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Ref Type Journal Article
PMID (42625895)
Authors Ganesan GS, Moosbrugger ZR, Parker PS, Goff NJ, Kumar AK, Bernstein KA
Title RAD51C breast cancer-identified variants with attenuated homologous recombination function exhibit sensitivity to combined PARP1 and ATR inhibition.
Journal Vol Issue Date Pages Journal Short Title
NAR cancer 8 3 2026 Sep zcag018 NAR Cancer
URL
Abstract Text The tumor suppressor RAD51C is essential for DNA double-strand break repair through the homologous recombination (HR) pathway. RAD51C loss is linked to an increased risk of breast cancer, but the majority of RAD51C missense mutations identified in patients are variants of unknown significance. In addition to promoting HR, RAD51C also protects damaged replication forks. Here, we characterized 33 clinically identified breast cancer variants and assayed their ability to perform HR. We identified one HR-deficient variant and five variants with intermediate HR proficiency. While these variants have modestly attenuated HR, they misregulate replication fork progression and accumulate single-strand DNA gaps. We then assessed their sensitivity to PARP1 and ATR inhibition. While RAD51C variants with attenuated HR are largely resistant to monotherapy, cells expressing a subset of these RAD51C variants exhibit increased sensitivity to combination PARP1i and ATRi treatment, Saruparib and Ceralasertib, respectively. Collectively, we pinpoint the key functional regions of RAD51C and uncover a new C-terminal region proximal to the ATP-binding site in the folded RAD51C structure. Together, our findings suggest that variants with partial HR function can cause profound defects in the repair of replicative damage, and that this, in turn, may lead to distinct therapeutic responses.

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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 D141H missense loss of function RAD51C D141H does not lie within any known functional domains of the Rad51c protein (UniProt.org). D141H confers a loss of function to Rad51c as demonstrated by reduced homology-directed DNA repair activity, abnormal replication fork progression leading to accumulation of ssDNA breaks in culture, defective interaction with Rad51d in a yeast assay (PMID: 42625895), and decreased survival in a high-throughput cell culture assay (PMID: 39299233).
RAD51C E36K missense unknown RAD51C E36K lies within the region required for Holliday junction resolution activity of the Rad51c protein (UniProt.org). E36K maintains functional homology-directed DNA repair activity in cell culture reporter assays (PMID: 42625895, PMID: 37253112), but demonstrates reduced binding to Rad51d and Xrcc3 in a yeast assay (PMID: 42625895), and therefore, its effect on Rad51 protein function is unknown.
RAD51C E45G missense no effect - predicted RAD51C E45G lies within a region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). E45G maintains functional homology-directed DNA repair activity in cell culture reporter assays (PMID: 42625895, PMID: 37253112), and demonstrates binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C E67G missense no effect - predicted RAD51C E67G lies within a region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). E67G maintains functional homology-directed DNA repair activity in cell culture reporter assays (PMID: 42625895, PMID: 37253112), and demonstrates binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C E80K missense no effect - predicted RAD51C E80K lies within a region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). E80K maintains functional homology-directed DNA repair activity in cell culture reporter assays, and demonstrates binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C E92D missense no effect - predicted RAD51C E92D lies within a region of the Rad51c protein required for Holliday junction resolution activity and the RAD51B, RAD51D, and XRCC3-interacting region (UniProt.org). E92D maintains functional homology-directed DNA repair activity in cell culture reporter assays, and demonstrates binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C G3R missense no effect - predicted RAD51C G3R lies within a region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). G3R demonstrates intermediate homology-directed DNA repair activity in one study (PMID: 42625895), but results in functional homology-directed DNA repair activity in a different study (PMID: 37253112), retains binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and rescues mitomycin C hypersensitivity and Rad51 foci formation similar to wild-type Rad51c in culture (PMID: 20400964), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C H207D missense no effect - predicted RAD51C H207D does not lie within any known functional domains of the Rad51c protein (UniProt.org). H207D maintains functional homology-directed DNA repair activity in cell culture reporter assays, and demonstrates binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C H316Y missense no effect - predicted RAD51C H316Y does not lie within any known functional domains of the Rad51c protein (UniProt.org). H316Y maintains functional homology-directed DNA repair activity in cell culture reporter assays, and demonstrates binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C I290T missense no effect - predicted RAD51C I290T does not lie within any known functional domains of the Rad51c protein (UniProt.org). I290T maintains functional homology-directed DNA repair activity in cell culture reporter assays, and demonstrates binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C I341M missense loss of function RAD51C I341M does not lie within any known functional domains of the Rad51c protein (UniProt.org). I341M confers a loss of function to Rad51c as demonstrated by defective homology-directed DNA repair activity, abnormal replication fork progression, failure to rescue hypersensitivity to PARP and ATR inhibitors in Rad51c-deficient cells in culture, defective interaction with Rad51d in a yeast assay (PMID: 42625895), and decreased survival in a high-throughput cell culture assay (PMID: 39299233).
