Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000565698 | SCV000662125 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-12-13 | criteria provided, single submitter | clinical testing | The p.R633* pathogenic mutation (also known as c.1897C>T), located in coding exon 16 of the MRE11A gene, results from a C to T substitution at nucleotide position 1897. This changes the amino acid from an arginine to a stop codon within coding exon 16. This alteration was first described in a homozygous state in first cousins with ataxia-telangiectasia-like disorder (ATLD). Both individuals had features of A-T and increased levels of radiosensitivity, but no detectable ATM mutations (Stewart GS et al. Cell 1999; 99:577-87). The MRE11A p.R633* mutation has also been described in the homozygous state in siblings with ataxia (Chaki et al. Cell. 2012; 150:533-548). In another study, this alteration was detected in one individual with a personal and family history of breast cancer (Bartkova et al. J Mol Oncol. 2008; 2(4):296-316). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
| Baylor Genetics | RCV000009327 | SCV000807235 | pathogenic | Ataxia-telangiectasia-like disorder 1 | 2017-09-01 | criteria provided, single submitter | clinical testing | This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 5-year-old female with ataxic gait, imbalance, frequent falls, similarly affected sib, and a cousin with death after progressive inability to walk |
| Invitae | RCV001034660 | SCV000832713 | pathogenic | Ataxia-telangiectasia-like disorder | 2023-10-14 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg633*) in the MRE11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MRE11 are known to be pathogenic (PMID: 23080121, 23912341). This variant is present in population databases (rs137852759, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia-like disorder, nephronophthisis-related ciliopathies and/or breast cancer (PMID: 8445618, 10612394, 19383352, 22863007). ClinVar contains an entry for this variant (Variation ID: 8782). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MRE11 function (PMID: 10612394, 14690604, 25040471). For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000009327 | SCV000029545 | pathogenic | Ataxia-telangiectasia-like disorder 1 | 2012-08-03 | no assertion criteria provided | literature only |