ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2838+4A>G (rs876659907)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222111 SCV000276849 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000222111 SCV000687421 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779800 SCV000916604 uncertain significance not specified 2018-10-29 criteria provided, single submitter clinical testing Variant summary: ATM c.2838+4A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 5' donor site; while two predict the variant abolishes this 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 246006 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2838+4A>G in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001215325 SCV001387063 uncertain significance Ataxia-telangiectasia syndrome 2019-08-04 criteria provided, single submitter clinical testing This sequence change falls in intron 18 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 232661). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare intronic change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.

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