rs2229020

chr11-108279589-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000051.4(ATM):c.3383A>G(p.Gln1128Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,611,350 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1128E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0059 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (12 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23 O:1
• Conservation: PhyloP100: 2.43

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008067787).
• BP6: Variant 11-108279589-A-G is Benign according to our data. Variant chr11-108279589-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 133615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108279589-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00595 (906/152330) while in subpopulation AFR AF= 0.0207 (859/41578). AF 95% confidence interval is 0.0195. There are 10 homozygotes in gnomad4. There are 458 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.3383A>G	p.Gln1128Arg	missense_variant	23/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.3383A>G	p.Gln1128Arg	missense_variant	23/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 904 AN: 152212 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00174 AC: 436 AN: 250902 Hom.: 9 AF XY: 0.00133 AC XY: 180 AN XY: 135616

Gnomad AFR exome AF: 0.0227

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000630 AC: 919 AN: 1459020 Hom.: 12 Cov.: 30 AF XY: 0.000537 AC XY: 390 AN XY: 725960

Gnomad4 AFR exome AF: 0.0203

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000694

Gnomad4 OTH exome AF: 0.00138

GnomAD4 genome AF: 0.00595 AC: 906 AN: 152330 Hom.: 10 Cov.: 33 AF XY: 0.00615 AC XY: 458 AN XY: 74492

Gnomad4 AFR AF: 0.0207

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000945 Hom.: 3

Bravo AF: 0.00703

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00217 AC: 264

Asia WGS AF: 0.000578 AC: 2 AN: 3474

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7 Other:1

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 08, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 29, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 12, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Ataxia-telangiectasia syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Apr 11, 2018	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2020	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	This variant is associated with the following publications: (PMID: 17333338, 20981092, 22529920, 11996792, 24728327, 25122203, 22071889, 21933854) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 28, 2016	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 20, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 30, 2020	- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2022

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Gln1128Arg variant was identified in 8 of 9204 proband chromosomes (frequency: 0.000869) from individuals or families with breast cancer, CLL, Ataxia telangiectasia and was present in 2 of 5218 control chromosomes (frequency: 0.0003) from healthy individuals (Austen 2005, Jacquemin 2011, Skowronska 2012, Tavtigian 2009). The variant was also identified in dbSNP (ID: rs2229020) as With other allele, ClinVar (classified as benign by GenDx, Ambry Genetics, Invitae), Clinvitae (classified as benign by ClinVar, Invitae), Cosmic (pathogenic), MutDB, databases. The variant was not identified in LOVD 3.0, ATM-LOVD, databases. The variant was identified in control databases in 601(8 homozygous) of 276616 chromosomes at a frequency of 0.002 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 528 of 24022 chromosomes (freq: 0.022). The p.Gln1128 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 Armadillo-type fold functional domain increasing the likelihood that it may have clinical significance. 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. -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	16
Dann	Uncertain	0.98
Eigen	Benign	-0.032
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.52	T;T;.
MetaRNN	Benign	0.0081	T;T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	0.97	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.91	.;P;P
Vest4		0.34, 0.72
MVP		0.82
MPC		0.13
ClinPred		0.026	T
GERP RS		3.4
Varity_R		0.056
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs2229020; hg19: chr11-108150316; COSMIC: COSV53734962;