ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7570G>C (p.Ala2524Pro) (rs769142993)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167357 SCV000218209 likely pathogenic Hereditary cancer-predisposing syndrome 2017-09-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000550379 SCV000622760 likely pathogenic Ataxia-telangiectasia syndrome 2017-04-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 2524 of the ATM protein (p.Ala2524Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs769142993, ExAC 0.05%). This variant has been reported in individuals and families affected with breast cancer (PMID: 16914028, 17166884, 11897822). It has also been reported in 3 individuals affected with ataxia-telangiectasia (A-T) (PMID: 11897822, 10980530, 22071889). In two of the A-T affected individuals this variant occurred with a different pathogenic variant in ATM, while the third individual was homozygous for this variant. This variant is also referred to as 7522G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 187613) Experimental studies in patient-derived lymphoblast cell lines have shown that this missense change results in the production of a stable ATM protein that demonstrates normal localization to the nucleus. However, the protein is expressed at significantly reduced levels, and has defective kinase activity (PMID: 17166884, 22071889). In summary, this variant is a rare missense change that disrupts ATM kinase activity and has been described in individuals and families affected with ataxia-telangiectasia and breast cancer. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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