Submissions for variant NM_000051.4(ATM):c.5497-1G>A

dbSNP: rs876660245

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220437	SCV000277507	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-09-20	criteria provided, single submitter	clinical testing	The c.5497-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 36 of the ATM gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6499 samples (12998 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 180000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in available vertebrate species. This splice prediction software predicts that this alteration will abolish the native splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
GeneDx	RCV000254723	SCV000322555	likely pathogenic	not provided	2016-04-18	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.5497-1G>A or IVS36-1G>A and consists of a G>A nucleotide substitutionat the -1 position of intron 36 of the ATM gene. This variant destroys a canonical splice acceptor site and is predictedto cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNAdecay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature.Based on the currently available information, we consider ATM c.5497-1G>A to be a likely pathogenic variant.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000254723	SCV001447199	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853622	SCV002282270	pathogenic	Ataxia-telangiectasia syndrome	2022-10-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 10330348, 31843900; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 233182). Disruption of this splice site has been observed in individual(s) with ataxia telangiectasia (PMID: 30772474). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 36 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
Baylor Genetics	RCV003469067	SCV004210166	pathogenic	Familial cancer of breast	2023-07-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220437	SCV004361747	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the -1 position of intron 36 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been observed in individuals affected with autosomal recessive ataxia telangiectasia (PMID: 30772474), indicating that this variant contributes to disease. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice donor site, c.5497-2A>C and c.5497-2A>G, are known to be disease-causing (ClinVar Variation ID: 449345, 187521). Loss of ATM function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV003469067	SCV004932040	likely pathogenic	Familial cancer of breast	2024-01-25	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.