chr11-108315883-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_000051.4(ATM):​c.6067G>A​(p.Gly2023Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,612,772 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0016 ( 4 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

4
10
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7B:22O:3

Conservation

PhyloP100: 9.47
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.15664351).
BP6
Variant 11-108315883-G-A is Benign according to our data. Variant chr11-108315883-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127416.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Benign=5, Likely_benign=14, not_provided=3}. Variant chr11-108315883-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00125 (190/152254) while in subpopulation NFE AF= 0.00226 (154/68028). AF 95% confidence interval is 0.00197. There are 0 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATMNM_000051.4 linkc.6067G>A p.Gly2023Arg missense_variant Exon 41 of 63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.6067G>A p.Gly2023Arg missense_variant Exon 41 of 63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
AF:
0.00125
AC:
190
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000314
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000786
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.000755
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00226
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00143
AC:
360
AN:
251402
Hom.:
1
AF XY:
0.00150
AC XY:
204
AN XY:
135870
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.00104
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000653
Gnomad FIN exome
AF:
0.000832
Gnomad NFE exome
AF:
0.00238
Gnomad OTH exome
AF:
0.00131
GnomAD4 exome
AF:
0.00158
AC:
2306
AN:
1460518
Hom.:
4
Cov.:
32
AF XY:
0.00159
AC XY:
1152
AN XY:
726704
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
Gnomad4 AMR exome
AF:
0.000962
Gnomad4 ASJ exome
AF:
0.000153
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000626
Gnomad4 FIN exome
AF:
0.000899
Gnomad4 NFE exome
AF:
0.00183
Gnomad4 OTH exome
AF:
0.00179
GnomAD4 genome
AF:
0.00125
AC:
190
AN:
152254
Hom.:
0
Cov.:
32
AF XY:
0.00110
AC XY:
82
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.000313
Gnomad4 AMR
AF:
0.000785
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.000755
Gnomad4 NFE
AF:
0.00226
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00210
Hom.:
2
Bravo
AF:
0.00132
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.00285
AC:
11
ESP6500AA
AF:
0.000682
AC:
3
ESP6500EA
AF:
0.00314
AC:
27
ExAC
AF:
0.00157
AC:
191
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00273
EpiControl
AF:
0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:7Benign:22Other:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:9Other:1
Jun 17, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26976419, 26787654, 26094658, 27153395, 21933854, 29445900, 26053404, 19404735, 11505391, 17393301, 12810666, 22529920, 23091097, 17968022, 12149228, 16461462, 21787400, 19781682, 24728327, 25624042, 26898890, 27664052, 25980754, 24584352, 27150160, 26483394, 26822149, 27882345, 25625042, 27498913, 28608266, 29678143, 23555315, 26822949, 27621404, 28779002, 30197789, 31108397, 30309722, 31159747, 30303537, 32854451) -

Dec 19, 2019
Athena Diagnostics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 21, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The ATM c.6067G>A (p.Gly2023Arg) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 397/277154 (1 homozygote) control chromosomes (gnomAD), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.002368 (300/126680). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. Multiple publications have cited the variant in affected BrC pts, along with multiple somatic occurrences in MCL and CLL pts. Skowronska_2012 suggestions, biallelic ATM inactivation in CLL patients was associated with disease progression and reduced survival. However, the variant has been reported to co-occur with a BRCA1 variant, although the exact variant was not indicated (Thorstenson_2003). In addition, two internal LCA samples report the variant to co-occur with a pathogenic ATM variant, c.6095G>A (p.Arg20232Lys) and BRCA1 variant, c.1326T>A (p.Cys442X). In addition, multiple clinical diagnostic laboratories cite the variant as "likely benign/benign." Taken together, this variant is classified as benign. -

Feb 17, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BS1 -

Oct 20, 2022
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 18, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ATM: BS1:Supporting -

-
GenomeConnect - Invitae Patient Insights Network
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 02-18-2016 by Lab GenPath. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Jun 10, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:3Benign:3
Aug 01, 2018
GeneKor MSA
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 08, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Jul 27, 2018
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely 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. -

Mar 16, 2018
True Health Diagnostics
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 17, 2020
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.6067G>A (p.Gly2023Arg) variant has an allele frequency of 0.0014 (0.14%, 374/268,256 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0023 (0.232%, 274/118,126 alleles) in the European (non-Finnish) subpopulation (BS1; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + PP3 (PMID: 33280026). -

Feb 11, 2015
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Uncertain:1Benign:4Other:1
Jul 14, 2021
Genome-Nilou Lab
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 22, 2023
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 18, 2020
Natera, Inc.
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

-
GenomeConnect - Brain Gene Registry
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

Variant classified as Uncertain significance and reported on 02-03-2017 by Baylor Medical Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

not specified Benign:3Other:1
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 30, 2021
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:1Benign:1
May 30, 2024
Myriad Genetics, Inc.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign. 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]. -

Dec 05, 2018
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Tip-toe gait Pathogenic:1
-
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

Gait disorder -

Hereditary breast ovarian cancer syndrome Uncertain:1
Apr 19, 2022
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1
Mar 30, 2023
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely 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.Gly2023Arg variant was identified in 15 of 8674 proband chromosomes (frequency: 0.002) from individuals or families with CLL, lymphoid neoplasms, colorectal or breast cancer and was identified in 2 of 1602 chromosomes (frequency: 0.001) from healthy individuals (Broeks 2008, Gronbaek 2002, Mangone 2015, Paglia 2010, Podralska 2018, Skowronska 2012, Thorstenson 2003, Yurgelun 2015, Balmana 2016, Tung 2016). The variant was also identified in dbSNP (ID: rs11212587) as "With other allele", ClinVar (classified as benign by two clinical laboratories; as likely benign by Invitae, Ambry Genetics and three other submitters; as uncertain significance by one submitter), Cosmic (3x in Large intestine, or Haematopoietic and lymphoid tissue), MutDB, and in LOVD 3.0 (3x) databases. The variant was not identified in COGR. The variant was identified in control databases in 397 of 277154 chromosomes (1 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 10 of 24034 chromosomes (freq: 0.0004), Other in 7 of 6460 chromosomes (freq: 0.001), Latino in 36 of 34418 chromosomes (freq: 0.001), European in 300 of 126680 chromosomes (freq: 0.002), Ashkenazi Jewish in 1 of 10152 chromosomes (freq: 0.0001), East Asian in 1 of 18852 chromosomes (freq: 0.00005), Finnish in 22 of 25778 chromosomes (freq: 0.0009), and South Asian in 20 of 30780 chromosomes (freq: 0.0007). The p.Gly2023 residue is conserved in mammals but not in more distantly related organisms, and 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) do not predict a difference in splicing. In silico analysis predicted the variant induces or contributes to increased exon skipping (Caminsky 2016). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.42
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Uncertain
0.070
CADD
Uncertain
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.14
T;T
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;.
M_CAP
Uncertain
0.28
D
MetaRNN
Benign
0.16
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.6
M;M
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-3.5
D;D
REVEL
Uncertain
0.51
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
D;D
Vest4
0.83
MutPred
0.54
Loss of ubiquitination at K2025 (P = 0.0258);Loss of ubiquitination at K2025 (P = 0.0258);
MVP
0.96
MPC
0.62
ClinPred
0.056
T
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.81
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs11212587; hg19: chr11-108186610; COSMIC: COSV53761885; API