chr11-108345818-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3PM3_StrongPS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.8494C>T variant in ATM is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 2832 (p.Arg2832Cys). This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID:26896183, 22017321, 26846839). The highest minor allele frequency in gnomAD v2.1.1 of 0.01% (2/16244 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor, Revel (Score: 0.83), predicts a damaging effect on ATM function. Additionally, experimental studies showed that this variant has impact on ATM kinase activity and protein levels but radiosensitivity was found to be intermediate compared to wild type (PMID:18634022). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3_Strong, PP3, PS3_supporting) LINK:https://erepo.genome.network/evrepo/ui/classification/CA287019/MONDO:0016419/020

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:27O:1

Conservation

PhyloP100: 5.00

Publications

57 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 6 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.

PP3

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

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATM	NM_000051.4	MANE Select	c.8494C>T	p.Arg2832Cys	missense	Exon 58 of 63	NP_000042.3
ATM	NM_001351834.2		c.8494C>T	p.Arg2832Cys	missense	Exon 59 of 64	NP_001338763.1
C11orf65	NM_001330368.2		c.641-36747G>A		intron	N/A	NP_001317297.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATM	ENST00000675843.1	MANE Select	c.8494C>T	p.Arg2832Cys	missense	Exon 58 of 63	ENSP00000501606.1
ATM	ENST00000452508.7	TSL:1	c.8494C>T	p.Arg2832Cys	missense	Exon 59 of 64	ENSP00000388058.2
ATM	ENST00000527805.6	TSL:1	n.*3558C>T		non_coding_transcript_exon	Exon 56 of 61	ENSP00000435747.2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251268

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461578

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1111834

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.0000132

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000653

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:27Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:8Other:1

Sep 23, 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.

Jan 06, 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 2832 of the ATM protein (p.Arg2832Cys). This variant is present in population databases (rs587779872, gnomAD 0.01%). This missense change has been observed in individuals with ataxia-telangiectasia and/or breast cancer (PMID: 9443866, 10817650, 10873394, 12552559, 18634022, 26681312). ClinVar contains an entry for this variant (Variation ID: 127459). 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) indicates that this missense variant is expected to disrupt ATM protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ATM function (PMID: 10873394, 19431188). For these reasons, this variant has been classified as Pathogenic.

Jul 10, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 02, 2018

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lifecell International Pvt. Ltd

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A Homozygote Missense variant c.8494C>T in Exon 58 of the ATM gene that results in the amino acid substitution p.Arg2832Cys was identified. The observed variant has a minor allele frequency of 0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic. (Variation ID: 127459). The variant has been previously reported for Ataxia-Telangiectasia by Telatar M, et al., 1988. Experimental study revealed the missense variant affects the protein function (Mitui M, et al., 2009). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

Jan 05, 2018

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jun 07, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

not provided

Pathogenic:7

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 24, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: reduced ATM protein levels and reduced or absent ATM kinase activity (Becker-Catania et al., 2000; Sun et al., 2002; Butch et al., 2004; Chun and Gatti, 2004; Barone et al., 2009; Mitui et al., 2009; Reiman et al., 2011; Fievet et al., 2019; Schon et al., 2019); Observed in the heterozygous state in individuals with ATM-related cancers (Schroeder et al., 2015; Hansen et al., 2017; Renault et al., 2018; Girard et al., 2019); 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; This variant is associated with the following publications: (PMID: 15503472, 25793145, 9443866, 16448697, 29665859, 32980694, 29922827, 28888541, 12673797, 12072877, 20301790, 23091097, 15486025, 19431188, 10817650, 25040471, 12497634, 18634022, 15279807, 27135926, 26681312, 26312527, 26022348, 28008555, 28195393, 12552559, 22529920, 25827173, 30093976, 30549301, 31050087, 21792198, 22017321, 23532176, 29625052, 30875412, 35264596, 34926252, 35737913, 33328602, 35486574, 33471991, 32155193, 36988593, 35454905, 35365198, 36521553, 26896183, 26846839, 21665257, 10873394, 30303537)

