ClinVar Miner

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

dbSNP: 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 2020-01-17 criteria provided, single submitter clinical testing The c.3806_3807delAT variant, located in coding exon 25 of the RAD50 gene, results from a deletion of two nucleotides at nucleotide positions 3806 to 3807, causing a translational frameshift with a predicted alternate stop codon (p.H1269Rfs*2). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of RAD50, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 44 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. This alteration has been previously reported in a Chinese ovarian cancer patient who underwent multi-gene panel testing (Zhao Q et al. J Gynecol Oncol. 2017 Jan;28:e39). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000572364 SCV001237366 likely pathogenic Hereditary cancer-predisposing syndrome 2021-11-15 criteria provided, single submitter clinical testing Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 225451). This premature translational stop signal has been observed in individual(s) with breast or ovarian cancer (PMID: 28541631, 29726012). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.His1269Argfs*2) in the RAD50 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 44 amino acid(s) of the RAD50 protein. This variant disrupts the ATPase-C domain, 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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