Submissions for variant NM_058216.3(RAD51C):c.905-2A>G

dbSNP: rs779582317

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236382	SCV000293251	pathogenic	not provided	2018-12-26	criteria provided, single submitter	clinical testing	This variant is denoted RAD51C c.905-2A>G or IVS6-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 6 of the RAD51C gene. This variant has been reported in at least one individual with ovarian cancer, and splicing assays have demonstrated that this variant results in skipping of exon 7 and introduction of a frameshift (Coulet 2013). Based on currently available evidence, we consider this variant to be pathogenic.
Invitae	RCV000473356	SCV000550188	pathogenic	Fanconi anemia complementation group O	2021-07-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 22725699). ClinVar contains an entry for this variant (Variation ID: 245991). Disruption of this splice site has been observed in individual(s) with ovarian cancer (PMID: 22725699). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 6 of the RAD51C gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.
Ambry Genetics	RCV000575723	SCV000663783	pathogenic	Hereditary cancer-predisposing syndrome	2020-10-30	criteria provided, single submitter	clinical testing	The c.905-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 7 in the RAD51C gene. This mutation was identified in an individual with ovarian cancer diagnosed at age 42, and was demonstrated to result in out-of-frame exon 7 skipping via a splicing mini-gene assay, which was confirmed by RT-PCR from cDNA from the patient (Coulet F et al. Clin. Genet. 2013 Apr;83(4):332-6). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic/a disease-causing mutation.
GeneKor MSA	RCV000575723	SCV000821779	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change occurs 2 nucleotides before exon 7 of the RAD51C gene. This position is highly conserved in the human and other genomes and is crucial in mRNA processing. Experimental studies of this variant have shown that it causes incorrect splicing, resulting in skipping of exon 7, alteration in the reading frame and a truncated protein (PMID: 22725699). Truncating variants in RAD51C are known to be pathogenic. This variant has been described in the international literature in one family affected with ovarian cancer and lower abdominal tumors (PMID: 22725699) and in an individual undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID: 245991).