Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000212557 | SCV000149826 | likely pathogenic | not provided | 2021-05-03 | criteria provided, single submitter | clinical testing | Published functional studies suggest a damaging effect: impaired binding to Nbs1, reduced homologous recombination, reduced cell growth, abnormal nuclear localization, and decreased telomere length (Stewart et al., 1999; Lee et al., 2003; Limbo et al., 2012; Schiller et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22078559, 12966088, 14532133, 15279810, 22705791, 23080121, 24030952, 15279769, 10612394, 11371508, 27535533) |
Ambry Genetics | RCV000115917 | SCV000185772 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-08-17 | criteria provided, single submitter | clinical testing | The p.N117S variant (also known as c.350A>G), located in coding exon 4 of the MRE11A gene, results from an A to G substitution at nucleotide position 350. The asparagine at codon 117 is replaced by serine, an amino acid with highly similar properties. This variant was described in two siblings with ataxia-telangiectasia-like disorder (ATLD). Both siblings had features of ataxia-telangiectasia (A-T) and intermediate levels of radiosensitivity, but no detectable ATM mutations. Sequence analysis of cDNA combined with parental studies suggest p.N117S was in trans with a null mutation in the affected siblings (Stewart GS et al. Cell, 1999 Dec;99:577-87; Pitts SA et al. Hum. Mol. Genet., 2001 May;10:1155-62). This variant has also been reported in a child with progressive balance disorder after age 2 with dystonia and myoclonic jerks and marked atrophy of cerebellar vermis by age 12. This child was also found to carry a second MRE11A alteration, however the phase (cis or trans) of these two alterations was not determined (Németh AH et al. Brain, 2013 Oct;136:3106-18). Functional analyses of p.N117S in yeast have demonstrated growth inhibition, impaired homologous recombination, decreased telomere length, decreased MRE11 accumulation in the nucleus, and impaired Nbs1 interaction compared to wild type protein (Schiller CB et al. Nat. Struct. Mol. Biol., 2012 Jul;19:693-700; Limbo O et al. Nucleic Acids Res., 2012 Dec;40:11435-49; Park YB et al. Structure, 2011 Nov;19:1591-602). This amino acid position is highly conserved in available vertebrate species. 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 | RCV001034646 | SCV000642133 | likely pathogenic | Ataxia-telangiectasia-like disorder | 2023-04-19 | criteria provided, single submitter | clinical testing | 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. Experimental studies have shown that this missense change affects MRE11 function (PMID: 10612394, 22705791, 23080121). 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. ClinVar contains an entry for this variant (Variation ID: 8783). This missense change has been observed in individual(s) with ataxia-telangiectasia-like disorder and/or breast cancer (PMID: 10612394, 11371508, 24030952, 28715532, 32986223). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs137852760, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 117 of the MRE11 protein (p.Asn117Ser). |
Equipe Genetique des Anomalies du Developpement, |
RCV000009328 | SCV000965779 | pathogenic | Ataxia-telangiectasia-like disorder 1 | 2016-01-04 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000212557 | SCV001248582 | likely pathogenic | not provided | 2021-11-01 | criteria provided, single submitter | clinical testing | |
Molecular Diagnostics Laboratory, |
RCV000009328 | SCV001477512 | likely pathogenic | Ataxia-telangiectasia-like disorder 1 | 2020-08-07 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000009328 | SCV002023517 | likely pathogenic | Ataxia-telangiectasia-like disorder 1 | 2019-05-17 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000009328 | SCV004193776 | likely pathogenic | Ataxia-telangiectasia-like disorder 1 | 2023-10-19 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000009328 | SCV000029546 | pathogenic | Ataxia-telangiectasia-like disorder 1 | 2001-05-15 | no assertion criteria provided | literature only |