NM_000051.4:c.68G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1BP4

The NM_000051.4(ATM):​c.68G>A​(p.Arg23Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R23P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

6
9
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 8.67

Publications

19 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 37 uncertain in NM_000051.4
BP4
Computational evidence support a benign effect (MetaRNN=0.4027972).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATMNM_000051.4 linkc.68G>A p.Arg23Gln missense_variant Exon 2 of 63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.68G>A p.Arg23Gln missense_variant Exon 2 of 63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000890
AC:
13
AN:
1461418
Hom.:
0
Cov.:
30
AF XY:
0.0000138
AC XY:
10
AN XY:
727032
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33460
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26118
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39598
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86238
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53412
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.0000108
AC:
12
AN:
1111740
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60368
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3
May 30, 2021
Sema4, Sema4
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:curation

- -

May 31, 2023
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces arginine with glutamine at codon 23 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been reported together with another ATM missense variant (p.Gly2020Asp) in an individual affected with atypical ataxia telangiectasia (PMID: 31050087). Cells derived from this individual had normal ATM protein levels and CHK2 phosphorylation and decreased KAP1 phosphorylation (PMID: 31050087). This variant has also been reported in individuals affected with breast cancer (PMID: 25186627, 30303537, 33471991) and in a healthy control (PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

May 01, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.R23Q variant (also known as c.68G>A), located in coding exon 1 of the ATM gene, results from a G to A substitution at nucleotide position 68. This alteration was detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration was also identified in 1/1207 cases of French women diagnosed with breast cancer who had a sister with breast cancer and were BRCA1 and BRCA2 negative and 0/1199 general population controls (Girard E et al. Int J Cancer, 2019 04;144:1962-1974). This alteration has also been reported in a patient with atypical features of ataxia-telangiectasia, in conjunction with another missense alteration; both ATM variants were classified as uncertain significance by study authors (Fi&eacute;vet A et al. Hum Mutat, 2019 10;40:1713-1730). The arginine at codon 23 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified Uncertain:2
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 04, 2022
Mendelics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:2
Aug 09, 2024
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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; Identified with another ATM variant in a patient with atypical ataxia-telangiectasia (PMID: 31050087); Observed in individuals with breast or gastric cancer (PMID: 25186627, 30303537, 33525650); This variant is associated with the following publications: (PMID: 30303537, 17344846, 28873162, 25186627, 31050087, 33525650) -

Jun 25, 2021
Mayo Clinic Laboratories, Mayo Clinic
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Familial cancer of breast Uncertain:2
Sep 21, 2022
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 11, 2023
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Ataxia-telangiectasia syndrome Uncertain:1
Nov 05, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 23 of the ATM protein (p.Arg23Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia, gastric cancer, and/or personal/family history of breast/ovarian cancer (PMID: 30303537, 31050087, 32068069, 33525650). ClinVar contains an entry for this variant (Variation ID: 127429). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Breast and/or ovarian cancer Uncertain:1
Mar 01, 2021
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

ATM-related disorder Uncertain:1
Jun 12, 2024
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

The ATM c.68G>A variant is predicted to result in the amino acid substitution p.Arg23Gln. This variant has been reported in an individual with colorectal adenocarcinoma (Table S2 in Greenman et al. 2007. PubMed ID: 17344846), in five individuals with breast cancer and in one case control (Table s1 in Breast Cancer Association Consortium et al 2021. PubMed ID: 33471991; Table S1 in Kwong et al 2020. PubMed ID: 32068069; Table S3 in Girard et al. 2019. PubMed ID: 30303537; Table S1 in Tung et al 2014. PubMed ID: 25186627), in an individual with gastric cancer (Table S1 in Herrera-Pariente et al. 2021. PubMed ID: 33525650), and in an individual with ataxia-telangiectasia who also harbored a second variant in ATM (Figure 2b in Fiévet et al. 2019. PubMed ID: 31050087). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/127429/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.75
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.18
.;T;T;T;.;T;T;T;T;T;T
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;.;.;.;.;.;D
M_CAP
Pathogenic
0.33
D
MetaRNN
Benign
0.40
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.25
D
MutationAssessor
Uncertain
2.6
.;M;.;.;.;M;.;.;.;.;.
PhyloP100
8.7
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-2.8
D;N;D;D;.;N;.;.;.;.;.
REVEL
Uncertain
0.57
Sift
Pathogenic
0.0
D;D;D;D;.;D;.;.;.;.;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;.;.;.;D;D
Polyphen
1.0, 0.45
.;D;.;.;.;D;B;B;B;B;.
Vest4
0.87, 0.85, 0.58, 0.89
MutPred
0.24
Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);
MVP
0.90
MPC
0.60
ClinPred
1.0
D
GERP RS
4.4
Varity_R
0.39
gMVP
0.74
Mutation Taster
=69/31
polymorphism

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

Other links and lift over

dbSNP: rs587779858; hg19: chr11-108098419; COSMIC: COSV53740048; COSMIC: COSV53740048; API