Submissions for variant NM_000051.4(ATM):c.8152-1G>A

dbSNP: rs1398616877

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523454	SCV000620518	likely pathogenic	not provided	2021-07-07	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion that disrupts the critical kinase domain (Stracker 2013); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31130284, 32552793, 15279808, 23532176, 27535533, 23807571, 25614872, 28975465, 27533158)
Ambry Genetics	RCV000574836	SCV000660743	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-24	criteria provided, single submitter	clinical testing	The c.8152-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 55 of the ATM gene. This alteration has been observed in an individual with breast cancer (Siraj AK et al. Hum Genet, 2017 11;136:1431-1444). This variant has been reported in a homozygous state in an individual with dystonia, microcephaly, speech delay, fine and gross motor delay, but without ataxia and telangiectasia (Monies D et al. Am J Hum Genet, 2019 Jun;104:1182-1201). 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. As such, this alteration is classified as likely pathogenic.
Invitae	RCV001060841	SCV001225555	pathogenic	Ataxia-telangiectasia syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 55 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (no rsID available, gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of ATM-related conditions (PMID: 28975465, 31130284). ClinVar contains an entry for this variant (Variation ID: 451773). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the ATM protein in which other variant(s) (p.Gln2730Pro) have been determined to be pathogenic (PMID: 16189143, 19431188, 22869595). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001060841	SCV001520234	pathogenic	Ataxia-telangiectasia syndrome	2020-01-13	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Baylor Genetics	RCV003470658	SCV004212167	pathogenic	Familial cancer of breast	2022-11-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001060841	SCV004801165	pathogenic	Ataxia-telangiectasia syndrome	2024-03-14	criteria provided, single submitter	research
Myriad Genetics, Inc.	RCV003470658	SCV004931253	likely pathogenic	Familial cancer of breast	2024-02-01	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.
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV001060841	SCV003927869	pathogenic	Ataxia-telangiectasia syndrome	2023-04-01	no assertion criteria provided	clinical testing