ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs137852760
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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 2021-08-31 criteria provided, single submitter clinical testing
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 Center for Human Genetics Tuebingen RCV000212557 SCV001248582 likely pathogenic not provided 2021-11-01 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
PerkinElmer Genomics RCV000009328 SCV002023517 likely pathogenic Ataxia-telangiectasia-like disorder 1 2019-05-17 no assertion criteria provided clinical testing

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