ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.3806_3807del (p.His1269fs) (rs1085307088)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490333 SCV000267470 uncertain significance Nijmegen breakage syndrome-like disorder 2016-03-18 criteria provided, single submitter reference population
Ambry Genetics RCV000572364 SCV000667083 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-14 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000572364 SCV001237366 likely pathogenic Hereditary cancer-predisposing syndrome 2019-01-23 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the RAD50 gene (p.His1269Argfs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 44 amino acids of the RAD50 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individual affected with breast or ovarian cancer (PMID: 28541631, 29726012). ClinVar contains an entry for this variant (Variation ID: 225451). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant disrupts the C-terminal ATPase-C domain (residues Ser1257-His1312), which is important for RAD50 ATPase activity (PMID: 10892749, 24894818). While functional studies have not been performed to directly test the effect of this variant on RAD50 protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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