ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1352G>A (p.Arg451His) (rs554805703)

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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 RCV000566799 SCV000660530 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000566799 SCV000904441 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-30 criteria provided, single submitter clinical testing
GeneDx RCV000481180 SCV000568038 uncertain significance not provided 2017-09-07 criteria provided, single submitter clinical testing This variant is denoted ATM c.1352G>A at the cDNA level, p.Arg451His (R451H) 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 being pathogenic or benign. ATM Arg451His was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. ATM Arg451His occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Arg451His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000463733 SCV000547043 uncertain significance Ataxia-telangiectasia syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 451 of the ATM protein (p.Arg451His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs554805703, ExAC 0.02%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 407670). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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