Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002229382 | SCV000642119 | uncertain significance | Ataxia-telangiectasia-like disorder | 2021-07-14 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine with valine at codon 47 of the MRE11 protein (p.Ala47Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with autosomal recessive progressive myoclonic ataxia (PMID: 24332946, 24733832). This variant has been reported in individual(s) with autosomal dominant ataxia-telangiectasia-like disorder (ATLD) (PMID: 2433832); however, the role of the variant in this condition is currently unclear. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MRE11 protein function (PMID: 2433832, 24332946). 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. |
| Ambry Genetics | RCV001011397 | SCV001171711 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-02-15 | criteria provided, single submitter | clinical testing | The p.A47V variant (also known as c.140C>T), located in coding exon 2 of the MRE11A gene, results from a C to T substitution at nucleotide position 140. The alanine at codon 47 is replaced by valine, an amino acid with similar properties. This variant was reported in the homozygous state in a Japanese patient with progressive myoclonic ataxia, who underwent exome sequencing (Miyamoto R et al. J. Neurol. Sci. 2014 Feb;337:219-23). It has also been reported in the heterozygous state, in a Japanese patient with Ataxia-Telangiectasia-like disorder; this patient was not found to have another MRE11A variant (Yoshida T et al. Am. J. Med. Genet. A. 2014 Jul;164A:1830-4). Both of these patients showed reduced MRE11 protein expression compared to healthy controls (Miyamoto R et al. J. Neurol. Sci. 2014 Feb;337:219-23; Yoshida T et al. Am. J. Med. Genet. A. 2014 Jul;164A:1830-4). This alteration has also been reported in 1/235 Korean patients with Hereditary Breast Cancer, who previously tested negative for BRCA1/2 (Kim H et al. Breast Cancer Res. Treat. 2017 01;161:95-102). 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. |
| OMIM | RCV000157663 | SCV000207624 | pathogenic | Ataxia-telangiectasia-like disorder 1 | 2014-02-15 | no assertion criteria provided | literature only |