ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3284+1G>A (rs864622129)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206819 SCV000259409 likely pathogenic Ataxia-telangiectasia syndrome 2018-06-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 22 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. ClinVar contains an entry for this variant (Variation ID: 219508). 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 RCV000220530 SCV000274367 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-20 criteria provided, single submitter clinical testing The c.3284+1G>A intronic variant results from a G to A one nucleotide after coding exon 21 of the ATM gene. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice 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.
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.

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