ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6347+1G>A (rs1057517120)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409839 SCV000486777 likely pathogenic Ataxia-telangiectasia syndrome 2016-08-04 criteria provided, single submitter clinical testing
Invitae RCV000409839 SCV000818964 pathogenic Ataxia-telangiectasia syndrome 2020-02-17 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 43 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 been observed in an individual affected with Ataxia-Telangiectasia (PMID: 10330348). ClinVar contains an entry for this variant (Variation ID: 371243). Experimental study has shown that this variant causes abnormal splicing which creates a transcript that is lacking of exon 43-45 and results in a frameshift protein (PMID: 10330348). 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). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV001180642 SCV001345609 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000409839 SCV001623206 pathogenic Ataxia-telangiectasia syndrome 2021-04-28 criteria provided, single submitter clinical testing Variant summary: ATM c.6347+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: Four predict the variant abolishes a 5 splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and resulted in the production of multiple incorrectly spliced transcripts identified in cDNA (Teraoka_1999). The variant allele was found at a frequency of 5.5e-05 in 36660 control chromosomes (gnomAD and publication data). c.6347+1G>A has been reported in the literature in one homozygous individual affected with Ataxia-Telangiectasia (Teraoka_1999). These data indicate that the variant may be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.

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