ClinVar Miner

Submissions for variant NM_005591.4(MRE11):c.1897C>T (p.Arg633Ter) (rs137852759)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000565698 SCV000662125 pathogenic Hereditary cancer-predisposing syndrome 2018-03-16 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 mutation 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 mutation was detected in one individual with a personal and family history of breast cancer. Tumor testing of the breast tumor in this individual demonstrated loss of all three proteins of the MRE11-RAD50-NBS1 (MRN) complex (Bartkova et al. J Mol Oncol. 2008; 2(4):296-316). 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 2020-10-20 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. This variant is present in population databases (rs137852759, ExAC 0.02%). This variant has been reported as homozygous in the literature in families affected with ataxia-telangiectasia-like disorder (PMID: 10612394, 8445618), and nephronophthisis-related ciliopathies (PMID: 22863007). This variant has also been reported as heterozygous in an individual affected with breast cancer (PMID: 19383352). ClinVar contains an entry for this variant (Variation ID: 8782). Experimental studies using patient-drived lymphoblastoid and fibroblast cells have shown that this nonsense change results in loss of MRE11 protein expression that disrupts the function of the MRE11-RAD50-NBS1 (MRN) complex, resulting in increased radiosensitivity and impairment of DNA damage-dependent cell cycle checkpoints (PMID: 10612394, 25040471). In addition, studies performed in engineered mice modeling this variant have also shown that this change results in cellular radiosensitivity, defective DNA damage checkpoints, and chromosomal instability (PMID: 14690604). Loss-of-function variants in MRE11 are known to be pathogenic (PMID: 23080121, 23912341). 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

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