ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.263+1G>A (rs1555570242)

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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 RCV000568603 SCV000663842 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-19 criteria provided, single submitter clinical testing The c.263+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 3 of the RAD51D gene. This alteration has been identified in a 64 year old woman with ovarian cancer (Norquist BM et al. JAMA Oncol, 2016 Apr;2:482-90) and in an unaffected 53 year old patient with a family history of ovarian cancer (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). 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 donor site. However, RNA data has shown that exon 3 is excluded in several naturally occurring RAD51D isoforms (Davy G et al. Eur. J. Hum. Genet., 2017 10;25:1147-1154; Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001069125 SCV001234272 likely pathogenic Breast-ovarian cancer, familial 4 2020-07-22 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the RAD51D gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with ovarian cancer (PMID: 26261251, 26720728) and an individual with pancreatic cancer (PMID: 29506128). ClinVar contains an entry for this variant (Variation ID: 480542). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RAD51D are known to be pathogenic (PMID: 21822267). 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.
Color Health, Inc RCV000568603 SCV001343912 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-03 criteria provided, single submitter clinical testing

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