ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.145+1G>T (rs757128712)

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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 RCV000216860 SCV000278210 pathogenic Hereditary cancer-predisposing syndrome 2017-10-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
GeneDx RCV000479141 SCV000568392 pathogenic not provided 2018-01-05 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.145+1G>T or IVS1+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 1 of the RAD51C gene. This variant destroys the canonical splice donor site of intron 1, leading to decreased expression of normal RAD51C transcript and increased expression of a nonfunctional transcript that is created using an alternative 5' splice site (Meindl 2010). RAD51C c.145+1G>T was not present in unaffected controls, but was observed in two affected sisters from a German breast and ovarian cancer family; the breast tumor from one sister demonstrated loss of the wild-type allele (Meindl 2010). Based on the currently available information, we consider RAD51C c.145+1G>T to be a pathogenic.
Invitae RCV000648240 SCV000770054 pathogenic Fanconi anemia, complementation group O 2018-01-04 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 1 of the RAD51C 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 reported in two siblings affected with breast and ovarian cancer, respectively (PMID: 20400964). ClinVar contains an entry for this variant (Variation ID: 233766). Experimental studies have shown that this intronic change alters RNA splicing (PMID: 20400964). 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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