Submissions for variant NM_058216.3(RAD51C):c.964del (p.Arg322fs)

dbSNP: rs1555603056

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000584392	SCV000691294	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-09-01	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 7 of the RAD51C gene, creating a frameshift and premature translation stop signal in the last coding exon. While this mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein, it is expected to have disrupted or deleted ATPase domain (amino acid 100-347) (PMID: 1731253), RAD51 paralog binding domain (amino acid 79-376) (PMID: 14704354), and nuclear localization signal (amino acid 366-370) (PMID: 12966089). While functional studies have not been reported for this variant, cells carrying a mutant RAD51C protein without the nuclear localization signal showed increased sensitivity to a DNA cross-linking agent (PMID: 12966089). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701832	SCV000830651	likely pathogenic	Fanconi anemia complementation group O	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg322Glyfs*42) in the RAD51C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the RAD51C protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. ClinVar contains an entry for this variant (Variation ID: 492399). 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. 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.
Myriad Genetics, Inc.	RCV003451314	SCV004189600	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2023-12-06	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.