Submissions for variant NM_000051.4(ATM):c.8148_8151+2del

dbSNP: rs1565541335

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704009	SCV000832942	likely pathogenic	Ataxia-telangiectasia syndrome	2018-04-24	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 55 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. 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. 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). 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.
Ambry Genetics	RCV002422588	SCV002681750	likely pathogenic	Hereditary cancer-predisposing syndrome	2017-03-31	criteria provided, single submitter	clinical testing	The c.8148_8151+2delTAAGGT variant results from a deletion of six nucleotides at the splice junction boundary of coding exon 54 and intron 54 of the ATM gene. The deleted nucleotide region is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor 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.	RCV003453493	SCV004186554	likely pathogenic	Familial cancer of breast	2023-09-26	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.