ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7462T>C (p.Cys2488Arg) (rs1555123216)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000529170 SCV000622750 uncertain significance Ataxia-telangiectasia syndrome 2017-02-25 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 2488 of the ATM protein (p.Cys2488Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant occurs with a pathogenic variant (p.His46Glnfs*9) in ATM in an individual with ataxia telangiectasia (PMID: 22071889). While it is unknown if these two variants are on the same or opposite chromosomes, this observation suggests the c.7462T>C substitution may contribute to the cause of disease. This variant has also been reported heterozygous in an individual affected with breast cancer (PMID: 19781682) and in an individual affected with chronic lymphocytic leukemia (PMID: 23585524). Experimental studies using lymphoblastoid cell lines from the individual affected with ataxia telangiectasia (PMID: 22071889) indicate these cells were defective in H2AX and KAP1 phosphorylation after exposure to ionizing radiation and showed significantly reduced levels of nuclear-localized ATM protein. Because p.His46Glnfs*9 is not expected to produce a protein product, these results suggest that the p.Cys2488Arg variant impairs ATM function. In summary, this variant is a rare missense change that shows impaired ATM function in a functional study. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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