rs587776547

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM4PP5_Very_Strong

The NM_000051.4(ATM):c.7638_7646del(p.Arg2547_Ser2549del) variant causes a 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 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23U:1

Conservation

PhyloP100: 3.51

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:

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]

C11orf65 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_000051.4

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/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.7638_7646del	p.Arg2547_Ser2549del	inframe_deletion	52/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.7638_7646del	p.Arg2547_Ser2549del	inframe_deletion	52/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

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:

AN:

251148

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135760

show subpopulations

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:

AN:

1461142

Hom.:

AF XY:

0.0000784

AC XY:

AN XY:

726924

show subpopulations

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:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74278

show subpopulations

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.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:7

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 23, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 27, 2017	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 05, 2018	- -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	Oct 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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 protein 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 26, 2016	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 29, 2021	- -

Hereditary cancer-predisposing syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Apr 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 29, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 27, 2023	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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 24, 2022	- -

Familial cancer of breast

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 23, 2023	- -
Pathogenic, criteria provided, single submitter	research	Department of Pediatrics, Memorial Sloan Kettering Cancer Center	Dec 15, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 31, 2024	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]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Apr 03, 2017	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

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 07, 2021

- -

T-cell prolymphocytic leukemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2002

- -

ATM-related condition

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2023

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

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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 laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Breast neoplasm

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Aug 01, 2016

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

Name

Calibrated prediction

Score

Prediction

Splicing

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