ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.1114C>T (p.Gln372Ter) (rs104895046)

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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 RCV000566508 SCV000671822 pathogenic Hereditary cancer-predisposing syndrome 2016-11-01 criteria provided, single submitter clinical testing The p.Q372* pathogenic mutation (also known as c.1114C>T), located in coding exon 8 of the RAD50 gene, results from a C to T substitution at nucleotide position 1114. This changes the amino acid from a glutamine to a stop codon within coding exon 8. One study assessed the role of this mutation in the primary antibody deficiency syndromes IgAD and CVID, and found that cell lines harboring this mutation displayed an impaired ability of the MRN complex to repair ionizing radiation-induced DNA double strand breaks, suggesting an increased sensitivity to ionizing radiation (Offer SM et al. PLoS ONE, 2010 Aug;5:e12260). 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.
Invitae RCV000566508 SCV000956155 pathogenic Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln372*) in the RAD50 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs104895046, ExAC 0.002%). This variant has not been reported in the literature in individuals with RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 126999). Experimental studies have shown that this nonsense change results in increased sensitivity to ionizing radiation compared to the wild-type controls (PMID: 20805886). Loss-of-function variants in RAD50 are known to be pathogenic (PMID: 16385572, 19409520). For these reasons, this variant has been classified as Pathogenic.
Harris Lab, University of Minnesota RCV000114865 SCV000148760 not provided not provided no assertion provided not provided

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