Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mendelics | RCV000709182 | SCV000838545 | likely pathogenic | Ataxia-telangiectasia syndrome | 2025-02-05 | criteria provided, single submitter | clinical testing | The c.4775A>G variant leads to a replacement of amino acid glutamate with glycine, at codon 1592 of the ATM protein (p.Glu1592Gly). It has been previously reported in individuals with breast cancer (PMID: 33606809). In silico analysis predicts that this alteration will weaken the native splice donor site. ClinVar has two entries by two independent laboratories stating that their RNA studies have shown that this variant causes abnormal splicing. Other variants that disrupt at the same splice site have been shown to be pathogenic in homozygous or compound heterozygous state in multiple patients with ataxia-telangiectasia (PMID: 12815592, 9497252, 9600235, 9711876, 31050087, 20840352). Therefore the available evidence suggests that this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV000709182 | SCV001390516 | pathogenic | Ataxia-telangiectasia syndrome | 2023-10-30 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1592 of the ATM protein (p.Glu1592Gly). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 584790). 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. Studies have shown that this missense change results in skipping of 31, but is expected to preserve the integrity of the reading-frame (Invitae). Other variant(s) that result in skipping of exon 31 have been determined to be pathogenic (PMID: 2491181, 9497252, 9711876; Invitae). This suggests that this variant may also be clinically significant and likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV004026763 | SCV005017344 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-12-13 | criteria provided, single submitter | clinical testing | The c.4775A>G variant (also known as p.E1592G), located in coding exon 30 of the ATM gene, results from an A to G substitution at nucleotide position 4775. The glutamic acid at codon 1592 is replaced by glycine, an amino acid with similar properties. This variant was detected in a cohort of 224 unrelated Brazilian individuals with breast cancer (Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |