ClinVar Miner

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

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Total submissions: 13
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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.

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