ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.3277C>T (p.Arg1093Ter) (rs121912628)

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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 RCV000575384 SCV000663600 pathogenic Hereditary cancer-predisposing syndrome 2019-02-18 criteria provided, single submitter clinical testing The p.R1093* pathogenic mutation (also known as c.3277C>T), located in coding exon 21 of the RAD50 gene, results from a C to T substitution at nucleotide position 3277. This changes the amino acid from an arginine to a stop codon within coding exon 21. This alteration was previously reported in the compound heterozygous state in a patient with a phenotype similar to Nijmegen breakage syndrome. Sequence analysis of cDNA revealed quasi-hemizygous expression of the other mutation, implying that the p.R1093* allele was subject to nonsense mediated decay (Waltes R et al. Am. J. Hum. Genet. 2009 May;84:605-16). 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.
Counsyl RCV000006230 SCV000785384 likely pathogenic Nijmegen breakage syndrome-like disorder 2017-07-19 criteria provided, single submitter clinical testing
Invitae RCV000575384 SCV000829513 pathogenic Hereditary cancer-predisposing syndrome 2020-10-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1093*) in the RAD50 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121912628, ExAC 0.001%). This variant has been observed in an individual affected with medulloblastoma (PMID: 19409520) and in an individual affected with Nijmegen breakage syndrome-like disorder who had a different pathogenic variant in RAD50 on the opposite chromosome (trans) (PMID: 19409520). ClinVar contains an entry for this variant (Variation ID: 5872). Loss-of-function variants in RAD50 are known to be pathogenic (PMID: 16385572, 19409520). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000006230 SCV000026412 pathogenic Nijmegen breakage syndrome-like disorder 2009-05-01 no assertion criteria provided literature only

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