ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8716G>A (p.Val2906Ile) (rs587780643)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000573392 SCV000660468 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000779782 SCV000916573 uncertain significance not specified 2018-04-13 criteria provided, single submitter clinical testing Variant summary: ATM c.8716G>A (p.Val2906Ile) results in a conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 246234 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4.1e-05 vs 0.004), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.8716G>A in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000122890 SCV000166148 uncertain significance Ataxia-telangiectasia syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2906 of the ATM protein (p.Val2906Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs587780643, ExAC 0.03%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 135784). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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