rs149636614

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP2_StrongBP4BS1

This summary comes from the ClinGen Evidence Repository: The ATM c.1073A>G (p.Asn358Ser) variant has a gnomAD v2.1.1 filtering allele frequency of 0.1523% (African/African-American; exomes) which exceeds the ATM BS1 threshold of 0.05% (BS1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without biallelic disease (BP2_Strong; GTR Lab IDs: 500031, 61756). In silico protein predictors (ALIGN GVGD: Class C0; REVEL: 0.054; SIFT: tolerated; PolyPhen2: benign) predict that this alteration is not deleterious and in silico splicing predictors (SpliceAI: AL 0.13/DL 0.00/AG 0.00/DG 0.00; MaxEntScan: 0.00% (wild type = 10.82, variant = 10.82)) find that this variant is unlikely to affect splicing (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA286708/MONDO:0016419/020

Frequency

Genomes: 𝑓 0.00072 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:4B:13

Conservation

PhyloP100: 1.17

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP2

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

BP4

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

BS1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.1073A>G	p.Asn358Ser	missense_variant	9/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.1073A>G	p.Asn358Ser	missense_variant	9/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.000717

AC:

109

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000159

AC:

AN:

246050

Hom.:

AF XY:

0.000128

AC XY:

AN XY:

133234

show subpopulations

Gnomad AFR exome

AF:

0.00208

Gnomad AMR exome

AF:

0.0000889

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:

0.00000893

Gnomad OTH exome

AF:

0.000335

GnomAD4 exome

AF:

0.0000771

AC:

112

AN:

1453586

Hom.:

Cov.:

AF XY:

0.0000760

AC XY:

AN XY:

723290

show subpopulations

Gnomad4 AFR exome

AF:

0.00222

Gnomad4 AMR exome

AF:

0.000137

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:

0.0000162

Gnomad4 OTH exome

AF:

0.000217

GnomAD4 genome

AF:

0.000716

AC:

109

AN:

152208

Hom.:

Cov.:

AF XY:

0.000766

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00248

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000374

Hom.:

Bravo

AF:

0.000869

ESP6500AA

AF:

0.00205

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:4Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 25, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 01, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2018	This variant is denoted ATM c.1073A>G at the cDNA level, p.Asn358Ser (N358S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). ATM Asn358Ser was reported in an individual with breast cancer, in an individual with a personal history of a Lynch syndrome-related cancer and/or colon polyps, and in an individual undergoing multigene hereditary cancer panel testing (Yurgelun 2015, Mu 2016, Decker 2017). This variant was observed at an allele frequency of 0.23% (55/23,886) in individuals of African ancestry in large population cohorts (Lek 2016). ATM Asn358Ser is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Asn358Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 06, 2019	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 23, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 28, 2021	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 02, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 08, 2024	Variant summary: ATM c.1073A>G (p.Asn358Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 1605794 control chromosomes, predominantly at a frequency of 0.0024 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1073A>G has been reported in the literature in individuals affected with Breast Cancer (e.g. Decker_2017) and Lynch Syndrome (e.g. Yurgelun_2015). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. The following publications have been ascertained in the context of this evaluation (PMID: 27621404, 28779002, 27720647, 30541756, 28652578, 25980754, 31206626). ClinVar contains an entry for this variant (Variation ID: 127329). Based on the evidence outlined above, the variant was classified as likely benign. -

Familial cancer of breast

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 25, 2024	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]. -
Benign, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Mar 09, 2022	The ATM c.1073A>G (p.Asn358Ser) variant has a gnomAD v2.1.1 filtering allele frequency of 0.1523% (African/African-American; exomes) which exceeds the ATM BS1 threshold of 0.05% (BS1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without biallelic disease (BP2_Strong; GTR Lab IDs: 500031, 61756). In silico protein predictors (ALIGN GVGD: Class C0; REVEL: 0.054; SIFT: tolerated; PolyPhen2: benign) predict that this alteration is not deleterious and in silico splicing predictors (SpliceAI: AL 0.13/DL 0.00/AG 0.00/DG 0.00; MaxEntScan: 0.00% (wild type = 10.82, variant = 10.82)) find that this variant is unlikely to affect splicing (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Oct 03, 2019

- -

Ataxia-telangiectasia syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

ATM-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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.Asn358Ser variant was identified in 1 of 562 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer and triple-negative breast cancer and was present in 2 of 488 control chromosomes (frequency: 0.004) from healthy individuals (Lovejoy 2018, Rosenstein 2006). The variant was also identified in dbSNP (ID: rs149636614) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics and Integrated Genetics and as uncertain significance by GeneDx, Invitae, University of Chicago and EGL Genetic Diagnostics), LOVD 3.0 (classified as likely benign by VKGL data sharing initiative). The variant was identified in control databases in 60 of 272346 chromosomes at a frequency of 0.0002 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 55 of 23886 chromosomes (freq: 0.002), Other in 1 of 6350 chromosomes (freq: 0.0002), Latino in 3 of 33660 chromosomes (freq: 0.00009), European Non-Finnish in 1 of 125094 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Asn358 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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

Benign

0.060

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.29

DEOGEN2

Benign

0.049

.;T;T

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.71

T;T;.

M_CAP

Benign

0.020

MetaRNN

Benign

0.0083

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.23

.;N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.054

Sift

Benign

0.72

T;T;T

Sift4G

Benign

0.41

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.085, 0.080

MVP

0.66

MPC

0.097

ClinPred

0.018

GERP RS

1.0

Varity_R

0.058

gMVP

0.088

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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