ClinVar Miner

Submissions for variant NM_005591.3(MRE11):c.659+1G>A (rs759130031)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217276 SCV000273416 pathogenic Hereditary cancer-predisposing syndrome 2017-01-10 criteria provided, single submitter clinical testing The c.659+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 6 of the MRE11A gene. This alteration was detected in a patient with a disorder resembling a Nijmegen breakage syndrome-like severe microcephaly but without reported immunodeficiency. The authors performed RT-PCR and sequencing analysis which demonstrated that this mutation results in exon 7 skipping leading to premature protein truncation (Matsumoto Y et al. DNA Repair (Amst.). 2011 Mar;10:314-21). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Counsyl RCV000410656 SCV000488843 likely pathogenic Ataxia-telangiectasia-like disorder 1 2016-07-18 criteria provided, single submitter clinical testing
Invitae RCV000812799 SCV000953124 pathogenic Ataxia-telangiectasia-like disorder 2018-10-11 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the MRE11 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs759130031, ExAC 0.02%). This variant has been observed in in individuals affected with Nijmegen breakage syndrome-like severe microcephaly or ovarian cancer (PMID: 29348823, 21227757). ClinVar contains an entry for this variant (Variation ID: 230014). Experimental studies have shown that this splice site change leads to skipping of exon 7, which is predicted to result in an absent protein product (PMID: 21227757). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MRE11 are known to be pathogenic (PMID: 23080121, 23912341). For these reasons, this variant has been classified as Pathogenic.

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