ClinVar Genomic variation as it relates to human health

Canonical splice site variant shown to result in aberrant splicing and a nonfunctional transcript in a gene for which loss of function is a known mechanism of disease (Meindl et al., 2010); Observed in individuals with RAD51C-related cancers (Meindl et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24993905, 21537932, 25470109, 23117857, 32398771, 20400964)

The c.145+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the RAD51C gene. This mutation was identified in a German breast and ovarian cancer family. RT-PCR analysis of a c.145+1G>T splicing reporter showed complete inactivation of the donor site. In addition, breast tumor tissue from a c.145+1G>T mutation carrier demonstrated loss of the wild-type allele (Meindl A et al. Nat Genet. 2010 May;42(5):410-4). In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (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 a disease-causing mutation.

This variant causes a G to T nucleotide substitution at the +1 position of intron 1 of the RAD51C gene. A RNA study has shown reduced level of the wild-type transcript and increased level of a non-functional transcript that uses an alternative intron 1 splice donor site (PMID:20400964). This variant has been observed in related individuals affected with breast or ovarian cancer (PMID:20400964). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

This sequence change affects a donor splice site in intron 1 of the RAD51C gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 20400964). ClinVar contains an entry for this variant (Variation ID: 233766). Studies have shown disruption of this splice site is associated with increased skipping of partial exon 1, introducing a premature termination codon, but one or more of the resulting mRNA isoform(s) may be naturally occurring (PMID: 20400964, 32398771; Invitae). For these reasons, this variant has been classified as Pathogenic.

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.

Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen.