11-108304736-A-T

Position:

chr11-108304736-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000051.4(ATM):c.5558A>T(p.Asp1853Val) variant causes a missense change. The variant allele was found at a frequency of 0.00484 in 1,614,054 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1853N) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0049 ( 27 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:33O:1

Conservation

PhyloP100: 5.47

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]

ATM links:

ATM (HGNC:):

ATM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016077608).

BP6

Variant 11-108304736-A-T is Benign according to our data. Variant chr11-108304736-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133623.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1, not_provided=1, Benign=15}. Variant chr11-108304736-A-T is described in Lovd as [Likely_benign]. Variant chr11-108304736-A-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00439 (668/152296) while in subpopulation NFE AF= 0.00729 (496/68028). AF 95% confidence interval is 0.00676. There are 0 homozygotes in gnomad4. There are 311 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 27 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.5558A>T	p.Asp1853Val	missense_variant	37/63	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.5558A>T	p.Asp1853Val	missense_variant	37/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00439

AC:

668

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000821

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00496

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00729

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00488

AC:

1226

AN:

250992

Hom.:

AF XY:

0.00522

AC XY:

708

AN XY:

135648

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00295

Gnomad ASJ exome

AF:

0.00695

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00575

Gnomad FIN exome

AF:

0.00370

Gnomad NFE exome

AF:

0.00662

Gnomad OTH exome

AF:

0.00556

GnomAD4 exome

AF:

0.00489

AC:

7150

AN:

1461758

Hom.:

Cov.:

AF XY:

0.00494

AC XY:

3592

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00315

Gnomad4 ASJ exome

AF:

0.00708

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00579

Gnomad4 FIN exome

AF:

0.00360

Gnomad4 NFE exome

AF:

0.00521

Gnomad4 OTH exome

AF:

0.00502

GnomAD4 genome

AF:

0.00439

AC:

668

AN:

152296

Hom.:

Cov.:

AF XY:

0.00418

AC XY:

311

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00497

Gnomad4 FIN

AF:

0.00292

Gnomad4 NFE

AF:

0.00729

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00653

Hom.:

Bravo

AF:

0.00389

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00686

AC:

ExAC

AF:

0.00516

AC:

627

Asia WGS

AF:

0.00231

AC:

AN:

3476

EpiCase

AF:

0.00698

EpiControl

AF:

0.00670

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:33Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:1Benign:7

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 21, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, 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. 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. -

not specified

Benign:7Other:1

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 30, 2018	- -
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	Eurofins Ntd Llc (ga)	Sep 27, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided

Benign:7

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ATM: BP4, BS2 -
Likely 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	Athena Diagnostics	Jan 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 31, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:6

Benign, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.5558A>T (p.Asp1853Val) missense variant has an allele frequency of 0.48%, (1282/267,858 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.67%, (797/117,840 alleles) in the European (non-Finnish) subpopulation (BA1; http://gnomad.broadinstitute.org). Therefore, it meets criteria to be classified as benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BA1 (PMID: 33280026). -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 15, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 01, 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	curation	Sema4, Sema4	Sep 06, 2020	- -

Familial cancer of breast

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	This variant was identified as compound heterozygous. -

Breast and/or ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 25, 2020

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Oct 13, 2022

This variant has been reported in the literature in numerous individuals with a variety of indications, including breast cancer, chronic lymphocytic leukemia, melanoma and common variable immunodeficiency (Teraoka 2001 PMID:11505391, Concannon 2008 PMID:18701470, Navrkalova 2013 PMID:23585524, Maxwell 2016 PMID:27153395, Casula 2019 PMID:31382929, Hargreaves 2021 PMID:34009545). Of note, multiple publications classify this variant as a benign polymorphism. This variant is present in the Genome Aggregation Database (Highest reported MAF 0.6% (881/128846) including 4 homozygotes (https://gnomad.broadinstitute.org/variant/11-108175463-A-T?dataset=gnomad_r2_1). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:133623). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as Likely Benign. -

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.Asp1853Val variant was identified in 39 of 2578 proband chromosomes (frequency: 0.02) from individuals or families with prostate, breast and ovarian cancer and was present in 4 of 880 control chromosomes (frequency: 0.005) from healthy individuals (Angele 2004, Paglia 2010, Johnson 2007, Tapia 2008). The variant was also identified in dbSNP (ID: rs1801673) as â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹,ClinVar (classified as benign by Invitae, Ambry Genetics, Color Genomics; classified as likely benign by GeneDx, Prevention Genetics), Cosmic (classified as pathogenic (score 0.97)), MutDB (clasified as polymorphism), LOVD 3.0, databases. The variant was not identified in GeneInsight-COGR, ATM-LOVD, databases. The variant was identified in control databases in 1360 (6 homozygous) of 276730 chromosomes at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Asp1853 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, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Armadillo-type fold functional domain increasing the likelihood that it may have clinical significance. The study by Angele (2004) observed no significant differences in the frequency between the cases and controls. However, functional study by Tapia (2008) suggests a possible alteration of normal splicing due to variant affect an ESE sequence. 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. -

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

Uncertain

0.42

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;.

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.016

T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Uncertain

0.48

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.88

P;P

Vest4

0.67

MVP

0.86

MPC

0.23

ClinPred

0.032

GERP RS

5.5

Varity_R

0.61

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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