Reference Detail

Request Content

Contact

Missing content? – Request curation!

Request curation for specific Genes, Variants, or PubMed publications.

Have questions, comments, or suggestions? - Let us know!

Email us at : ckbsupport@genomenon.com

Ref Type Journal Article
PMID (40670332)
Authors Rein HL, Rawal Y, Palovcak-Lightbourn AL, Ganesan GS, Parker PS, Russell R, Darrah KE, Afsar M, Sullivan MR, Hengel SR, Radke MR, Opresko PL, Yanowitz JL, Greene EC, Lee JM, Domchek SM, Swisher EM, Olsen SK, Sung P, Bernstein KA
Title Comprehensive RAD51C ovarian cancer variant analysis uncouples homologous recombination and replicative functions.
Journal Vol Issue Date Pages Journal Short Title
Nature communications 16 1 2025 Jul 16 6539 Nat Commun
URL
Abstract Text RAD51C is a tumor suppressor gene with over 285 variants of unknown significance (VUS) found in primary ovarian tumors. RAD51C is a paralog of the recombinase RAD51, and it forms complexes with other paralogs to regulate RAD51 activity. We screened 27 ovarian cancer-derived RAD51C VUS to identify those that affect the assembly of functional tetrameric RAD51B-C-D-XRCC2 (BCDX2) complex. With yeast 3-hybrid and biochemical analyses, we identify a mutation cluster of the RAD51C Walker B region affecting protein interactions with other RAD51 paralogs. By further analyzing these variants for homologous recombination (HR), replication fork regression, DNA binding and ATPase activity, and RAD51 filament formation, we identified separation-of-function alleles that uncouple RAD51C distinct enzymatic activities with HR and replication. Thus, our analysis of RAD51C identifies additional VUS with functional defects, which will aid in pathogenicity classification and inform future strategies to treat individuals harboring RAD51C loss-of-function alleles.

Filtering

  • Case insensitive filtering will display rows if any text in any cell matches the filter term
  • Use simple literal full or partial string matches
  • Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
  • Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

  • Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
RAD51C A354V missense no effect - predicted RAD51C A354V does not lie within any known functional domains of the Rad51c protein (UniProt.org). A354V retains binding to Rad51d similar to wild-type Rad51c in a yeast assay, and demonstrates functional homology-directed DNA repair activity in culture (PMID: 40670332), and therefore is predicted to have no effect on Rad51c protein function.
RAD51C D291V missense no effect - predicted RAD51C D291V does not lie within any known functional domains of the Rad51c protein (UniProt.org). D291V retains binding to Rad51d similar to wild-type Rad51c in a yeast assay, demonstrates functional homology-directed DNA repair activity in culture, and rescues viability in Rad51c-deficient cells (PMID: 40670332), and therefore is predicted to have no effect on Rad51c protein function.
RAD51C D318N missense loss of function - predicted RAD51C D318N does not lie within any known functional domains of the Rad51c protein (UniProt.org). D318N retains binding to Rad51d similar to wild-type Rad51c in a yeast assay, but demonstrates defective homology-directed DNA repair activity in cell culture (PMID: 40670332), and therefore, is predicted to lead to a loss of Rad51c protein function.
RAD51C E67K missense no effect - predicted RAD51C E67K lies within a region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). E67K retains binding to Rad51d similar to wild-type Rad51c in a yeast assay, demonstrates functional homology-directed DNA repair activity in culture, and rescues viability in Rad51c-deficient cells (PMID: 40670332), and therefore is predicted to have no effect on Rad51c protein function.
RAD51C F164L missense unknown RAD51C F164L does not lie within any known functional domains of the Rad51c protein (UniProt.org). F164L results in reduced interaction with Rad51d in a yeast assay (PMID: 40670332), and a genomic change (c.490T>A) demonstrates decreased survival in a high-throughput cell culture assay (PMID: 39299233), but demonstrates functional homology-directed DNA repair activity in culture, and rescues cisplatin sensitivity in Rad51c-deficient cells (PMID: 40670332), and therefore, its effect on Rad51c protein function is unknown.
RAD51C G162A missense no effect - predicted RAD51C G162A does not lie within any known functional domains of the Rad51c protein (UniProt.org). G162A results in reduced interaction with Rad51d in a yeast assay, but demonstrates functional homology-directed DNA repair activity in culture, and rescues viability and cisplatin and PARP inhibitor sensitivity in Rad51c-deficient cells (PMID: 40670332), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C G189R missense no effect - predicted RAD51C G189R does not lie within any known functional domains of the Rad51c protein (UniProt.org). G189R demonstrates functional homology-directed DNA repair activity in culture (PMID: 40670332, PMID: 37253112), retains binding to Rad51d similar to wild-type Rad51c in a yeast assay, and rescues viability in Rad51c-deficient cells (PMID: 40670332), and therefore is predicted to have no effect on Rad51c protein function.
RAD51C H207R missense no effect - predicted RAD51C H207R does not lie within any known functional domains of the Rad51c protein (UniProt.org). H207R retains binding to Rad51d similar to wild-type Rad51c in a yeast assay, and demonstrates functional homology-directed DNA repair activity in culture (PMID: 40670332), and therefore is predicted to have no effect on Rad51c protein function.
RAD51C H82N missense no effect - predicted RAD51C H82N lies within a region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). H82N retains binding to Rad51d similar to wild-type Rad51c in a yeast assay, and demonstrates functional homology-directed DNA repair activity in culture (PMID: 40670332), and therefore is predicted to have no effect on Rad51c protein function.
RAD51C K84N missense no effect - predicted RAD51C K84N lies within a region of the Rad51c protein required for Holliday junction resolution activity and the RAD51B, RAD51D, and XRCC3-interacting region of the Rad51c protein (UniProt.org). K84N retains binding to Rad51d similar to wild-type Rad51c in a yeast assay (PMID: 40670332), and demonstrates functional homology-directed DNA repair activity in culture (PMID: 40670332, PMID: 37253112), and therefore is predicted to have no effect on Rad51c protein function.
RAD51C L182R missense no effect - predicted RAD51C L182R does not lie within any known functional domains of the Rad51c protein (UniProt.org). L182R retains binding to Rad51d similar to wild-type Rad51c in a yeast assay, and demonstrates functional homology-directed DNA repair activity in culture (PMID: 40670332), and therefore is predicted to have no effect on Rad51c protein function.
RAD51C L238R missense loss of function RAD51C L238R does not lie within any known functional domains of the Rad51c protein (UniProt.org). L238R retains replication fork reversal similar to wild-type Rad51c, but confers a loss of function to Rad51c as demonstrated by reduced interaction with Rad51d in a yeast assay, decreased protein levels, defective homology-directed DNA repair activity, failure to form stable BCDX2 and CX3 complexes, failure to rescue hypersensitivity to cisplatin and PARP inhibitors, and impaired growth in cultured cells (PMID: 40670332), and results in decreased survival in a high-throughput cell culture assay (PMID: 39299233).
RAD51C M10R missense unknown RAD51C M10R lies within the region required for Holliday junction resolution activity of the Rad51c protein (UniProt.org). M10R retains binding to Rad51d similar to wild-type Rad51c in a yeast assay (PMID: 40670332), demonstrates functional homology-directed DNA repair activity in cell culture (PMID: 37253112, PMID: 40670332), and rescues viability in Rad51c-deficient cells (PMID: 40670332), but results in decreased survival in a high-throughput cell culture assay (PMID: 39299233), and therefore, its effect on Rad51c protein function is unknown.
RAD51C M136I missense no effect - predicted RAD51C M136I lies within the Rad51b, Rad51d, and Xrcc3-interacting region of the Rad51c protein (UniProt.org). M136I retains binding to Rad51d similar to wild-type Rad51c in a yeast assay (PMID: 40670332), and demonstrates functional homology-directed DNA repair activity in culture (PMID: 40670332, PMID: 37253112), and therefore is predicted to have no effect on Rad51c protein function.
RAD51C M165L missense no effect - predicted RAD51C M165L does not lie within any known functional domains of the Rad51c protein (UniProt.org). M165L retains binding to Rad51d similar to wild-type Rad51c in a yeast assay, and demonstrates functional homology-directed DNA repair activity in culture (PMID: 40670332), and therefore is predicted to have no effect on Rad51c protein function.
RAD51C N203D missense no effect - predicted RAD51C N203D does not lie within any known functional domains of the Rad51c protein (UniProt.org). N203D retains binding to Rad51d similar to wild-type Rad51c in a yeast assay, and demonstrates functional homology-directed DNA repair activity in culture (PMID: 40670332), and therefore is predicted to have no effect on Rad51c protein function.
RAD51C N71K missense no effect - predicted RAD51C N71K lies within a region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). N71K retains binding to Rad51d similar to wild-type Rad51c in a yeast assay, and demonstrates functional homology-directed DNA repair activity in culture (PMID: 40670332), and therefore is predicted to have no effect on Rad51c protein function.
RAD51C Q178E missense unknown RAD51C Q178E does not lie within any known functional domains of the Rad51c protein (UniProt.org). Q178E results in protein levels and binding to Rad51d similar to wild-type Rad51c in a yeast assay, but demonstrates lack of protein expression in a mammalian cell system (PMID: 40670332), and therefore, its effect on Rad51c protein function is unknown.
RAD51C Q181R missense unknown RAD51C Q181R does not lie within any known functional domains of the Rad51c protein (UniProt.org). Q181R retains binding to Rad51d similar to wild-type Rad51c in a yeast assay, but demonstrates partial loss of homology-directed DNA repair activity in culture (PMID: 40670332), and therefore, its effect on Rad51c protein function is unknown.
RAD51C S364G missense no effect - predicted RAD51C S364G does not lie within any known functional domains of the Rad51c protein (UniProt.org). S364G retains binding to Rad51d similar to wild-type Rad51c in a yeast assay, and demonstrates functional homology-directed DNA repair activity in culture (PMID: 40670332, PMID: 37253112), and therefore is predicted to have no effect on Rad51c protein function.
RAD51C T120A missense no effect - predicted RAD51C T120A lies within the region required for Holliday junction resolution activity and the Rad51b, Rad51d, and Xrcc3-interacting region of the Rad51c protein (UniProt.org). T120A results in reduced interaction with Rad51d in yeast assays, but demonstrates functional homology-directed DNA repair activity in culture, and rescues viability and cisplatin sensitivity in Rad51c-deficient cells (PMID: 40670332), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C T174S missense unknown RAD51C T174S does not lie within any known functional domains of the Rad51c protein (UniProt.org). T174S retains binding to Rad51d similar to wild-type Rad51c in a yeast assay, and demonstrates functional homology-directed DNA repair activity in culture (PMID: 40670332), but a genomic change (c.521C>G) results in decreased survival in a high-throughput cell culture assay (PMID: 39299233), and therefore, its effect on Rad51c protein function is unknown.
RAD51C V166G missense unknown RAD51C V166G does not lie within any known functional domains of the Rad51c protein (UniProt.org). V166G retains binding to Rad51d similar to wild-type Rad51c in a yeast assay, demonstrates functional homology-directed DNA repair activity in cell culture, and rescues viability and cisplatin sensitivity in Rad51c-deficient cells (PMID: 40670332), but results in decreased survival in a high-throughput cell culture assay (PMID: 39299233), and therefore, its effect on Rad51c protein function is unknown.
RAD51C V170G missense no effect - predicted RAD51C V170G does not lie within any known functional domains of the Rad51c protein (UniProt.org). V170G retains binding to Rad51d similar to wild-type Rad51c in a yeast assay, demonstrates functional homology-directed DNA repair activity in cell culture, and rescues viability and cisplatin sensitivity in Rad51c-deficient cells (PMID: 40670332), and therefore is predicted to have no effect on Rad51c protein function.
RAD51C V239G missense unknown RAD51C V239G does not lie within any known functional domains of the Rad51c protein (UniProt.org). V239G retains functional homology-directed DNA repair activity in culture, maintains the ability to form stable complexes with Xrcc3 in in vitro assays, and rescues viability and cisplatin hypersensitivity in Rad51c-deficient cells, but forms a complex with Rad51b, Rad51d and Xrcc2 that binds DNA but demonstrates partially reduced ATPase activity and defective Rad51 filament formation in in vitro assays, and impaired replication fork reversal leading to accumulation of ssDNA breaks in cell culture, and results in reduced interaction with Rad51d in yeast assays (PMID: 40670332), and therefore, its effect on Rad51c protein function is unknown.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RAD51C A279P Advanced Solid Tumor sensitive Cisplatin Preclinical - Cell culture Actionable In a preclinical study, Platinol (cisplatin) decreased viability in cells expressing RAD51C A279P in culture (PMID: 40670332). 40670332
RAD51C V166G Advanced Solid Tumor no benefit Cisplatin Preclinical - Cell culture Actionable In a preclinical study, cells expressing RAD51C V166G were not sensitive to Platinol (cisplatin) in culture (PMID: 40670332). 40670332
RAD51C F164L Advanced Solid Tumor no benefit Cisplatin Preclinical - Cell culture Actionable In a preclinical study, cells expressing RAD51C F164L were not sensitive to Platinol (cisplatin) in culture (PMID: 40670332). 40670332
RAD51C L238R Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) decreased viability in cells expressing RAD51C L238R in culture (PMID: 40670332). 40670332
RAD51C L238R Advanced Solid Tumor sensitive Cisplatin Preclinical - Cell culture Actionable In a preclinical study, Platinol (cisplatin) decreased viability in cells expressing RAD51C L238R in culture (PMID: 40670332). 40670332
RAD51C A279P Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) decreased viability in cells expressing RAD51C A279P in culture (PMID: 40670332). 40670332
RAD51C V239G Advanced Solid Tumor no benefit Cisplatin Preclinical - Cell culture Actionable In a preclinical study, cells expressing RAD51C V239G were not sensitive to Platinol (cisplatin) in culture (PMID: 40670332). 40670332