ClinVar

Description

The inherited c.1090C>T, p.(Arg364Ter) variant identified in the MRE11 gene is a nonsense variant leading to the premature termination of the protein at amino acid 364/709 (exon 10/20), and is expected to undergo nonsense mediated decay. This variant occurs upstream of the Helix-Loop-Helix and GAR domains of MRE11 which include regions that are critical for both RAD50 and DNA binding (for Review, [PMID:36358700]). This variant is found with low frequency in population databases (gnomADv3.1.2, gnomADv2.1.1, BRAVO-TOPMed and All of Us) with highest allele frequency of 5.2e-5 (14 heterozygotes; 0 homozygotes, gnomADv2.1.1). The c.1090C>T, p.(Arg364Ter) variant is reported in ClinVar as Pathogenic (VarID:140953; 2 stars, 5 submissions, no conflicts) and has been reported in the literature in individuals with hereditary cancer predisposition [PMID:24763289, 25503501, 27153395, 28559769]. Additional nonsense and frameshift variants downstream of the one identified here have also been reported in ClinVar as Pathogenic (VarIDs:8782, 1681558, 820257, 481748, others), and reported in individuals with Ataxia-Telangiectasia-like Disorder [PMID:33426167, 11371508]. The inherited c.1090C>T, p.(Arg364Ter) variant identified in the MRE11 gene is reported here as Pathogenic.