ClinVar Miner

Submissions for variant NM_005591.4(MRE11):c.659+1G>A

gnomAD frequency: 0.00002  dbSNP: 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 2021-08-02 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the MRE11 gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs759130031, ExAC 0.02%). Disruption of this splice site has been observed in individual(s) with Nijmegen breakage syndrome-like severe microcephaly or ovarian cancer (PMID: 21227757, 29348823). ClinVar contains an entry for this variant (Variation ID: 230014). Studies have shown that disruption of this splice site results in skipping of exon 7, which introduces a premature termination codon (PMID: 21227757). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

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