ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3665T>C (p.Leu1222Pro) (rs863224563)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197547 SCV000254089 uncertain significance Ataxia-telangiectasia syndrome 2018-12-08 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1222 of the ATM protein (p.Leu1222Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant was reported in an individual from the National Cancer Institute Breast Cancer Family Registry (PMID: 21787400). ClinVar contains an entry for this variant (Variation ID: 216203). 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.
Ambry Genetics RCV000220901 SCV000277988 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000780885 SCV000918514 uncertain significance not specified 2018-02-16 criteria provided, single submitter clinical testing Variant summary: ATM c.3665T>C (p.Leu1222Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant was absent in 120124 control chromosomes (ExAC). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.3665T>C, has been reported in the literature in individuals affected with Ataxia-Telangiectasia. These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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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