ATM NM_000051.3:c.4397_4398delinsCG, Arg1466Pro

The c.4397_4398delGAinsCG pathogenic mutation (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 (A-T) (Ambry internal data). In addition, an alteration resulting in the same protein change, c.4397G>C, has been identified in conjunction with a pathogenic ATM mutation in a cohort of individuals from the UK diagnosed with A-T (Jackson TJ et al. Dev Med Child Neurol. 2016 07;58:690-7). This alteration is located in the HEAT domain of the ATM protein and based on internal structural assessment, it is more disruptive than nearby known pathogenic variants (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. In addition, this alteration is predicted to be deleterious by in silico analysis and is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1466 of the ATM protein (p.Arg1466Pro). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 26896183). ClinVar contains an entry for this variant (Variation ID: 254753). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.