ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3137T>C (p.Leu1046Pro) (rs568461905)

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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 RCV000166173 SCV000216948 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000166173 SCV000913918 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-11 criteria provided, single submitter clinical testing
Counsyl RCV000667954 SCV000792486 uncertain significance Ataxia-telangiectasia syndrome 2017-06-26 criteria provided, single submitter clinical testing
Invitae RCV000667954 SCV000823337 uncertain significance Ataxia-telangiectasia syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1046 of the ATM protein (p.Leu1046Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual with ataxia-telangiectasia (PMID: 27664052). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 186558). Experimental studies have shown that cell lines from an individual bearing this variant, along with a predicted loss of function variant in ATM, lacked protein expression of ATM and showed increased radiosensitivity relative to controls (PMID: 27664052). 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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