ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.552-1G>A

gnomAD frequency: 0.00001  dbSNP: rs1236278956
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570029 SCV000671814 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-06 criteria provided, single submitter clinical testing The c.552-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 5 of the RAD50 gene. This variant was reported in 1/1313 early-onset breast cancer cases and 0/1123 population controls (Damiola F et al. Breast Cancer Res., 2014 Jun;16:R58). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Invitae RCV000570029 SCV000753395 likely pathogenic Hereditary cancer-predisposing syndrome 2023-10-05 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 of the RAD50 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 24894818). ClinVar contains an entry for this variant (Variation ID: 484675). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.
Revvity Omics, Revvity Omics RCV001783075 SCV002019616 pathogenic Nijmegen breakage syndrome-like disorder 2019-01-09 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV001783075 SCV002538526 likely pathogenic Nijmegen breakage syndrome-like disorder 2021-11-17 criteria provided, single submitter curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002271531 SCV002556112 likely pathogenic Hereditary breast ovarian cancer syndrome 2022-06-23 criteria provided, single submitter clinical testing Variant summary: RAD50 c.552-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 249730 control chromosomes (gnomAD). c.552-1G>A has been reported in the literature in at least one individual affected with early-onset breast cancer (e.g. Damiola_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two laboratories classified the variant as likely pathogenic and one classified it as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV001783075 SCV004207312 likely pathogenic Nijmegen breakage syndrome-like disorder 2023-10-26 criteria provided, single submitter clinical testing

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