11-108250866-CAA-C

Variant names:

• chr11-108250866-CAA-C
• rs587781347
• NM_000051.4:c.1402_1403delAA

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PM3_Strong PM5_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1402_1403del (p.Lys468Glufs*18) variant in ATM is a frameshift variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID:23807571, 26896183, 31691010). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0003 in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1, PM5_Supporting, PM3_Strong) LINK:https://erepo.genome.network/evrepo/ui/classification/CA163840/MONDO:0700270/020

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:25
• Conservation: PhyloP100: 2.79
• Publications: 31 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: Pathogenic. The variant received 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.1402_1403delAA	p.Lys468GlufsTer18	frameshift_variant	Exon 10 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.1402_1403delAA	p.Lys468GlufsTer18	frameshift_variant	Exon 10 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251414 AF XY: 0.0000515

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461852 Hom.: 0 AF XY: 0.0000138 AC XY: 10 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74270

African (AFR) AF: 0.0000241 AC: 1 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:7

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2015

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant causes the premature termination of ATM protein synthesis. In addition, it has been reported in individuals affected with breast and ovarian cancer, as well as ataxia-telangiectasia, in the published literature (PMID: 31815095 (2019), 26094658 (2015), 20308662 (2010), 9792409 (1998)). Therefore, the variant is classified as pathogenic and this individual is at increased risk of developing ATM related cancers. -

Dec 27, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 23322442, 22649200, 25892863, 26094658, 20308662, 32866655, 24733792, 10817650, 9792409, 12552559, 23807571, 24763289, 23264026, 21933854, 23726790, 25101980, 27433846, 28779002, 28152038, 30322717, 30607632, 31815095, 32318955, 31447099, 31980526, 26896183, 31691010, 32761968, 34247626, 21665257, 35171259, 34771502, 34917121, 33277227, 30613976, 28724667, 29922827) -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 08, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_strong, PVS1 -

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Pathogenic:5

Jan 19, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 28, 2015

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys468Glufs*18) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs587781347, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and breast, rectal, prostate or ovarian cancer (PMID: 9792409, 12552559, 20308662, 22649200, 23322442, 24733792, 25892863, 26094658, 27433846, 30322717, 31815095). ClinVar contains an entry for this variant (Variation ID: 140889). For these reasons, this variant has been classified as Pathogenic. -

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). This homozygous variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000140889 / PMID: 9792409). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jul 03, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.1402_1403delAA (p.Lys468GlufsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-05 in 251414 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.1402_1403delAA has been reported in the literature in homozygous and compound heterozygous genotypes among multiple individuals affected with Ataxia-Telangiectasia (example, Broeks_1998, Lin_2010, Buzin_2003, Carney_2012, Jeddane_2013), and in heterozygosity among multiple individuals with a variety of cancers, such as breast and ovarian (example, Kurian_2015, Alorafi_2015, Manchana_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Carney_2012). The most pronounced variant effect results in a complete absence of ATM protein as measured by western blot and no ATM activity. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial cancer of breast Pathogenic:4

Mar 24, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Apr 28, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 04, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.1402_1403del (p.Lys468GlufsTer18) change deletes two nucleotide to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in the homozygous and compound heterozygous state in individuals with ataxia telangiectasia (PMID 9792409; 12552559; 20308662; 21665257; 22649200; 23322442; 23726790; 23807571). This variant has a maximum subpopulation frequency of 0.03% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:3

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1+PM3 -

Sep 26, 2022

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Sep 23, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 2 nucleotides in exon 10 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in the homozygous state and in the compound heterozygous state with an additional ATM pathogenic variant in individuals affected with ataxia telangiectasia (PMID: 9792409, 20308662, 21665257, 22649200, 23322442, 23726790, 23807571). This variant has also been reported in individuals affected with breast cancer and ovarian cancer (PMID: 24733792, 26094658, 31815095). This variant has been identified in 13/282780 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Nov 19, 2012

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Alterations resulting in premature truncation (e.g.reading frame shift, nonsense) -

Breast and/or ovarian cancer Pathogenic:1

Oct 03, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATM-related cancer predisposition Pathogenic:1

Nov 26, 2024

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1402_1403del (p.Lys468Glufs*18) variant in ATM is a frameshift variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID: 23807571, 26896183, 31691010). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0003 in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1, PM5_Supporting, PM3_Strong) -

ATM-related disorder Pathogenic:1

Dec 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.1402_1403delAA variant is predicted to result in a frameshift and premature protein termination (p.Lys468Glufs*18). This variant has previously been reported in individuals with autosomal recessive ataxia telangiectasia (Broeks et al. 1998. PubMed ID: 9792409; Lin et al. 2010. PubMed ID: 20308662), breast cancer (Kurian et al. 2014. PubMed ID: 24733792; Aloraifi et al. 2015. PubMed ID: 26094658), and non-polyposis colorectal cancer (Zhang et al. 2015. PubMed ID: 25892863). This variant is reported in 0.030% of alleles in individuals of East Asian descent in gnomAD and is interpreted as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/140889/). Frameshift variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic. -

Familial colorectal cancer type X Pathogenic:1

Apr 12, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587781347; hg19: chr11-108121593; COSMIC: COSV53744739; COSMIC: COSV53744739;