Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000160576 | SCV000218111 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-22 | criteria provided, single submitter | clinical testing | The p.M26T variant (also known as c.77T>C), located in coding exon 2 of the MRE11A gene, results from a T to C substitution at nucleotide position 77. The methionine at codon 26 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in trans with a second pathogenic mutation in MRE11A in an individual with combined dystonia (Zech M et al. Neurogenetics, 2017 Dec;18:195-205), and was detected in an individual with nervous system abnormalities who underwent whole exome sequencing (Retterer K et al. Genet Med, 2016 07;18:696-704). This variant was also reported in 12/60,466 breast cancer cases and in 5/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well 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 | RCV001034631 | SCV000288950 | likely pathogenic | Ataxia-telangiectasia-like disorder | 2023-12-04 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 26 of the MRE11 protein (p.Met26Thr). This variant is present in population databases (rs372068015, gnomAD 0.005%). This missense change has been observed in individual(s) with ataxia-telangiectasia, abnormalities of the nervous system, generalized combined dystonia and ovarian cancer (PMID: 26633542, 28849312, 30441849, 33098801; Invitae; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 182553). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Ce |
RCV000761799 | SCV000891996 | likely pathogenic | not provided | 2020-11-01 | criteria provided, single submitter | clinical testing | |
| Institute Of Human Genetics Munich, |
RCV000684815 | SCV001150167 | likely pathogenic | Ataxia-telangiectasia-like disorder 1 | 2019-06-13 | criteria provided, single submitter | clinical testing | |
| Illumina Laboratory Services, |
RCV000684815 | SCV001271865 | uncertain significance | Ataxia-telangiectasia-like disorder 1 | 2018-01-12 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
| Institute for Clinical Genetics, |
RCV000761799 | SCV002009662 | uncertain significance | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003317108 | SCV004021024 | uncertain significance | not specified | 2023-06-05 | criteria provided, single submitter | clinical testing | Variant summary: MRE11 c.77T>C (p.Met26Thr) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type (IPR004843) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251142 control chromosomes (gnomAD). c.77T>C has been reported in the literature in an individual affected with an abnormality of the nervous system (Retterer_2016) and another with dystonia who had a pathogenic variant in trans (Zech_2017, 2020). These data indicate that the variant may be associated with disease in the context of Ataxia Telangiectasia-Like Disorder. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.5946del, p.Ser1982fs, internal database), providing supporting evidence for a benign role in the context of Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33098801, 26633542, 28849312). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=3) or likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Baylor Genetics | RCV000684815 | SCV004193774 | uncertain significance | Ataxia-telangiectasia-like disorder 1 | 2023-10-20 | criteria provided, single submitter | clinical testing |