ATM NM_000051.3:c.8161G>A, Asp2721Asn

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2721 of the ATM protein (p.Asp2721Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia telangiectasia and/or clinical features of ataxia-telangiectasia (PMID: 21665257, 25122203, 29906526). ClinVar contains an entry for this variant (Variation ID: 1054111). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ATM protein function with a positive predictive value of 95%. 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.

The p.D2721N variant (also known as c.8161G>A), located in coding exon 55 of the ATM gene, results from a G to A substitution at nucleotide position 8161. The aspartic acid at codon 2721 is replaced by asparagine, an amino acid with highly similar properties. This variant has been identified in the homozygous state and/or in conjunction with other ATM variant(s) in individual(s) who met clinical criteria for ataxia telangiectasia (Méneret A et al. Neurology, 2014 Sep;83:1087-95). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.