Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001023344 | SCV001185207 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-12-23 | criteria provided, single submitter | clinical testing | The p.E166K variant (also known as c.496G>A), located in coding exon 4 of the ATM gene, results from a G to A substitution at nucleotide position 496. The amino acid change results in glutamic acid to lysine at codon 166, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is well conserved in available vertebrate species. This amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001056172 | SCV001220596 | uncertain significance | Ataxia-telangiectasia syndrome | 2024-01-03 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 166 of the ATM protein (p.Glu166Lys). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. 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: 825334). 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 tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Color Diagnostics, |
RCV001023344 | SCV001342203 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-17 | criteria provided, single submitter | clinical testing | This variant causes a G to A nucleotide substitution at the last nucleotide of exon 5 of the ATM gene and replaces glutamic acid with lysine at codon 166 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing, although a minigene splicing study has reported only a minor impact on splicing (PMID: 35716007). In a large international case-control study, this variant was reported in 2/60464 breast cancer cases and 0/53461 controls (OR=3.537, 95%CI 0.159 to 78.433, p-value=0.502; PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Natera, |
RCV001056172 | SCV002093963 | uncertain significance | Ataxia-telangiectasia syndrome | 2021-10-19 | no assertion criteria provided | clinical testing |