ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6198G>C (p.Gln2066His) (rs786203341)

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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 RCV000166609 SCV000217413 uncertain significance Hereditary cancer-predisposing syndrome 2014-10-28 criteria provided, single submitter clinical testing
GeneDx RCV000235567 SCV000293831 uncertain significance not provided 2016-01-18 criteria provided, single submitter clinical testing This variant is denoted ATM c.6198G>C at the cDNA level, p.Gln2066His (Q2066H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Gln2066His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Gln2066His occurs at a position that is not conserved and is located in the FAT domain (Stracker 2013, Uniprot). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may damage the nearby natural splice donor site and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether ATM Gln2066His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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