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATM: PM1, PM2, PM5, PS3:Moderate, BP1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 28, 2024

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the ATM gene demonstrated a sequence change, c.8494C>T, in exon 58 that results in an amino acid change, p.Arg2832Cys. The p.Arg2832Cys change affects a highly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Arg2832Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). This sequence change has previously been described in several individuals with ataxia-telangiectasia (A-T) and other cancers including breast and colorectal cancer (PMID: 9443866, 10817650, 10873394, 12552559, 18634022, 22017321, 26681312, 28195393). Published functional studies suggested deleterious impact on ATM function including reduced ATM protein expression levels, reduced ATM kinase activity and intermediate radio sensitivity compared to wild type ATM (PMID: 10873394, 18634022, 19431188, 22017321). This sequence change has been described in the gnomAD database with an overall frequency of 0.0032% (dbSNP rs587779872). These collective evidences indicate that this sequence change is pathogenic.

Familial cancer of breast

Pathogenic:4

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PP4,PP3.

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 02, 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: 18634022, 21792198]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10873394, 21665257].

Mar 27, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Pathogenic:4

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 2832 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant results in significantly reduced ATM protein expression and kinase activity, and intermediate radiosensitivity (PMID: 10873394, 18634022, 19431188, 22017321). This variant has also been observed homozygous or in compound heterozygous state with another pathogenic variant in individuals affected with ataxia-telangiectasia (PMID: 9443866, 10817650, 10873394, 12552559, 12673797, 18634022, 19147735, 19431188, 21792198, 22017321). This variant has also been reported in individuals affected with breast cancer (PMID: 18634022, 26022348, 26681312, 28008555, 29665859, 30093976). This variant has been identified in 8/251268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Jul 23, 2021

Sema4, Sema4

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

Dec 20, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R2832C pathogenic mutation (also known as c.8494C>T), located in coding exon 57 of the ATM gene, results from a C to T substitution at nucleotide position 8494. The arginine at codon 2832 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected both as the only mutation and in conjunction with a second mutation in many ataxia-telangiectasia (A-T) patients (Telatar M et al. Am. J. Hum. Genet. 1998 Jan;62:86-97; Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Mitui M et al. Hum. Mutat. 2009 Jan;30:12-21). Functional analyses of p.R2832C have shown abolished kinase activity, reduced protein levels, and increased radiosensitivity compared to wild type ATM. In addition, four of five mild A-T patients carrying this alteration developed cancer, including breast cancers, melanoma, and hematologic malignancies. Three of four p.R2832C carrier mothers from these families developed breast cancer (Mitui M et al. Hum. Mutat. 2009 Jan;30:12-21). It was also seen in a patient with a personal and family history of colorectal cancer (Hansen MF et al. Clin. Genet. 2017 Oct;92:405-414). Of note, this alteration is also designated as R2831C in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Mar 26, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Abnormal central motor function

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATM-related cancer predisposition

Pathogenic:1

Jan 25, 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.8494C>T variant in ATM is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 2832 (p.Arg2832Cys). This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID: 26896183, 22017321, 26846839). The highest minor allele frequency in gnomAD v2.1.1 of 0.01% (2/16244 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor, Revel (Score: 0.83), predicts a damaging effect on ATM function. Additionally, experimental studies showed that this variant has impact on ATM kinase activity and protein levels but radiosensitivity was found to be intermediate compared to wild type (PMID: 18634022). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3_Strong, PP3, PS3_supporting)

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:1

Jun 12, 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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.62

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

3.6

PhyloP100

5.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.93

MutPred

0.90

Loss of helix (P = 0.1706)

MVP

0.97

MPC

0.67

ClinPred

1.0

GERP RS

5.5

Varity_R

0.84

gMVP

0.77

Mutation Taster

=6/94

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over