Submissions for variant NM_000051.4(ATM):c.3284+1G>A

dbSNP: rs864622129

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206819	SCV000259409	likely pathogenic	Ataxia-telangiectasia syndrome	2022-12-29	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 219508). This variant is also known as IVS25+1G>A. Disruption of this splice site has been observed in individual(s) with autosomal recessive ataxia-telangiectasia (A-T) (PMID: 21665257). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 22 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).
Ambry Genetics	RCV000220530	SCV000274367	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-11-22	criteria provided, single submitter	clinical testing	The c.3284+1G>A intronic variant results from a G to A substitution of one nucleotide after coding exon 21 of the ATM gene. In one study, this variant was reported in 3/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was identified homozygous in an individual with autosomal recessive ataxia-telangiectasia (Micol R et al. J Allergy Clin Immunol, 2011 Aug;128:382-9.e1). Of note, this alteration is also designated as "IVS25+1G>A" in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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). 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.
GeneDx	RCV000235974	SCV000293995	likely pathogenic	not provided	2018-05-18	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.3284+1G>A or IVS22+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 22 of the ATM gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. Based on the current evidence, we consider ATM 3284+1G>A to be a likely pathogenic variant.
Counsyl	RCV000206819	SCV000487177	likely pathogenic	Ataxia-telangiectasia syndrome	2016-10-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000206819	SCV000918554	likely pathogenic	Ataxia-telangiectasia syndrome	2021-03-04	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3284+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251026 control chromosomes (gnomAD). c.3284+1G>A has been reported in the literature in one homozygous individual affected with Ataxia-Telangiectasia (Micol_2011). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV004020504	SCV004930493	likely pathogenic	Familial cancer of breast	2024-01-19	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.