11-108304736-A-T

Variant names:

• chr11-108304736-A-T
• rs1801673
• NM_000051.4:c.5558A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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 Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (27 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:33 O:1
• Conservation: PhyloP100: 5.47
• Publications: 75 publications found

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 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 133623.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 27 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.5558A>T	p.Asp1853Val	missense_variant	Exon 37 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5558A>T	p.Asp1853Val	missense_variant	Exon 37 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.00439 AC: 668 AN: 152178 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00488 AC: 1226 AN: 250992 AF XY: 0.00522

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 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.: 27 Cov.: 32 AF XY: 0.00494 AC XY: 3592 AN XY: 727184

African (AFR) AF: 0.000508 AC: 17 AN: 33472

American (AMR) AF: 0.00315 AC: 141 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00708 AC: 185 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39678

South Asian (SAS) AF: 0.00579 AC: 499 AN: 86252

European-Finnish (FIN) AF: 0.00360 AC: 192 AN: 53402

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.00521 AC: 5789 AN: 1111950

Other (OTH) AF: 0.00502 AC: 303 AN: 60382

GnomAD4 genome AF: 0.00439 AC: 668 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00418 AC XY: 311 AN XY: 74468

African (AFR) AF: 0.000818 AC: 34 AN: 41544

American (AMR) AF: 0.00294 AC: 45 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4830

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00729 AC: 496 AN: 68028

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00653 Hom.: 1

Bravo AF: 0.00389

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00516 AC: 627

Asia WGS AF: 0.00231 AC: 8 AN: 3476

EpiCase AF: 0.00698

EpiControl AF: 0.00670

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:1 Benign:7

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 21, 2018

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 22, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:7 Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2014

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 30, 2018

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:7

Jan 31, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 09, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: BP4, BS2 -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 07, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:6

Nov 14, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 15, 2021

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 17, 2020

Spanish ATM Cancer Susceptibility Variant Interpretation Working Group

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Sep 06, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 15, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Benign:2

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as compound heterozygous. -

May 23, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Breast and/or ovarian cancer Benign:1

Nov 25, 2020

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 “With Likely benign allele”,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

Apr 19, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;.
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.016	T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.5	M;M
PhyloP100		5.5
PrimateAI	Uncertain	0.48	T
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	T
GERP RS		5.5
Varity_R		0.61
gMVP		0.58
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs1801673; hg19: chr11-108175463; COSMIC: COSV53725804; COSMIC: COSV53725804;