ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3328G>A (p.Ala1110Thr) (rs147112946)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165692 SCV000216430 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000470366 SCV000546858 uncertain significance Ataxia-telangiectasia syndrome 2018-10-10 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1110 of the ATM protein (p.Ala1110Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs147112946, ExAC 0.01%) but has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 186152). 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000165692 SCV000682118 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-09 criteria provided, single submitter clinical testing
Counsyl RCV000470366 SCV000791182 uncertain significance Ataxia-telangiectasia syndrome 2017-05-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763697 SCV000894577 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779805 SCV000916609 uncertain significance not specified 2018-12-14 criteria provided, single submitter clinical testing Variant summary: The variant, ATM c.3328G>A (p.Ala1110Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 276350 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant c.3328G>A has been reported in the literature in individuals affected with Chronic Lymphocytic Leukemia (CLL) (Tiao_2017). This report does not provide any conclusion about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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