Submissions for variant NM_058216.3(RAD51C):c.1027-1G>A

dbSNP: rs1567818502

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698010	SCV000826648	uncertain significance	Fanconi anemia complementation group O	2020-02-27	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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 the last intron (intron 8) of the RAD51C gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.
Ambry Genetics	RCV002386224	SCV002694682	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-24	criteria provided, single submitter	clinical testing	The c.1027-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 9 of the RAD51C gene. 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 and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of two amino acids; however, the exact functional impact of the deleted amino acids are unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV002386224	SCV004357137	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This variant substitutes a G to A nucleotide at the -1 position of the acceptor site in intron 8 of the RAD51C gene. Splicing prediction tools indicate that this variant disrupts the native intron 8 splice acceptor site and is also expected to activate a cryptic acceptor site in exon 9, causing an in-frame deletion of 6 basepairs at the beginning of exon 9. A ClinVar report has stated the detection of this 6 basepair deletion in carrier RNA (ClinVar accession: SCV002694682.1). To our knowledge, functional studies have not been reported for this variant nor has this variant has been reported in individuals affected with RAD51C-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.