Submissions for variant NM_000051.4(ATM):c.7638_7646del (p.Arg2547_Ser2549del)

dbSNP: rs587776547

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000185637	SCV000186502	pathogenic	Hereditary cancer-predisposing syndrome	2024-08-08	criteria provided, single submitter	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.
GeneDx	RCV000212075	SCV000209607	pathogenic	not provided	2023-03-07	criteria provided, single submitter	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206671	SCV000262210	pathogenic	Ataxia-telangiectasia syndrome	2025-02-03	criteria provided, single submitter	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.
Eurofins Ntd Llc (ga)	RCV000212075	SCV000331662	pathogenic	not provided	2016-08-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000206671	SCV000487009	pathogenic	Ataxia-telangiectasia syndrome	2016-09-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000185637	SCV000682427	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709706	SCV000839880	likely pathogenic	Familial cancer of breast	2017-04-03	criteria provided, single submitter	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000206671	SCV000916557	pathogenic	Ataxia-telangiectasia syndrome	2017-10-27	criteria provided, single submitter	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.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV000709706	SCV001478108	pathogenic	Familial cancer of breast	2020-12-15	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000212075	SCV001961311	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001797988	SCV002042923	pathogenic	Breast and/or ovarian cancer	2021-12-07	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000212075	SCV002502830	likely pathogenic	not provided	2021-12-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000185637	SCV002538126	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-29	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV000206671	SCV002556947	pathogenic	Ataxia-telangiectasia syndrome	2021-09-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000709706	SCV004204412	pathogenic	Familial cancer of breast	2024-03-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000709706	SCV004932506	likely pathogenic	Familial cancer of breast	2024-01-31	criteria provided, single submitter	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].
Mayo Clinic Laboratories, Mayo Clinic	RCV000212075	SCV005414008	pathogenic	not provided	2023-12-13	criteria provided, single submitter	clinical testing	PP4, PM2_moderate, PM3_strong, PM4, PS3
Athena Diagnostics	RCV000212075	SCV005620742	pathogenic	not provided	2024-11-08	criteria provided, single submitter	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
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000206671	SCV005689224	pathogenic	Ataxia-telangiectasia syndrome	2025-02-05	criteria provided, single submitter	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000709706	SCV005911813	pathogenic	Familial cancer of breast	2017-10-04	criteria provided, single submitter	clinical testing
OMIM	RCV000206671	SCV000023313	pathogenic	Ataxia-telangiectasia syndrome	1995-06-23	no assertion criteria provided	literature only
OMIM	RCV000003163	SCV000023321	pathogenic	T-cell prolymphocytic leukemia	2002-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000206671	SCV000328309	pathogenic	Ataxia-telangiectasia syndrome	2016-10-27	no assertion criteria provided	literature only
CSER _CC_NCGL, University of Washington	RCV000417362	SCV000503545	uncertain significance	Breast neoplasm	2016-08-01	no assertion criteria provided	research	Found in a male patient having exome sequencing for an unrelated indication. No known personal or family history of breast cancer.
PreventionGenetics, part of Exact Sciences	RCV004547454	SCV000805616	pathogenic	ATM-related disorder	2024-06-17	no assertion criteria provided	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355331	SCV001550193	pathogenic	Malignant tumor of breast		no assertion criteria provided	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.
Natera, Inc.	RCV000206671	SCV002080799	pathogenic	Ataxia-telangiectasia syndrome	2018-01-05	no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000185637	SCV002506605	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-01-24	no assertion criteria provided	clinical testing