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

dbSNP: rs587776552

Total submissions: 10

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.
Invitae	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	2023-08-05	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.
OMIM	RCV000003184	SCV000023342	pathogenic	Ataxia-telangiectasia syndrome	2004-01-01	no assertion criteria provided	literature only