rs587776547

Variant names:

• chr11-108331884-CTCTAGAATT-C
• rs587776547
• NM_000051.4:c.7638_7646delTAGAATTTC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM4 PP5_Very_Strong

The NM_000051.4(ATM):​c.7638_7646delTAGAATTTC​(p.Arg2547_Ser2549del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,216 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: ATM NM_000051.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26 U:1
• Conservation: PhyloP100: 3.51

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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000051.4.
• PP5: Variant 11-108331884-CTCTAGAATT-C is Pathogenic according to our data. Variant chr11-108331884-CTCTAGAATT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.7638_7646delTAGAATTTC	p.Arg2547_Ser2549del	disruptive_inframe_deletion	Exon 52 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.7638_7646delTAGAATTTC	p.Arg2547_Ser2549del	disruptive_inframe_deletion	Exon 52 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152074 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 251148 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135760

Gnomad AFR exome AF: 0.0000617

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: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000678 AC: 99 AN: 1461142 Hom.: 0 AF XY: 0.0000784 AC XY: 57 AN XY: 726924

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

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: 0.0000837

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74278

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:8

Oct 27, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The ATM c.7638_7646delTAGAATTTC (p.Arg2547_Ser2549del) variant involves the inframe deletion of 9 nucleotides located in the PIK-related kinase domain (IPR014009) (InterPro). One in silico tool predicts a damaging outcome for this variant. Functional studies confirmed that there is no detectable ATM kinase activity associated with this variant and that LCLs with this variant exhibited p53, p21, and MDM2 response that was indistinguishable from classical A-T (Stewart_2001). This variant was found in 5/246251 control chromosomes at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). This variant was reported in multiple AT patients (Stankovic_1998, Skowronska_2012, Stewart_2001). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Jun 23, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 05, 2018

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 20, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.7638_7646del, results in the deletion of 3 amino acid(s) of the ATM protein (p.Arg2547_Ser2549del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587776547, gnomAD 0.007%). This variant has been observed in individuals with breast cancer and ataxia-telangiectasia (PMID: 7792600, 8797579, 11382771, 12552559, 21787400, 22649200). This variant is also known as 7636del9 and 7638del9. ClinVar contains an entry for this variant (Variation ID: 3019). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ATM function (PMID: 11382771, 12195425, 19431188, 22649200). For these reasons, this variant has been classified as Pathogenic. -

Sep 26, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2016

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 05, 2025

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.7638_7646del p.(Arg2547_Ser2549del) change deletes nine nucleotides at position 7638 to 7646 resulting in an in-frame deletion of three amino acid residues at codon 2547 to 2549. This variant has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in several individuals with ataxia telangiectasia (PMID: 12552559, 21665257, 21792198, 22649200, 26896183). Functional studies have shown that this variant results in no detectable kinase activity (PMID: 19431188). In summary, this variant meets criteria to be classified as pathogenic. -

not provided Pathogenic:6

Dec 29, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with ataxia-telangiectasia. Assessment of experimental evidence suggests this variant results in abnormal protein function. PMID: 19431188 -

Jul 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 31, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in the heterozygous state in individuals with ATM-related cancers (Vorechovsky et al., 1996; Goldgar et al., 2011; Bunnell et al., 2017; Decker et al., 2017; Na et al., 2017; Lu et al., 2019); Published functional studies demonstrate a damaging effect: absence of kinase activity and reduced ATM protein expression (Stewart et al., 2001; Barone et al., 2009; Reiman et al., 2011); In-frame deletion of 3 amino acids in a non-repeat region predicted to critically alter the protein; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Also known as c.7636del9 and 7638del9; This variant is associated with the following publications: (PMID: 25038946, 12552559, 21787400, 10817650, 19781682, 26556299, 32866655, 29922827, 8789452, 21792198, 9537233, 19431188, 11382771, 22649200, 21933854, 10330348, 8808599, 27276934, 8797579, 8845835, 7792600, 15279808, 12195425, 28779002, 27989354, 30128536, 34308366, 26896183, 31447099, 31948886, 32853339, 32338768, 34308104, 33804961, 23532176, 9150358, 9463314) -

Dec 13, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM2_moderate, PM3_strong, PM4, PS3 -

