showed that this variant impacts ATM kinase activity and radiosensitivity compared to wild type (PMID: 19431188). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PM3_Very Strong, PS3_Supporting) -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:1

Jan 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Gastric cancer

Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;D

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;.

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.4

M;M

PhyloP100

5.7

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.3

D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.75

MutPred

0.84

Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);

MVP

0.97

MPC

0.67

ClinPred

0.99

GERP RS

5.2

Varity_R

0.45

gMVP

0.84

Mutation Taster

=11/89

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over