ClinVar Miner

Submissions for variant NM_001351834.2(ATM):c.5763-1050A>G (rs774925473)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229886 SCV000282999 pathogenic Ataxia-telangiectasia syndrome 2019-12-18 criteria provided, single submitter clinical testing This sequence change falls in intron 38 of the ATM mRNA. It does not directly change the encoded amino acid sequence of the ATM protein. This variant is not present in population databases (rs774925473, ExAC no frequency). This variant has been reported in several individuals affected with atypical ataxia-telangiectasia (characterized by later disease onset and/or slower disease progression and attenuated disease features than classical ataxia-telangiectasia) (PMID: 8755918, 21792198, 10330348, 8808599). Notably, one individual carried this variant in trans with a second pathogenic variant, c.9139C>T (p.Arg3047*), and two affected brothers have been reported to be homozygous for this variant (PMID: 10234507, 15174027). This variant is also known as 5762ins137, the 4-1-8 variant, IVS40-1050A>G, IVS40+1126A>G, IVS40ins137, and 5763ins130 in the literature. ClinVar contains an entry for this variant (Variation ID: 3021). Experimental studies have shown that this intronic change results in the insertion of part of intron 38 in between exons 38 and 39, resulting in a frameshift (PMID: 8755918, 19823873). However, this variant is described as a "leaky splice site mutation", as only a portion of the transcripts from this allele contain this insertion, as shown by cDNA sequencing (PMID: 8755918). The remaining transcripts expressed from this allele result in low-level expression of ATM protein with near wild-type levels of kinase activity (PMID: 11382771, 25040471). These results may explain the atypical disease associated with this variant. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000229886 SCV000485197 pathogenic Ataxia-telangiectasia syndrome 2016-01-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000494077 SCV000581456 pathogenic Hereditary cancer-predisposing syndrome 2019-06-20 criteria provided, single submitter clinical testing Functionally-validated splicing mutation;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other strong data supporting pathogenic classification
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724150 SCV000700719 pathogenic not provided 2016-12-12 criteria provided, single submitter clinical testing
Color RCV000494077 SCV000902857 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-17 criteria provided, single submitter clinical testing
OMIM RCV000003157 SCV000023315 pathogenic Ataxia-telangiectasia variant 2004-06-01 no assertion criteria provided literature only
GeneReviews RCV000229886 SCV000328266 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only

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