rs587779817

chr11-108251025-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000051.4(ATM):c.1564_1565del(p.Glu522IlefsTer43) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000545 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R521R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:38 O:1
• Conservation: PhyloP100: 4.59

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-108251025-CAG-C is Pathogenic according to our data. Variant chr11-108251025-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 127340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108251025-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.1564_1565del	p.Glu522IlefsTer43	frameshift_variant	10/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.1564_1565del	p.Glu522IlefsTer43	frameshift_variant	10/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000558 AC: 14 AN: 250850 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000106

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000547 AC: 80 AN: 1461862 Hom.: 0 AF XY: 0.0000454 AC XY: 33 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000710

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000491

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:38 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:12

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ATM: PM3:Very Strong, PVS1, PM2:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 18, 2020	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Additionally, the variant was found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Apr 12, 2023	PVS1, PS4, PM2_SUP, PM3 -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2022	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; Observed in the heterozygous state in individuals with breast, pancreatic, and other cancers (Huang 2015, Hansford 2015, Mansfield 2016, Brand 2018, Dudley 2018, Waszak 2018, West 2018, Young 2018, Long 2019); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 1561_1562delAG, 1563_1564delAG, and 1562delAG; This variant is associated with the following publications: (PMID: 31447099, 29625052, 26689913, 28390840, 27533158, 29360161, 29753700, 28152038, 28843361, 31285527, 8789452, 21965147, 9792409, 23566627, 25980754, 22213089, 26506520, 11756177, 18634022, 26681312, 27083775, 28126470, 26182300, 27988859, 27479817, 28779002, 29785153, 28767289, 25186627, 30549301, 29445900, 30322717, 30612635, 31407689, 30772474, 30067863, 29945567, 29522266, 23242139, 31589614, 33436325, 32885271, 32427313, 32441320, 33098801, 33280026) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 18, 2020	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Ataxia-telangiectasia syndrome Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 09, 2018	Variant summary: ATM c.1564_1565delGA (p.Glu522IlefsX43) 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. The variant allele was found at a frequency of 5.3e-05 in 246034 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (5.3e-05 vs 0.004), allowing no conclusion about variant significance. The variant, c.1564_1565delGA, has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Demuth_2011, Stankovic_1998, Sandoval_199). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submission from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	Oct 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change creates a premature translational stop signal (p.Glu522Ilefs*43) 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 (rs751357509, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia-telangiectasia (PMID: 9000145, 9463314, 10330348, 10817650, 12497634, 21965147, 27083775). This variant is also known as 1561delAG, 521ΔAG, 1563_1564delAG, 1563delAG, c.1564_1565delAG and c.1561_1562delAG. ClinVar contains an entry for this variant (Variation ID: 127340). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	Jun 03, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 30, 2022	The ATM c.1564_1565del variant is classified as a PATHOGENIC variant (PVS1, PM2, PS4_supporting) The variant is a 2-base pair deletion in exon 10/63 of the ATM gene which results in a frameshift starting at codon Glutamic acid 522, changes this amino acid to an Isoleucine, and creating a premature STOP codon 43 amino acids downstream (denoted p.Glu522Ilefs*43) (PVS1). The variant has been reported in dbSNP (rs1374409941) but is rare in the disease databases (gnomAD: 8/152158, 0 homozygote) (PM2). The variant has been reported in both ClinVar (ID: #127340) and HGMD (accession: CD961794) as a disease causing variant (PS4_supporting). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Feb 21, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Familial cancer of breast Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 30, 2017	This c.1564_1565del (p.Glu522Ilefs*43) has previously been reported a patient with ataxia telangiectasia [p.R521fs in PMID 8789452]. It has also been reported in patients with gastric cancer and suspected lynch syndrome [c.1561_1562del, p.R521fs in PMID 26506520]. This c.1564_1565del (p.Glu522Ilefs*43) variant been observed in 6 heterozygous individuals in the ExAC population database (http://exac.broadinstitute.org/variant/11-108121752-CAG-C). It is thus interpreted as a likely pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -
Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1, PM3_VSTR -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 17, 2024	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 22, 2021	The c.1564_1565delGA pathogenic mutation, located in coding exon 9 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 1564 to 1565, causing a translational frameshift with a predicted alternate stop codon (p.E522Ifs*43). This alteration is a commonly recurring mutation in Ataxia-Telangiectasia cohorts and has been observed in both the homozygous and compound heterozygous states (Byrd PJ et al. Hum. Mol. Genet. 1996 Jan;5:145-9; McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Broeks A et al. Hum. Mutat. 1998;12:330-7; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79; Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Verhagen MM et al. Neuropediatrics. 2007 Jun;38:117-21; Verhagen MM et al. Neurology. 2009 Aug;73:430-7; Reiman A et al. Br. J. Cancer. 2011 Aug;105:586-91; Demuth I et al. Neurogenetics. 2011 Nov;12:273-82; Verhagen MM et al. Hum. Mutat. 2012 Mar;33:561-71; van Os NJH et al. Clin. Immunol. 2017 05;178:45-55). This mutation has also been observed in patients with breast cancer (Hansford S et al. JAMA Oncol. 2015 Apr;1:23-32; Seifert BA et al. Clin. Cancer Res. 2016 Aug;22:4087-4094; Decker B et al. J. Med. Genet. 2017 Nov;54:732-741; Hauke J et al. Cancer Med. 2018 Apr;7:1349-1358). Additionally, this mutation has been identified in multiple cohorts of patients with pancreatic cancer (Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390; Young EL et al. BMC Cancer. 2018 Jun;18:697; Dudley B et al. Cancer. 2018 Apr;124:1691-1700; Brand R et al. Cancer. 2018 Aug;[Epub ahead of print]). Of note, this alteration is also designated as 1560CAG>C, 1561delAG, 1561_1562delAG, 1563delAG, and 1563_1564delAG in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 08, 2024	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 individuals affected with breast cancer (PMID: 16652348, 17393301, 29785153), pancreatic cancer (PMID: 29945567, 30067863), and gastric cancer (PMID: 31514334). This variant has also 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: 10817650, 22213089, 30772474). This variant has been identified in 14/250850 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.1564_1565del p.(Glu522Ilefs*43) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein, due to nonsense mediated decay (NMD) (PVS1). It has an allele frequency of 0.00004232 (0.004%, 10/236,314 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.000078 (0.008%, 8/102,512 alleles) in the Non-Finnish European subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). This variant has been reported in at least four ataxia-telangiectasia probands in trans with pathogenic variants (PMID: 15880721, 16266405) and in three homozygous probands (PMID: 12497634), which awards it with 4 points as per ClinGen SVI Recommendation for in trans Criterion (PM3_VeryStrong). It has also been observed in at least 10 other ataxia-telangiectasia probands (PMID: 9463314, 21965147, 30772474). In summary, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM3_VeryStrong (PMID: 33280026). -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This variation is a deletion of 2 nucleotides in exon 10 of the ATM mRNA (c.1564_1565delGA), causing a frameshift after codon 522 and the creation of a premature translational stop signal 43 amino acid residues later -p.(Glu522Ilefs*43). This is expected to result in an absent or disrupted protein product. Truncating variants in ATM are known to be pathogenic. This particular variant has been reported in the literature in individuals affected with ataxia-telangiectasia and in breast cancer patients (PMID: 10817650, PMID: 12497634, PMID: 27083775). The mutation database ClinVar contains multiple entries for this variant (Variation ID: 127340). -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 28, 2022

