ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2839-579_2839-576del

dbSNP: rs587776552
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000003184 SCV000796746 likely pathogenic Ataxia-telangiectasia syndrome 2017-12-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV001016574 SCV001177540 pathogenic Hereditary cancer-predisposing syndrome 2022-09-22 criteria provided, single submitter clinical testing The c.2839-579_2839-576delAAGT intronic pathogenic mutation, located in intron 17 of the ATM gene, results from a deletion of 4 nucleotides within intron 17 of the ATM gene. This variant has been identified in multiple patients with Ataxia Telangiectasia in a compound heterozygous state with other pathogenic ATM variants; cell lines derived from these patients showed radiosensitivity and low or no detectable ATM protein (Mitui M et al. Hum. Mutat., 2003 Jul;22:43-50; Eng L et al. Hum. Mutat., 2004 Jan;23:67-76; Pagani F et al. Nat. Genet., 2002 Apr;30:426-9; Pastor T et al. Nucleic Acids Res., 2009 Nov;37:7258-67). This variant results in the inclusion of 65 nucleotides of intron 17 leading to a predicted frameshift and premature termination codon (Pagani F et al. Nat. Genet., 2002 Apr;30:426-9; Eng L et al. Hum. Mutat., 2004 Jan;23:67-76). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp RCV000003184 SCV001234323 pathogenic Ataxia-telangiectasia syndrome 2024-01-31 criteria provided, single submitter clinical testing This sequence change falls in intron 18 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with ataxia-telangiectasia (PMID: 11889466, 14695534; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as a deletion of 4 bp (GTAA) in intron 20, IVS20+1874delGTAA, and IVS20-579delAAGT. ClinVar contains an entry for this variant (Variation ID: 3043). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 11889466, 14695534, 19773425; Invitae). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001557139 SCV001778845 pathogenic not provided 2023-08-25 criteria provided, single submitter clinical testing Non-canonical splice site variant demonstrated to result in loss-of-function (Pagani et al., 2002; Kim et al., 2023); No data available from control populations to assess the frequency of this variant; Also known as IVS20-579delAAGT or IVS20-579_IVS20-576delAAGT; This variant is associated with the following publications: (PMID: 19823873, 19773425, 14695534, 31611883, 11889466, 22213089, 12815592, 37438524)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000003184 SCV002500162 pathogenic Ataxia-telangiectasia syndrome 2022-03-01 criteria provided, single submitter clinical testing Variant summary: ATM c.2839-579_2839-576delAAGT is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: two predict the variant weakens a cryptic 5 prime donor site; two predict the variant abolishes a 5 prime splicing donor site. However, at least one publication reports experimental evidence that this variant affects mRNA splicing. The variant was absent in 152078 control chromosomes. c.2839-579_2839-576delAAGT has been reported in the literature in individuals affected with Ataxia-Telangiectasia. These data indicate that the variant may be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sema4, Sema4 RCV001016574 SCV002532885 likely pathogenic Hereditary cancer-predisposing syndrome 2021-06-27 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV003137487 SCV003806576 likely pathogenic Familial cancer of breast 2023-01-11 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11889466, 12815592, 14695534, 22213089]. Functional studies indicate this variant impacts protein function [PMID: 11889466].
Baylor Genetics RCV003137487 SCV004210079 pathogenic Familial cancer of breast 2024-03-14 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001016574 SCV004361578 pathogenic Hereditary cancer-predisposing syndrome 2023-11-07 criteria provided, single submitter clinical testing This variant causes a 4 base-pair deletion in intron 18 of the ATM gene and is described in the literature as 'a deletion of 4 bp (GTAA) in intron 20' (numbering based on the U33841 transcript) and 'IVS20-579del-AAGT'. RNA studies have shown that this variant disrupts a non-canonical U1 small nuclear ribonucleoprotein binding site resulting in the insertion of a 65 base-pair cryptic exon, which is predicted to cause a frameshift and premature stop codon (PMID: 11889466, 12815592, 14695534, 19773425). An allele-specific RT-PCR assay using cells from a carrier individual has shown that the mutant allele does not produce normal transcript (PMID: 11889466). This variant has been reported in the compound heterozygous state in individuals affected with ataxia telangiectasia (PMID: 11889466, 12815592, 14695534, 22213089). Lymphoblastoid cell lines derived from two of these individuals showed radiosensitivity and a significant reduction in protein expression (PMID: 14695534). This variant has not been identified 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000003184 SCV005044894 pathogenic Ataxia-telangiectasia syndrome 2024-05-21 criteria provided, single submitter clinical testing
OMIM RCV000003184 SCV000023342 pathogenic Ataxia-telangiectasia syndrome 2004-01-01 no assertion criteria provided literature only

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