ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.1564_1565del (p.Glu522fs)

dbSNP: rs587779817
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Total submissions: 39
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211964 SCV000149053 pathogenic not provided 2022-03-01 criteria provided, single submitter 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; 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)
Ambry Genetics RCV000115144 SCV000185620 pathogenic Hereditary cancer-predisposing syndrome 2024-10-23 criteria provided, single submitter clinical testing 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000169147 SCV000219160 pathogenic Ataxia-telangiectasia syndrome 2024-01-21 criteria provided, single submitter clinical testing 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.
Counsyl RCV000169147 SCV000220368 pathogenic Ataxia-telangiectasia syndrome 2014-06-03 criteria provided, single submitter literature only
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000211964 SCV000610563 pathogenic not provided 2017-08-29 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115144 SCV000681982 pathogenic Hereditary cancer-predisposing syndrome 2024-01-08 criteria provided, single submitter 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 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.
GeneKor MSA RCV000115144 SCV000821698 pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing 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).
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709705 SCV000839878 pathogenic Familial cancer of breast 2017-01-30 criteria provided, single submitter clinical testing 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169147 SCV000918549 pathogenic Ataxia-telangiectasia syndrome 2018-07-09 criteria provided, single submitter clinical testing 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.
Athena Diagnostics RCV000211964 SCV001143097 pathogenic not provided 2020-11-18 criteria provided, single submitter clinical testing 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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000169147 SCV001150019 pathogenic Ataxia-telangiectasia syndrome 2019-02-21 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000211964 SCV001249798 pathogenic not provided 2024-05-01 criteria provided, single submitter clinical testing ATM: PM3:Very Strong, PVS1, PM2:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000709705 SCV001368645 pathogenic Familial cancer of breast 2022-12-09 criteria provided, single submitter research PVS1, PM3_VSTR
Institute of Human Genetics, University of Leipzig Medical Center RCV000709705 SCV001428899 pathogenic Familial cancer of breast 2023-05-30 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000709705 SCV001499655 pathogenic Familial cancer of breast 2020-04-02 criteria provided, single submitter clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group RCV000115144 SCV001911474 pathogenic Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing 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).
Revvity Omics, Revvity RCV000169147 SCV002020066 pathogenic Ataxia-telangiectasia syndrome 2019-06-11 criteria provided, single submitter clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino RCV002051809 SCV002319223 pathogenic Tip-toe gait 2022-03-15 criteria provided, single submitter clinical testing Gait disorder
Sema4, Sema4 RCV000115144 SCV002532727 pathogenic Hereditary cancer-predisposing syndrome 2021-09-10 criteria provided, single submitter curation
Genetics and Molecular Pathology, SA Pathology RCV000169147 SCV002556657 pathogenic Ataxia-telangiectasia syndrome 2022-03-30 criteria provided, single submitter clinical testing 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).
MGZ Medical Genetics Center RCV000709705 SCV002580051 pathogenic Familial cancer of breast 2022-05-23 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002477274 SCV002792624 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2024-03-07 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000211964 SCV004026334 pathogenic not provided 2023-04-12 criteria provided, single submitter clinical testing PVS1, PS4, PM2_SUP, PM3
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000211964 SCV004027153 pathogenic not provided 2024-07-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000709705 SCV004208319 pathogenic Familial cancer of breast 2024-03-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000211964 SCV004219985 pathogenic not provided 2024-08-17 criteria provided, single submitter clinical testing The ATM c.1564_1565del (p.Glu522Ilefs*43) variant alters the translational reading frame of the ATM mRNA and causes the premature termination of ATM protein synthesis. This variant has been reported in the published literature in individuals affected with ataxia-telangiectasia (PMIDs: 30772474 (2019), 21965147 (2011), 10817650 (2000), 10330348 (1999)) and breast cancer (PMIDs: 29785153 (2018), 26681312 (2015)). The frequency of this variant in the general population, 0.00011 (12/113526 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003492453 SCV004240325 pathogenic Breast and/or ovarian cancer 2022-09-28 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000709705 SCV004931069 pathogenic Familial cancer of breast 2024-01-17 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Clinical Genetics Laboratory, Skane University Hospital Lund RCV000211964 SCV005198479 pathogenic not provided 2024-03-04 criteria provided, single submitter clinical testing
GeneReviews RCV000169147 SCV000328297 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
Natera, Inc. RCV000169147 SCV001461007 pathogenic Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357511 SCV001553000 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000211964 SCV001741364 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000211964 SCV001808811 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute RCV000211964 SCV001905931 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000211964 SCV001969119 pathogenic not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000211964 SCV002036395 pathogenic not provided no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV002508921 SCV002818374 not provided Ataxia-telangiectasia syndrome; Hereditary cancer-predisposing syndrome no assertion provided phenotyping only 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.
PreventionGenetics, part of Exact Sciences RCV004549540 SCV004732468 pathogenic ATM-related disorder 2024-01-22 no assertion criteria provided clinical testing 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.

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