Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000167115 | SCV000217945 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-05-10 | criteria provided, single submitter | clinical testing | The p.A2386E variant (also known as c.7157C>A), located in coding exon 48 of the ATM gene, results from a C to A substitution at nucleotide position 7157. The alanine at codon 2386 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration was seen as homozygous in two Lebanese siblings with features of ataxia telangiectasia (A-T) and determined to have an “atypical” phenotype. In vitro studies using patient-derived cell lines showed reduced, but not absent, protein levels, reduced response to heat treatment suggesting protein instability, and levels of p53-MCL similar to what is observed for A-T heterozygous carriers (Biagiotti S et al. Front Genet, 2021 Oct;12:759467). This alteration was detected in a cohort of 36 patients with A-T in another patient with “atypical” phenotype. ATM protein levels were 40% of wild-type, and kinase activity was considered "intermediary" (Fiévet A et al. Hum Mutat, 2019 Oct;40:1713-1730). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Gene |
RCV000487239 | SCV000569677 | uncertain significance | not provided | 2016-03-21 | criteria provided, single submitter | clinical testing | This variant is denoted ATM c.7157C>A at the cDNA level, p.Ala2386Glu (A2386E) at the protein level, and results in the change of an Alanine to a Glutamic Acid (GCA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ala2386Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ala2386Glu occurs at a position that is conserved across species and is located in the FAT domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Ala2386Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Labcorp Genetics |
RCV000627922 | SCV000748806 | likely pathogenic | Ataxia-telangiectasia syndrome | 2023-12-02 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2386 of the ATM protein (p.Ala2386Glu). This variant is present in population databases (rs786203697, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 31050087, 34759960). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 187391). 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. Experimental studies have shown that this missense change affects ATM function (PMID: 31050087, 34759960). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |