Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001027369 | SCV001189912 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-09-11 | criteria provided, single submitter | clinical testing | The p.G2765V variant (also known as c.8294G>T), located in coding exon 56 of the ATM gene, results from a G to T substitution at nucleotide position 8294. The glycine at codon 2765 is replaced by valine, an amino acid with dissimilar properties. Another alteration at the same codon, p.G2765S (c.8293G>A), has been reported in several patients with a clinical diagnosis of ataxia-telangiectasia, including a woman with ataxia-telangiectasia and breast cancer diagnosed under the age of 50 (Reiman A et al. Br. J. Cancer. 2011 Aug; 105(4):586-91; Taylor AM et al. Clin. Genet. 2014 Jul; 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV001862405 | SCV002119748 | likely pathogenic | Ataxia-telangiectasia syndrome | 2023-11-24 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2765 of the ATM protein (p.Gly2765Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 827559). 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. This variant disrupts the p.Gly2765 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10534763, 19431188, 19781682, 21792198). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |