Submissions for variant NM_000051.4(ATM):c.2838+1G>A

dbSNP: rs1555083469

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002009248	SCV002288036	likely pathogenic	Ataxia-telangiectasia syndrome	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 18 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 12552559, 32531373). This variant is also known as IVS18+1G>A. ClinVar contains an entry for this variant (Variation ID: 1506993). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV002441201	SCV002748459	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-17	criteria provided, single submitter	clinical testing	The c.2838+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 17 of the ATM gene. This variant has been detected in conjunction with a ATM pathogenic variant in an individual diagnosed with ataxia telangiectasia (A-T); however, the phase of the two variants was not specified (Buzin CH et al. Hum Mutat, 2003 Feb;21:123-31). This variant has been identified in the homozygous state in an individual with clinical features of A-T (Fusaro M et al. J Allergy Clin Immunol, 2021 02;147:734-737). 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 or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV004046194	SCV004932479	likely pathogenic	Familial cancer of breast	2024-01-18	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.