ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5189G>T (p.Arg1730Leu) (rs373789346)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000580727 SCV000682255 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
Invitae RCV000463817 SCV000546731 uncertain significance Ataxia-telangiectasia syndrome 2018-08-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 1730 of the ATM protein (p.Arg1730Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with late onset ataxia and breast cancer. That individual also carried a second variant in ATM, c.8585del87, which results in an in-frame deletion of exon 59. It is not clear if these variants were in the same or different chromosomes (PMID: 22071889). ClinVar contains an entry for this variant (Variation ID: 407496). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). An experimental study has shown that a patient-derived lymphoblastoid cell line carrying this variant and an in-frame deletion of exon 59 of the ATM gene, have reduced expression and abnormal localization of the ATM protein, as well as, increased radiosensitivity (PMID: 22071889). 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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