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 12, 2022

- -

Tip-toe gait Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Mar 15, 2022

- -

ATM-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2024

The ATM c.1564_1565delGA variant is predicted to result in a frameshift and premature protein termination (p.Glu522Ilefs*43). This variant has previously been reported in patients with ataxia telangiectasia (Byrd et al. 1996. PubMed ID: 8789452), as well as in individuals with a personal or family history of breast, pancreatic, gastric, and colorectal cancers (Decker et al. 2017. PubMed ID: 28779002; Hansford et al. 2015. PubMed ID: 26182300; Huang et al. 2015. PubMed ID: 26506520; Shindo et al. 2017. PubMed ID: 28767289; Tung et al. 2014. PubMed ID: 25186627; Yurgelun et al. 2015. PubMed ID: 25980754). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127340/). Frameshift variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic. -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Glu522Ilefs*43 variant was identified in 24 of 22060 proband chromosomes (frequency: 0.002) from individuals or families with Ataxia-Telangiectasia, breast cancer, melanoma, or pancreatic cancer (Campbell 2003, Demuth 2011, Li 2000, Seifert 2016, Stankovic 1998, Susswein 2015, Teraoka 1999, Verhagen 2011, Mitu 2005). The variant was also identified in dbSNP (ID: rs587779817; Alias rs751357509) as "With Pathogenic allele", ClinVar (classified as pathogenic by GeneDx, Ambry Genetics, Invitae, Counsyl, Color Genomics and Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics), Cosmic (2x found in Haematopoietic and lymphoid tissue or Upper aerodigestive tract), and LOVD 3.0 (40x as pathogenic). The variant was not identified in the COGR database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1564_1565del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 522 and leads to a premature stop codon at position 564. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the ATM gene are an established mechanism of disease in ATM-associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Seizure Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Apr 07, 2020

- -

Ataxia-telangiectasia syndrome;C0027672:Hereditary cancer-predisposing syndrome Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant classified as Pathogenic and reported on 12-28-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs587779817; hg19: chr11-108121752;