Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000568757 | SCV000674690 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-01-11 | criteria provided, single submitter | clinical testing | The p.Q332* variant (also known as c.994C>T), located in coding exon 8 of the RAD51C gene, results from a C to T substitution at nucleotide position 994. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This alteration occurs at the 3' terminus of theRAD51C gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 45 amino acids of the protein. However, premature stop codons are typically deleterious in nature and this variant is predicted to truncate the C-terminal region of the protein including the terminal end of the RECA domain (Magrane M et al. Database (Oxford) 2011). This alteration has been detected in an ovarian cancer patient diagnosed at age 63 who had a sister diagnosed with breast cancer at age 46 (Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102). This variant was also reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Invitae | RCV000576180 | SCV000676967 | likely pathogenic | Fanconi anemia complementation group O | 2023-05-09 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 486279). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts a region of the RAD51C protein in which other variant(s) (p.Ser353Hisfs*8) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 27616075). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln332*) in the RAD51C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the RAD51C protein. |
Gene |
RCV000579112 | SCV000680938 | likely pathogenic | not provided | 2020-01-02 | criteria provided, single submitter | clinical testing | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 45 amino acids are lost including the nuclear localization signal (French 2003); Not observed in large population cohorts (Lek 2016); Observed in individuals with a personal or family history including ovarian and breast cancers (Kraus 2017); This variant is associated with the following publications: (PMID: 27616075) |
Color Diagnostics, |
RCV000568757 | SCV000911558 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-08-25 | criteria provided, single submitter | clinical testing | This variant changes 1 nucleotide in exon 8 of the RAD51C gene, creating a translation stop signal. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein lacking the nuclear localization signal (PMID: 12966089). To our knowledge, functional studies have not been reported for this variant. A functional study has reported that a truncation of the last 11 amino acids of the RAD51C protein partially reduced nuclear localization and ability to rescue sensitivity to mitomycin C treatment in RAD51C-deficient cell (PMID: 12966089). This variant has been reported in an individual affected with bilateral ovarian cancer (PMID: 27616075). 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. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000579112 | SCV001134797 | likely pathogenic | not provided | 2019-05-30 | criteria provided, single submitter | clinical testing | The variant is predicted to result in the loss of a functional protein. Not found in the total gnomAD dataset, and the data is high quality (0/281382 chr). |
Institute of Medical Genetics and Applied Genomics, |
RCV000579112 | SCV001905663 | likely pathogenic | not provided | 2021-09-15 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV003459395 | SCV004207998 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 3 | 2023-06-02 | criteria provided, single submitter | clinical testing |