Submissions for variant NM_058216.3(RAD51C):c.838-2A>G

dbSNP: rs748589398

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561624	SCV000663789	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-08-01	criteria provided, single submitter	clinical testing	The c.838-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 6 in the RAD51C gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). 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 mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000648242	SCV000770056	likely pathogenic	Fanconi anemia complementation group O	2017-10-10	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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). This variant has not been reported in the literature in individuals with RAD51C-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 5 of the RAD51C gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
GeneDx	RCV002259351	SCV002538904	likely pathogenic	not provided	2022-06-13	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003470841	SCV004208038	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2022-06-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003470841	SCV004931055	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2024-01-03	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.