Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001055703 | SCV001220104 | uncertain significance | Fanconi anemia complementation group O | 2021-05-31 | 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. Studies have shown that this variant is associated with altered splicing, including significant skipping of exon 8, the production of an isoform containing an in-frame insertion of 1 amino acid residue in exon 8, and low levels of the wild-type transcript. At this type it is uncertain whether the effect on protein and/or amount of abnormal transcripts is enough to cause disease PMID: 33333735). This variant has not been reported in the literature in individuals with RAD51C-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 7 of the RAD51C gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001328346 | SCV001519432 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2021-03-08 | criteria provided, single submitter | clinical testing | Variant summary: RAD51C c.966-1G>C 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: Three predict the variant abolishes a 5 splicing donor site and three predict the variant abolishes a 3 acceptor site. Three also predict that the variant strengthens a 3 cryptic acceptor site located 3 nucleotides upstream of the canonical site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251358 control chromosomes (gnomAD). To our knowledge, no occurrence of c.966-1G>C in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Ambry Genetics | RCV002379568 | SCV002694213 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-21 | criteria provided, single submitter | clinical testing | The c.966-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 8 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. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame insertion of 1 amino acid; however, the exact functional impact of the inserted amino acid is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003478682 | SCV004220158 | uncertain significance | not provided | 2022-09-15 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population, 0.0000066 (1/152046 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported to cause aberrant splicing with the creation of two alternative transcripts (PMID: 35740625 (2022)). However, the significance of these alternative transcripts and its effect on protein function has not been assessed. Further studies are required to determine the effect of aberrant splicing of RAD51C protein function. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper RAD51C mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. |