Submissions for variant NM_000051.4(ATM):c.1066-2A>T

dbSNP: rs1555069514

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523800	SCV000619247	likely pathogenic	not provided	2017-07-13	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.1066-2A>T or IVS8-2A>T and consists of an A>T nucleotide substitutionat the -2 position of intron 8 of the ATM gene. This variant destroys a canonical splice acceptor site and is predicted tocause 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.1066-2A>T to be a likely pathogenic variant
Color Diagnostics, LLC DBA Color Health	RCV000777178	SCV000912869	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-04-23	criteria provided, single submitter	clinical testing	This variant causes an A to T nucleotide substitution at the -2 position of intron 8 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 not been reported in individuals affected with hereditary cancer 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201887	SCV001372978	likely pathogenic	Ataxia-telangiectasia syndrome	2019-08-23	criteria provided, single submitter	clinical testing	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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 450641). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 8 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Ambry Genetics	RCV000777178	SCV002722332	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-09-10	criteria provided, single submitter	clinical testing	The c.1066-2A>T intronic variant results from an A to T substitution two nucleotides upstream from coding exon 8 in the ATM gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. 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.
Myriad Genetics, Inc.	RCV004023577	SCV004930676	likely pathogenic	Familial cancer of breast	2024-01-12	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.