ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6293T>C (p.Leu2098Pro) (rs587780631)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165084 SCV000215788 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000165084 SCV000682321 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-01 criteria provided, single submitter clinical testing
Counsyl RCV000122870 SCV000795557 uncertain significance Ataxia-telangiectasia syndrome 2017-11-09 criteria provided, single submitter clinical testing
GeneDx RCV000235401 SCV000292826 uncertain significance not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted ATM c.6293T>C at the cDNA level, p.Leu2098Pro (L2098P) at the protein level, and results in the change of a Leucine to a Proline (CTT>CCT). In two case-control studies, this variant was observed in a control individual, and was not observed in breast cancer or CLL cases, respectively (Decker 2017, Tiao 2017). ATM Leu2098Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Leu2098Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000122870 SCV000166128 uncertain significance Ataxia-telangiectasia syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 2098 of the ATM protein (p.Leu2098Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs587780631, ExAC 0.001%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 135766). 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 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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