Submissions for variant NM_000051.4(ATM):c.1803-2A>G

dbSNP: rs1057517358

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411840	SCV000487159	likely pathogenic	Ataxia-telangiectasia syndrome	2016-10-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411840	SCV000947487	likely pathogenic	Ataxia-telangiectasia syndrome	2022-06-26	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with ATM-related conditions. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 371548). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 11 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.
Ambry Genetics	RCV002411275	SCV002710828	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	The c.1803-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 11 in the ATM gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001573871	SCV004027163	likely pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003475972	SCV004212272	likely pathogenic	Familial cancer of breast	2024-01-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV002411275	SCV004359775	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-01	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 11 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing via activation of a cryptic acceptor site. Although this prediction has not been confirmed in published RNA studies in the literature, this variant is expected to result in an absent or disrupted protein product. Abnormal RNA splicing has been reported in testing done by other laboratories (ClinVar: SCV002710828.2, SCV000947487.5). This variant has not been reported in individuals affected with ATM-related disorders in the literature. 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 Likely Pathogenic.
Myriad Genetics, Inc.	RCV003475972	SCV004933306	likely pathogenic	Familial cancer of breast	2024-01-16	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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573871	SCV001800355	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001573871	SCV001929507	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001573871	SCV001958364	likely pathogenic	not provided		no assertion criteria provided	clinical testing