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

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
Ambry Genetics	RCV000116178	SCV000186640	pathogenic	Hereditary cancer-predisposing syndrome	2019-09-23	criteria provided, single submitter	clinical testing	Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Functionally-validated splicing mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes)
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
Counsyl	RCV000576612	SCV000677780	pathogenic	Breast-ovarian cancer, familial 3; Fanconi anemia, complementation group O	2017-01-12	criteria provided, single submitter	clinical testing
Color	RCV000116178	SCV000686377	pathogenic	Hereditary cancer-predisposing syndrome	2016-02-10	criteria provided, single submitter	clinical testing
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
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
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