ClinVar Genomic variation as it relates to human health

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); Published functional studies demonstrate a damaging effect: exon skipping (Lhota 2016); This variant is associated with the following publications: (PMID: 26261251, 28152038, 26822949, 31446535, 29625052, 26689913, 33333735, 30613976)

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.

The c.905-2_905-1delAG pathogenic mutation results from the deletion of two nucleotides located before the first nucleotide of coding exon 7 in the RAD51C gene. This alteration has been seen in multiple patients with personal and family histories of breast and ovarian cancer (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Lhota F et al. Clin. Genet. 2016 Oct;90(4):324-33; Li N et al. J. Natl. Cancer Inst. 2019 Apr; Rizzolo et al. Int. J. Cancer. 2019). In a large case control study, the c.905-2_905-1delAG variant was not seen in over 3000 pancreatic cancer patients (Hu C et al. JAMA. 2018 06;319:2401-2409). In another case control study, the c.905-2_905-1delAG variant was found to be statistically associated with breast cancer (OR= 6.9, 95% CI 1.34-35.61, p=0.02) (Sanoguera-Miralles L et al. Cancers (Basel), 2020 Dec;12:). The deleted nucleotide positions are highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA analyses have shown that this alteration results in skipping of exon 7 and the creation of an out of frame transcript (Lhota F et al. Clin. Genet. 2016 Oct;90(4):324-33, Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

The RAD51C c.905-2_905-1delAG variant has been reported in individuals with ovarian cancer (PMID: 26822949; 26261251).

Variant summary: RAD51C c.905-2_905-1delAG 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: Four predict the variant abolishes a 3' acceptor site. This has been confirmed via cDNA sequencing (Lhota_2016) and a minigene splicing assay (Sanoguera-Miralles_2020). The variant allele was found at a frequency of 1.2e-05 in 251328 control chromosomes (gnomAD). c.905-2_905-1delAG has been reported in the literature in multiple individuals affected with Breast and Ovarian Cancer (e.g. Song_2015, Lu_2015, Lhota_2016, Rizzolo_2019, Cerretini_2019, Dorling_2021). These data indicate that the variant is likely to be associated with disease. Nine ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance, four as likely pathogenic, and four as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant deletes the last two nucleotides in intron 6 of the RAD51C gene. This variant is also known as c.905-2delAG and c.905-2_1delAG in the literature. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have shown that this variant results in the skipping of exon 7 (r.905_965del) that is predicted to result in an absent or non-functional protein product (PMID: 26822949, 33333735). This variant has been observed in individuals affected with ovarian cancer, breast cancer, or pancreatic cancer (PMID: 26261251, 26822949, 30333958, 30613976, 33471991, 37065479). This variant has been identified in 3/251328 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.

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 present in population databases (rs587781995, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with ovarian cancer and breast cancer (PMID: 26261251, 26822949). This variant is also known as 905-2delAG and c.905-2_1delAG. ClinVar contains an entry for this variant (Variation ID: 141768). Studies have shown that disruption of this splice site results in skipping of exon 7 and introduces a new termination codon (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.

RAD51C: PVS1, PM2, PS4:Moderate

Curator: Arleen D. Auerbach. Submitter to LOVD: Zdenek Kleibl.