ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.905-2_905-1del (rs587781995)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130408 SCV000185270 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000130408 SCV000691288 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing
Counsyl RCV000662804 SCV000785628 likely pathogenic Breast-ovarian cancer, familial 3; Fanconi anemia, complementation group O 2017-10-17 criteria provided, single submitter clinical testing
GeneDx RCV000236611 SCV000293781 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.905-2_905-1delAG and consists of a deletion of two nucleotides starting at the -2 position of intron 6. The normal sequence, with the bases that are deleted in brackets, is tctc[delag]GGGA, where the lowercase letters are intronic and capital are exonic. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. RAD51C c.905-2_905-1delAG has been reported in a patient with breast cancer and another with a personal and family history of ovarian cancer, and has been shown by RT-PCR to result in skipping of exon 7 (Song 2015, Lhota 2016). Based on the currently evidence, we consider RAD51C c.905-2_905-1delAG to be pathogenic.
Invitae RCV000526987 SCV000650029 pathogenic Fanconi anemia, complementation group O 2018-12-29 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 of the RAD51C gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs587781995, ExAC 0.01%). This variant has been reported in the literature in individuals affected with ovarian cancer and breast cancer (PMID: 26261251, 26822949). This variant is also known as 905-2delAG and c.905-2_1delAG in the literature. ClinVar contains an entry for this variant (Variation ID: 141768). Different variants affecting this acceptor splice site (c.905-2A>G, c.905-2A>C, c.905-2delA) have been determined to be pathogenic (PMID: 22725699, 26824983, Invitae). This suggests that this splice site is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917). For these reasons, this variant has been classified as Pathogenic.

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