rs1801516

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000051.4(ATM):c.5557G>A(p.Asp1853Asn) variant causes a missense change. The variant allele was found at a frequency of 0.13 in 1,613,666 control chromosomes in the GnomAD database, including 15,385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1853V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.11 ( 1205 hom., cov: 32)

Exomes 𝑓: 0.13 ( 14180 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:23O:1

Conservation

PhyloP100: 5.93

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014446676).

BP6

Variant 11-108304735-G-A is Benign according to our data. Variant chr11-108304735-G-A is described in ClinVar as [Benign]. Clinvar id is 128458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108304735-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.5557G>A	p.Asp1853Asn	missense_variant	37/63	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.5557G>A	p.Asp1853Asn	missense_variant	37/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16174

AN:

152020

Hom.:

1205

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0240

Gnomad AMI

AF:

0.332

Gnomad AMR

AF:

0.0907

Gnomad ASJ

AF:

0.143

Gnomad EAS

AF:

0.00789

Gnomad SAS

AF:

0.0749

Gnomad FIN

AF:

0.238

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.145

Gnomad OTH

AF:

0.105

GnomAD3 exomes

AF:

0.114

AC:

28505

AN:

250874

Hom.:

2083

AF XY:

0.116

AC XY:

15745

AN XY:

135594

show subpopulations

Gnomad AFR exome

AF:

0.0226

Gnomad AMR exome

AF:

0.0612

Gnomad ASJ exome

AF:

0.129

Gnomad EAS exome

AF:

0.00632

Gnomad SAS exome

AF:

0.0772

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.143

Gnomad OTH exome

AF:

0.124

GnomAD4 exome

AF:

0.133

AC:

193944

AN:

1461528

Hom.:

14180

Cov.:

AF XY:

0.132

AC XY:

95950

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.0206

Gnomad4 AMR exome

AF:

0.0646

Gnomad4 ASJ exome

AF:

0.134

Gnomad4 EAS exome

AF:

0.00313

Gnomad4 SAS exome

AF:

0.0775

Gnomad4 FIN exome

AF:

0.236

Gnomad4 NFE exome

AF:

0.143

Gnomad4 OTH exome

AF:

0.121

GnomAD4 genome

AF:

0.106

AC:

16176

AN:

152138

Hom.:

1205

Cov.:

AF XY:

0.108

AC XY:

8064

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0240

Gnomad4 AMR

AF:

0.0906

Gnomad4 ASJ

AF:

0.143

Gnomad4 EAS

AF:

0.00791

Gnomad4 SAS

AF:

0.0758

Gnomad4 FIN

AF:

0.238

Gnomad4 NFE

AF:

0.145

Gnomad4 OTH

AF:

0.103

Alfa

AF:

0.130

Hom.:

2922

Bravo

AF:

0.0928

TwinsUK

AF:

0.140

AC:

518

ALSPAC

AF:

0.148

AC:

572

ESP6500AA

AF:

0.0284

AC:

125

ESP6500EA

AF:

0.140

AC:

1205

ExAC

AF:

0.110

AC:

13333

Asia WGS

AF:

0.0370

AC:

130

AN:

3476

EpiCase

AF:

0.141

EpiControl

AF:

0.139

ClinVar

Significance: Benign

Submissions summary: Benign:23Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9Other:1

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Ataxia-telangiectasia syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25591549, 31382929, 28652578, 18502988, 24728327, 16914028, 27599564, 27153395, 17333338, 15756685, 22792358, 22529920, 20396981, 18465141, 17517479, 23585524, 24599715, 19147782, 17351744) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 12, 2015	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	curation	Sema4, Sema4	May 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2014	- -

Familial cancer of breast

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 23, 2024	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Hereditary breast ovarian cancer syndrome

Benign:1

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

0.18

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.099

T;T

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

T;.

MetaRNN

Benign

0.0014

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

0.000051

P;P

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.12

Sift

Benign

0.20

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.044

B;B

Vest4

0.31

MPC

0.13

ClinPred

0.011

GERP RS

5.5

Varity_R

0.44

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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