ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.706-2A>G (rs587780259)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116178 SCV000186640 pathogenic Hereditary cancer-predisposing syndrome 2017-12-01 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,Functionally-validated splicing mutation
Color RCV000116178 SCV000686377 pathogenic Hereditary cancer-predisposing syndrome 2016-02-10 criteria provided, single submitter clinical testing
Counsyl RCV000576612 SCV000677780 pathogenic Breast-ovarian cancer, familial 3; Fanconi anemia, complementation group O 2017-01-12 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000234445 SCV000536783 pathogenic Fanconi anemia, complementation group O 2016-08-16 no assertion criteria provided research
Fulgent Genetics,Fulgent Genetics RCV000576612 SCV000893462 pathogenic Breast-ovarian cancer, familial 3; Fanconi anemia, complementation group O 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000254687 SCV000150087 likely pathogenic not provided 2018-04-30 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.706-2A>G or IVS4-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 4 of the RAD51C gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to an abnormal protein product. RAD51C c.706-2A>G was shown to result in skipping of exon 5, leading to the in-frame loss of 44 amino acids (Golmard 2013), and RNAseq analysis performed by Davy 2017 et al. revealed several splice products, the most predominant of which was exon 5 skipping, followed by a proportion of normal, wild-type transcript. This variant has been reported in association with breast and ovarian cancer (Walsh 2011, Loveday 2012, Golmard 2013, Couch 2015, Song 2015, Golmard 2017, Harter 2017, Kotoula 2017). Based on the current evidence, we consider this variant to be likely pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785234 SCV000923802 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000234445 SCV000291240 pathogenic Fanconi anemia, complementation group O 2018-12-11 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 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 (rs587780259, ExAC 0.003%). This variant has been reported in the literature in several individuals with breast and ovarian cancer (PMID: 22006311, 22538716, 24549055, 25452441, 26261251, 26681312, 29255180). In one family, it was reported to segregate with ovarian cancer in two individuals (PMID: 24139550). ClinVar contains an entry for this variant (Variation ID: 128209). Experimental studies have shown that this sequence change disrupts normal mRNA splicing (PMID: 24139550, 22006311). 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.
Laboratoire de Biologie et Génétique du Cancer,Centre François Baclesse RCV000456123 SCV000536677 pathogenic Breast-ovarian cancer, familial 3 criteria provided, single submitter clinical testing

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