ClinVar Miner

Submissions for variant NM_005591.4(MRE11):c.350A>G (p.Asn117Ser) (rs137852760)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212557 SCV000149826 uncertain significance not provided 2014-02-09 criteria provided, single submitter clinical testing MRE11A has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted MRE11A c.350A>G at the cDNA level, p.Asn117Ser (N117S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant was observed in two brothers with the recessively-inherited ataxia-telangiectasia-like disorder; however, functional studies revealed that the variant creates a full-length MRE11 protein and exhibits only a subtle effect on binding with the Nbs1 protein and no effect on binding with the RAD50 protein, thereby maintaining cell viability (Stewart 1999). This variant has not been reported in association with cancer to our knowledge, and it has been suggested that cancer predisposition may be due to mutations in MRE11A that cause major structure abnormalities rather than subtle effects on the MRE11A-RAD50-NBN complex stability (Regal 2013). MRE11A Asn117Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a conservative substitution of one neutral polar amino acid for another, altering a position that is highly conserved throughout evolution and is located in within the nuclease domain (Stracker 2011). Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the MRE11A gene, remain unclear.
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 2020-03-10 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 117 of the MRE11 protein (p.Asn117Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs137852760, ExAC 0.002%). This variant has been reported to segregate with an ataxia-telangiectasia-like disorder in one family, being observed on the opposite chromosome (in trans) from a pathogenic variant in two affected siblings (PMID: 10612394, 11371508). It has also been found in combination with a rare variant in the MRE11 gene in an unrelated individual affected with an ataxia-telangiectasia-like disorder, however the phase was unknown (PMID: 24030952). These findings are consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 8783). Experimental studies have shown that this missense change reduces the protein-to-protein interaction Mre11 with Nbs1, affecting its mitotic repair functions (PMID: 10612394, 22705791, 23080121). 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000009328 SCV000965779 pathogenic Ataxia-telangiectasia-like disorder 1 2016-01-04 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212557 SCV001248582 likely pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000009328 SCV001477512 likely pathogenic Ataxia-telangiectasia-like disorder 1 2020-08-07 criteria provided, single submitter clinical testing
OMIM RCV000009328 SCV000029546 pathogenic Ataxia-telangiectasia-like disorder 1 2001-05-15 no assertion criteria provided literature only

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