Hereditary cancer-predisposing syndrome Pathogenic:4

Aug 08, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7638_7646delTAGAATTTC pathogenic mutation (also known as p.R2547_S2549del), located in coding exon 51 of the ATM gene, results from an in-frame deletion of 9 nucleotides between positions 7638 and 7646. This results in the deletion of 3 amino acids between codons 2547 and 2549. This pathogenic mutation has been reported in individuals diagnosed with breast cancer, some of whom also had family histories of other cancers (Vorechovsky I et al. Cancer Res. 1996 Sep;56:4130-3; Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73). In addition, this mutation has been reported in a homozygous state and in conjunction with other deleterious ATM mutations in multiple individuals and/or families with ataxia-telagiectasia (Gilad S et al. Hum. Mol. Genet. 1996 Apr;5:433-9; Wright J et al. Am. J. Hum. Genet. 1996 Oct;59:839-46; Watters D et al. Oncogene. 1997 Apr;14:1911-21; Telatar M et al. Am. J. Hum. Genet. 1998 Jan;62:86-97; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Buzin C et al. Hum. Mutat. 2003 Feb;21:123-31). Further, functional analysis has shown that this mutation results in intact ATM protein expression but no kinase activity (Stewart GS et al. J. Biol. Chem. 2001 Aug;276:30133-41). Of note, this alteration is also designated as 7636del9, 2546delSRI, 7638del9 and 7638_7646del9 in published literature. Based on the available evidence, this alteration is interpreted as a disease-causing mutation. -

Apr 29, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 24, 2022

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 27, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an in-frame deletion of 3 amino acids in the ATM protein. This variant is also known as 7636del9, 7637del9 and delSRI in the literature. Functional studies have reported the mutant protein to show a severely defective kinase activity (PMID: 11382771, 19431188, 21778326, 22649200). This variant has been reported in over ten heterozygous individuals affected with breast cancer (PMID: 9288106, 16652348, 21787400; Color internal data) and pancreatic cancer (PMID: 33439686; Color internal data). This variant has been observed in homozygous and compound heterozygous states in over a dozen individuals affected with autosomal recessive ataxia-telangiectasia, indicating that this variant contributes to disease (PMID: 7792600, 8755918, 8845835, 8808599, 9443866, 9463314, 10817650). This variant is reported to be a founder mutation in individuals of Irish and British ancestry (PMID: 9443866, 9463314). This variant has been identified in 7/251148 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Familial cancer of breast Pathogenic:4

Mar 23, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2020

Department of Pediatrics, Memorial Sloan Kettering Cancer Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 31, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10817650]. Functional studies indicate this variant impacts protein function [PMID: 19431188]. -

Apr 03, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.7638_7646del (p.Arg2547_Ser2549del) has previously been reported in compound heterozygous and homozygous patients with ataxia telangiectasia [PMID 8808599]. Functional assays showed that the variant does not affect the level of ATM protein but does reduce the level of kinase activity [PMID 19431188]. A mouse model carrying this deletion has an increase susceptibility to develop tumors [reported as 7636del9 in PMID 12195425]. This variant was further detected in 12 out of 294 families with breast cancer. However, the difference in tumor incidence between carrier and non carrier was not statistically significant. However, this variant was detected in another patient with breast cancer [PMID 8797579]. This c.7638_7646del (p.Arg2547_Ser2549del) variant has not been observed the ExAC population database and has been observed in one individual in our internal database. It is thus interpreted as a likely pathogenic variant. -

Breast and/or ovarian cancer Pathogenic:1

Dec 07, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

T-cell prolymphocytic leukemia Pathogenic:1

Sep 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

ATM-related disorder Pathogenic:1

Jun 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.7638_7646del9 variant is predicted to result in an in-frame deletion (p.Arg2547_Ser2549del). This variant is also known in the literature as c.7636del9. This variant has been reported in patients with ataxia telangiectasia (Savitsky et al. 1995. PubMed ID: 7792600), prostate cancer (Supplemental Table 1 in Na et al. 2017. PubMed ID: 27989354), and breast cancer (Vorechovský et al. 1996. PubMed ID: 8797579; Chen et al. 1998. PubMed ID: 9537233; Lu et al. 2019. PubMed ID: 30128536, eTable 12; Goldgar et al. 2011. PubMed ID: 21787400). In vitro functional analysis showed that this variant had no kinase activity (Barone et al. 2009. PubMed ID: 19431188). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD and is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3019/). This variant is interpreted as pathogenic. -

Malignant tumor of breast Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM p.Arg2547_Ser2549del variant was identified in 14 of 6042 proband chromosomes (frequency: 0.002) from individuals or families with Ataxia-telangiectasia and breast cancer (Buzin 2003, Goldgar 2011, Li 2000, Reiman 2011). The variant was also identified in the following databases: dbSNP (ID: rs587776547) as "With Pathogenic allele", ClinVar (9x pathogenic, 1x uncertain significance), Clinvitae (5x pathogenic, 1x uncertain significance), Cosmic (1x, haematopoietic and lymphoid tumour), and the LOVD 3.0 (27x). The variant was not identified in the MutDB database. The variant was not identified in the 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). Multiple functional studies have shown the ATM protein lacks kinase activity and is expressed at low levels, confirming the pathogenicity of this variant (Barone 2009, Reiman 2011). This variant is an in-frame deletion resulting in the removal of three residues, from codon 2547 to 2549. 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. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Breast neoplasm Uncertain:1

Aug 01, 2016

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Found in a male patient having exome sequencing for an unrelated indication. No known personal or family history of breast cancer. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587776547; hg19: chr11-108202611;