ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.2983_2986del (p.Glu995fs) (rs587780154)

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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 RCV000115951 SCV000186628 pathogenic Hereditary cancer-predisposing syndrome 2013-07-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115951 SCV000216431 pathogenic Hereditary cancer-predisposing syndrome 2014-09-23 criteria provided, single submitter clinical testing
GeneDx RCV000656961 SCV000149860 pathogenic not provided 2014-01-14 criteria provided, single submitter clinical testing RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This mutation is denoted RAD50 c.2983_2986delGAAA at the cDNA level and p.Glu995ArgfsX2 (E995RfsX2) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CAAA[delGAAA]AGAT. The deletion causes a frameshift, which changes a Glutamic Acid to a Arginine at codon 995, and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not been previously reported to our knowledge, it is considered pathogenic. Mutations in RAD50 have recently been described in association with cancer risk. Heikkinen et al. (2006) reported a recurrent RAD50 mutation identified in 8 out of 317 Finnish breast cancer patients compared with 6 out of 1000 controls. Two of these patients were considered to have familial breast cancer in which incomplete segregation was observed between the RAD50 mutation and cancer. Another novel splicing variant was observed in a case with a family history of breast cancer. The authors conclude that the incomplete segregation data and the frequency of this mutation in controls suggest that the recurrent RAD50 variant is a low-penetrance breast cancer susceptibility allele (Heikkinen 2006). Walsh et al. (2011) also identified a RAD50 mutation carrier in 1/360 patients with ovarian cancer, peritoneal cancer, or fallopian tube cancer unselected for family history. Two mutations (one affecting each allele) in the RAD50 gene have been reported in a patient with a rare disorder called Nijmegen breakage syndrome-like disorder (NBSLD) associated with growth retardation, microcephaly, mental retardation and a characteristic facial appearance. At the time of the report, she was 23 years old without a diagnosis of cancer (Waltes 2009). If a RAD50 mutation carrier'spartner is also a carrier of a RAD50 mutation, the risk to have a child with NBSLD is 25% with each pregnancy.
Invitae RCV000115951 SCV000753385 pathogenic Hereditary cancer-predisposing syndrome 2019-01-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu995Argfs*2) in the RAD50 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587782488, ExAC 0.02%). This variant has not been reported in the literature in individuals with RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 128015). Loss-of-function variants in RAD50 are known to be pathogenic (PMID: 16385572, 19409520). For these reasons, this variant has been classified as Pathogenic.

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