rs145053092

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000051.4(ATM):c.670A>G(p.Lys224Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000101 in 1,613,070 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:20B:3

Conservation

PhyloP100: 5.62

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:

ATM (HGNC:):

ATM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24340346).

BP6

Variant 11-108244795-A-G is Benign according to our data. Variant chr11-108244795-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142522.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=15}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.670A>G	p.Lys224Glu	missense_variant	7/63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.670A>G	p.Lys224Glu	missense_variant	7/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000836

AC:

AN:

251098

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135706

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000103

AC:

150

AN:

1460906

Hom.:

Cov.:

AF XY:

0.0000991

AC XY:

AN XY:

726800

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000131

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000124

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:20Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:9Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 04, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 14, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The available data on the frequency of this variant in large general population databases was not informative towards the evaluation of its pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features of ataxia-telangiectasia. Computational tools disagree on the variant's effect on normal protein function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 11, 2024	The ATM c.670A>G (p.Lys224Glu) variant has been reported in the published literature in an individual affected with ataxia-telangiectasia along with another pathogenic ATM variant (PMID: 10817650 (2000)) and in individuals with breast cancer (PMID: 19781682 (2009), 20305132 (2010), 26689913 (2015), 27616075 (2016), 28779002 (2017)), melanoma (PMID: 34262154 (2021)), and prostate cancer (PMID: 33436325 (2021)). This variant has also been observed in reportedly healthy individuals (PMID: 19781682 (2009), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.0002 (10/50682 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 31, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2024	Observed in the compound heterozygous state with an ATM truncating variant in a patient with ataxia-telangiectasia (PMID: 10817650); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26689913, 24825865, 19781682, 23585524, 22114986, 28779002, 29659569, 29522266, 29449575, 26580448, 27616075, 29684080, 25186627, 20305132, 31422574, 31920950, 31567591, 33436325, 32095738, 33471991, 30303537, 34326862, 34262154, 36029002, 33850299, 35534704, 10817650, 38136308) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	ATM: BP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Ataxia-telangiectasia syndrome

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Ataxia telangiectasia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 31, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 03, 2023	Variant summary: ATM c.670A>G (p.Lys224Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.9e-05 in 258294 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.9e-05 vs 0.004), allowing no conclusion about variant significance. c.670A>G has been reported in the literature in an individual affected with Ataxia-Telangiectasia (Li_2000) and in several individuals affected with various types of cancers (example, Tavtigian_2009, Kraus_2016, Paulo_2018, Dalmasso_2021, Karlsson_2021). The variant has also been observed in unaffected control individuals (example, Tavtigian_2009, Girard_2019). These data do not allow any conclusion about variant significance. At-least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Navrkalova_2013). 12 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and three ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 18, 2016	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 27, 2024	The p.K224E variant (also known as c.670A>G), located in coding exon 6 of the ATM gene, results from an A to G substitution at nucleotide position 670. The lysine at codon 224 is replaced by glutamic acid, an amino acid with similar properties. This variant was reported in an individual with ataxia telangiectasia who also carried an ATM pathogenic mutation, however, detailed clinical information and the phase of the two detected alterations were not provided (Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7). This alteration has been detected in 1/4112 breast cancer patients and 1/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This alteration has also been identified in breast, pancreatic, prostate and melanoma cohorts, as well as in a pediatric leukemia case (Zhang J et al. N. Engl. J. Med. 2015 Dec;373(24):2336-2346; Decker B et al. J. Med. Genet. 2017 11;54(11):732-741; Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102; Bradbury et al. JCO Precis. Oncol. 2018 Apr;2; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Li C et al. Melanoma Res. 2020 Jun;30(3):247-251; Karlsson Q et al. Eur Urol Oncol, 2021 08;4:570-579). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 20, 2020	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jun 14, 2021	- -

Familial cancer of breast

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Apr 24, 2020	This variant has been reported in the literature in individuals with breast cancer (Tavtigian 2009, Bernstein 2010, Lu 2015, Kraus 2017) and in an individual with ataxia-telangiectasia who had a frameshift variant in the ATM gene on the other allele (Li 2000). This variant has an overall allele frequency of 0.00009 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. PP3; PM3 -

ATM-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2024

The ATM c.670A>G variant is predicted to result in the amino acid substitution p.Lys224Glu. This variant was reported in the compound heterozygous state with another variant in a patient with ataxia telangiectasia (Li et al. 2000. PubMed ID: 10817650). It was also reported in a patient with triple negative breast cancer and a family history of cervical and pancreatic cancer (Kraus et al. 2016. PubMed ID: 27616075, Suppl. Table 4). This variant has also been reported in additional individuals with breast cancer (Bernstein et al. 2010. PubMed ID: 20305132, Suppl. Table 2; Lu et al. 2015. PubMed ID: 26689913, Suppl. Table 12). However, in another study, it was reported at similar frequencies in cases and controls (Tavtigian et al. 2009. PubMed ID: 19781682, Suppl. Table 2). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142522/). 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

Benign

0.17

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.095

.;T;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

T;T;.

M_CAP

Benign

0.065

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

.;M;M

PrimateAI

Benign

0.39

PROVEAN

Benign

-2.2

N;N;N

REVEL

Benign

0.20

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.015

D;D;D

Polyphen

0.96

.;D;D

Vest4

0.43, 0.42

MVP

0.97

MPC

0.23

ClinPred

0.19

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over