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

Total submissions: 13

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	2019-12-16	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	2020-02-24	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
Integrated Genetics/Laboratory Corporation of America	RCV001194262	SCV001363654	pathogenic	Hereditary breast and ovarian cancer syndrome	2019-01-02	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.706-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3' acceptor site. Experimental evidence demonstrated that this variant affects mRNA splicing leading to the loss of 44 amino acids in a functional domain of the protein by an in-frame exon 5 skipping (Golmard_2013). The variant allele was found at a frequency of 2.2e-05 in 277092 control chromosomes (gnomAD). c.706-2A>G has been reported in the literature in multiple individuals affected with Breast and Ovarian Cancer (Couch_2015, Golmard_2013). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submissions from clinical diagnostic and research laboratories (evaluation after 2014) cite the variant as pathogenic (5x) and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253222	SCV001428832	pathogenic	Mental retardation, X-linked 1	2019-01-15	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000254687	SCV001447217	likely pathogenic	not provided	2020-10-23	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
Leiden Open Variation Database	RCV000254687	SCV001365271	likely pathogenic	not provided	2014-11-02	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen.