ClinVar Miner

Submissions for variant NM_001351834.2(ATM):c.4397_4398delinsCG (p.Arg1466Pro) (rs886038217)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000242236 SCV000301669 uncertain significance not specified criteria provided, single submitter clinical testing
Ambry Genetics RCV000494153 SCV000581436 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-05 criteria provided, single submitter clinical testing The c.4397_4398delGAinsCG variant, also known as p.R1466P, located in coding exon 28 of the ATM gene, results from an in-frame deletion of GA and insertion of CG at nucleotide positions 4397 to 4398. This results in the substitution of the arginine residue for a proline residue at codon 1466, an amino acid with dissimilar properties. This variant has been detected in trans with a pathogenic mutation in ATM in an individual with a clinical diagnosis of ataxia-telangiectasia (Ambry internal data). Based on internal structural assessment, this alteration likely disrupts a helix of the HEAT repeat region, where a similar pathogenic alteration is established (Drozdetskiy A et al. Nucleic Acids Res. 2015 Jul;43:W389-94; Perry J et al. Cell. 2003 Jan;112:151-5; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000628135 SCV000749028 uncertain significance Ataxia-telangiectasia syndrome 2017-12-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 1466 of the ATM protein (p.Arg1466Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 254753). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class 15"). 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.
Color Health, Inc RCV000494153 SCV001354414 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-26 criteria provided, single submitter clinical testing This missense variant replaces arginine with proline at codon 1466 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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