ClinVar Miner

Submissions for variant NM_005591.3(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 Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
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 RCV000009327 SCV000832713 pathogenic Ataxia-telangiectasia-like disorder 1 2018-05-11 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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