Submissions for variant NM_005591.4(MRE11):c.1090C>G (p.Arg364Gly)

dbSNP: rs371077728

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115902	SCV000149811	uncertain significance	not provided	2014-03-13	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.1090C>G at the cDNA level, p.Arg364Gly (R364G) at the protein level, and results in the change of an Arginine to a Glycine (CGA>GGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MRE11A Arg364Gly 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. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution and is likely to affect secondary protein structure. MRE11A Arg364Gly occurs at a position that is fully conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably 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	RCV000220133	SCV000276926	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-26	criteria provided, single submitter	clinical testing	The p.R364G variant (also known as c.1090C>G), located in coding exon 9 of the MRE11A gene, results from a C to G substitution at nucleotide position 1090. The arginine at codon 364 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV002228251	SCV002509480	uncertain significance	Ataxia-telangiectasia-like disorder	2021-04-09	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MRE11-related conditions. ClinVar contains an entry for this variant (Variation ID: 127968). This variant is present in population databases (rs371077728, ExAC 0.001%). This sequence change replaces arginine with glycine at codon 364 of the MRE11 protein (p.Arg364Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine.