Submissions for variant NM_000051.4(ATM):c.2250+1G>A

dbSNP: rs1565395193

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000702192	SCV000831036	pathogenic	Ataxia-telangiectasia syndrome	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 14 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 579018). Studies have shown that disruption of this splice site results in skipping of exon 14, but is expected to preserve the integrity of the reading-frame (Invitae). Other variant(s) that result in skipping of exon 14 have been determined to be pathogenic (PMID: 9887333, 10330348; Invitae). This suggests that this variant may also be clinically significant and likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000702192	SCV004047449	likely pathogenic	Ataxia-telangiectasia syndrome		criteria provided, single submitter	clinical testing	The c.2250+1G>A splice donor variant in ATM gene has been reported to the ClinVar database as Likely pathogenic. This variant has not been reported in the literature in individuals with ATM-related disease. The c.2250+1G>A variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has Donor and acceptor splice site variants typically lead to a loss of protein function (Baralle D, Baralle M., 2005). Loss-of-function variants in ATM are known to be pathogenic (Podralska et al., 2014; Huang et al., 2013). For these reasons, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004547869	SCV004103061	pathogenic	ATM-related disorder	2023-09-19	criteria provided, single submitter	clinical testing	The ATM c.2250+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in patient cohort with pancreatic cancer (see supplementary table 5 in Mizukami et al 2020. PubMed ID: 32980694). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/579018/). Loss of function variants and variants that disrupt the consensus splice sites in ATM are expected to be pathogenic (Baralle et al 2005. PubMed ID: 16199547; Huang et al 2013. PubMed ID: 23807571; Podralska et al 2014. PubMed ID: 25614872). This variant is interpreted as pathogenic.
Myriad Genetics, Inc.	RCV004026586	SCV004930574	likely pathogenic	Familial cancer of breast	2024-01-17	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.
Ambry Genetics	RCV004669093	SCV005170037	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-05-13	criteria provided, single submitter	clinical testing	The c.2250+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 13 of 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 donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein. As such, this alteration is classified as likely pathogenic.