ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2354G>A (p.Arg785His) (rs587782128)

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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 RCV000130667 SCV000185553 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000130667 SCV000687377 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-05 criteria provided, single submitter clinical testing
GeneDx RCV000482225 SCV000566215 uncertain significance not provided 2018-03-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.2354G>A at the cDNA level, p.Arg785His (R785H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Arg785His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. ATM Arg785His occurs at a position that is not conserved and is not located in a known functional domain (Tavtigian 2009). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether ATM Arg785His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000167917 SCV000218565 uncertain significance Ataxia-telangiectasia syndrome 2018-12-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 785 of the ATM protein (p.Arg785His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs587782128, ExAC 0.003%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 141944). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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