ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.129+5G>A (rs587781409)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129269 SCV000184029 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-27 criteria provided, single submitter clinical testing The c.129+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 1 in the RAD50 gene. This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to weaken the efficiency of the native splice donor site, but is not predicted to have a deleterious effect on this splice donor site by BDGP; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000129269 SCV000261012 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-21 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the RAD50 gene. It does not directly change the encoded amino acid sequence of the RAD50 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs587781409, ExAC 0.002%). This variant has not been reported in the literature in individuals with RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 140976). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780662 SCV000918121 uncertain significance not specified 2019-06-20 criteria provided, single submitter clinical testing Variant summary: RAD50 c.129+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 250648 control chromosomes, predominantly at a frequency of 5.3e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.129+5G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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