ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7156G>C (p.Ala2386Pro) (rs876659392)

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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 RCV000220079 SCV000275801 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000220079 SCV000682391 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
GeneDx RCV000477984 SCV000569975 uncertain significance not provided 2018-10-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.7156G>C at the cDNA level, p.Ala2386Pro (A2386P) at the protein level, and results in the change of an Alanine to a Proline (GCA>CCA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM Ala2386Pro 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 Ala2386Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000557855 SCV000622715 uncertain significance Ataxia-telangiectasia syndrome 2017-11-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 2386 of the ATM protein (p.Ala2386Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 231834). 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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