Submissions for variant NM_058216.3(RAD51C):c.905-2del

gnomAD frequency: 0.00001  dbSNP: rs876658652

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221587	SCV000274184	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-10	criteria provided, single submitter	clinical testing	The c.905-2delA intronic variant, located in intron 6 of the RAD51C gene, results from a deletion of one nucleotide within intron 6 of the RAD51C gene. This variant was detected in 3/6178 families with a history of tubo-ovarian carcinoma or breast cancer. (Yang X et al. J Natl Cancer Inst, 2020 Dec;112:1242-1250). 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Invitae	RCV000229896	SCV000291253	pathogenic	Fanconi anemia complementation group O	2023-08-02	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 32107557). This sequence change affects a splice site in intron 6 of the RAD51C gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 230587). Studies have shown that disruption of this splice site results in exon 7 skipping and introduces a new termination codon (PMID: 35740625; Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts the nuclear localization signal (NLS) of the RAD51C protein, which is important for proper localization and function of the RAD51C protein (PMID:12966089). While functional studies have not been performed to directly test the effect of this variant on RAD51C protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000221587	SCV001358584	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-04-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001195028	SCV002551144	likely pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001195028	SCV004145756	pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing	RAD51C: PVS1, PM2
Leiden Open Variation Database	RCV001195028	SCV001365281	pathogenic	not provided	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Christine Rappaport.