Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000212563 | SCV000149834 | uncertain significance | not provided | 2020-01-08 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15855896, 14684699, 23747889, 22078559, 18606567, 21715099) |
| Ambry Genetics | RCV000115925 | SCV000187182 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-08-16 | criteria provided, single submitter | clinical testing | The p.R305W variant (also known as c.913C>T), located in coding exon 8 of the MRE11A gene, results from a C to T substitution at nucleotide position 913. The arginine at codon 305 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in the compound heterozygous state with a second alteration in MRE11A (c.1442C>A, p.Thr481Lys) in a patient with ataxia at age 7; however, the phase of these two alterations was not confirmed (da Graça FF et al. Cerebellum, 2022 Feb;21:49-54). This alteration has also been reported in one ovarian cancer patient from a cohort of 151 families with signs of hereditary susceptibility to breast and/or ovarian cancer (Heikkinen K et al. J. Med. Genet. 2003 Dec;40:e131). Further, structural analysis of this amino acid position has shown that the p.R305W alteration is predicted to perturb interactions between the guanidium group of Arg305 and the carbonyl oxygen of Lys360 (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 deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV000627767 | SCV000260086 | uncertain significance | Ataxia-telangiectasia-like disorder | 2022-10-08 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 305 of the MRE11 protein (p.Arg305Trp). This variant is present in population databases (rs372000848, gnomAD 0.01%). This missense change has been observed in individual(s) with cerebellar ataxia and/or ovarian cancer (PMID: 14684699, 33956305). ClinVar contains an entry for this variant (Variation ID: 127989). 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. 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. |
| ARUP Laboratories, |
RCV000212563 | SCV000884127 | uncertain significance | not provided | 2018-01-17 | criteria provided, single submitter | clinical testing | The p.Arg305Trp variant has been reported in a heterozygous form in one individual with ovarian cancer (Heikkinen 2003). This variant (rs372000848) is listed in the Genome Aggregation Database (gnomAD) with allele frequency of 0.009 percent in non-Finnish European populations (identified on 11 out of 126,314) and has been reported to the ClinVar database (Variation ID: 127989). Arginine at codon 305 is highly conserved considering 13 species, up to Baker’s yeast (Alamut v2.10), and computational analyses support a deleterious impact on the protein structure and function (PolyPhen2: possibly damaging, SIFT: damaging, and Mutation Taster: disease causing). Altogether, the clinical significance of p.Arg305Trp variant cannot be determined with certainty. |
| Fulgent Genetics, |
RCV002490781 | SCV002782270 | uncertain significance | Ataxia-telangiectasia-like disorder 1 | 2022-01-08 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003323403 | SCV004028946 | uncertain significance | not specified | 2023-07-31 | criteria provided, single submitter | clinical testing | Variant summary: MRE11 c.913C>T (p.Arg305Trp) results in a non-conservative amino acid change located in the Mre11, DNA-binding domain (IPR007281) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-05 in 282364 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MRE11 causing Hereditary Breast And Ovarian Cancer Syndrome (5.7e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.913C>T has been reported in the literature in individuals affected with ovarian cancer, prostate cancer or cerebellar ataxia (Heikkinen_2003, Rantapero_2020, da Graa_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and it showed hR305W was sensitive to DNA damage reagents (MMS/HU) (Harris_2021). The following publications have been ascertained in the context of this evaluation (PMID: 33510186, 34075539, 14684699, 24093751, 22078559, 32183364, 33956305). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Baylor Genetics | RCV002490781 | SCV004193859 | uncertain significance | Ataxia-telangiectasia-like disorder 1 | 2023-04-11 | criteria provided, single submitter | clinical testing |