ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5618G>T (p.Cys1873Phe) (rs587782239)

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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 RCV000130940 SCV000185853 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000130940 SCV000913963 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing
GeneDx RCV000486615 SCV000570304 uncertain significance not provided 2018-11-12 criteria provided, single submitter clinical testing This variant is denoted ATM c.5618G>T at the cDNA level, p.Cys1873Phe (C1873F) at the protein level, and results in the change of a Cysteine to a Phenylalanine (TGT>TTT). This variant was observed in at least one individual with a glioblastoma and one individual with kidney cancer (Lu 2015, Yehia 2018). ATM Cys1873Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Cys1873Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000233487 SCV000282997 uncertain significance Ataxia-telangiectasia syndrome 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 1873 of the ATM protein (p.Cys1873Phe). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs587782239, ExAC 0.02%). This variant has been reported in an individual affected with glioblastoma multiforme (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 142107). 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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