RAD51C K188N missense no effect - predicted RAD51C K188N does not lie within any known functional domains of the Rad51c protein (UniProt.org). K188N maintains functional homology-directed DNA repair activity in cell culture reporter assays, and demonstrates binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C K235N missense loss of function - predicted RAD51C K235N does not lie within any known functional domains of the Rad51c protein (UniProt.org). K235N retains functional homology-directed DNA repair activity (PMID: 37253112, PMID: 42625895), and binding to Rad51d and Xrcc3 similar to wild-type Rad51c in culture (PMID: 42625895), however the genomic change (c.705G>C) leads to abnormal splicing leading to skipping of exon 4 and premature protein truncation in a minigene splicing assay (PMID: 33333735) and in patient cells (PMID: 35565380), and demonstrates decreased survival in a high-throughput cell culture assay (PMID: 39299233), and therefore, is predicted to lead to a loss of Rad51c protein function.
RAD51C L205F missense no effect - predicted RAD51C L205F does not lie within any known functional domains of the Rad51c protein (UniProt.org). L205F maintains functional homology-directed DNA repair activity in cell culture reporter assays, and demonstrates binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C L230F missense loss of function - predicted RAD51C L230F does not lie within any known functional domains of the Rad51c protein (UniProt.org). L230F retains homology-directed DNA repair activity similar to wild-type Rad51c in one study (PMID: 37253112), but demonstrates intermediate homology-directed DNA repair activity in a different study, and results in failure to rescue hypersensitivity to PARP and ATR inhibitors in Rad51c-deficient cells, and abnormal replication fork progression leading to accumulation of ssDNA breaks in culture (PMID: 42625895), and therefore, is predicted to lead to a loss of Rad51c protein function.
RAD51C R212H missense unknown RAD51C R212H does not lie within any known functional domains of the Rad51c protein (UniProt.org). R212H retains homology-directed DNA repair activity similar to wild-type Rad51c in one study (PMID: 37253112), but demonstrates intermediate homology-directed DNA repair activity in a different study, and results in abnormal replication fork progression leading to accumulation of single strand DNA breaks in culture (PMID: 42625895), and therefore, its effect on Rad51c protein function is unknown.
RAD51C R370G missense no effect - predicted RAD51C R370G does not lie within any known functional domains of the Rad51c protein (UniProt.org). R370G maintains functional homology-directed DNA repair activity in cell culture reporter assays, and demonstrates binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C R74K missense no effect - predicted RAD51C R74K lies within a region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). R74K maintains functional homology-directed DNA repair activity in cell culture reporter assays, and demonstrates binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C S231L missense no effect - predicted RAD51C S231L does not lie within any known functional domains of the Rad51c protein (UniProt.org). S231L maintains functional homology-directed DNA repair activity in cell culture reporter assays, and demonstrates binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C S353T missense no effect - predicted RAD51C S353T does not lie within any known functional domains of the Rad51c protein (UniProt.org). S353T maintains functional homology-directed DNA repair activity in cell culture reporter assays, and demonstrates binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C S44C missense no effect - predicted RAD51C S44C lies within the region required for Holliday junction resolution activity of the Rad51c protein (UniProt.org). S44C maintains functional homology-directed DNA repair activity in cell culture reporter assays, and demonstrates binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C T349A missense no effect - predicted RAD51C T349A does not lie within any known functional domains of the Rad51c protein (UniProt.org). T349A maintains functional homology-directed DNA repair activity in cell culture reporter assays, and demonstrates binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C T5M missense no effect - predicted RAD51C T5M lies within a region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). T5M maintains functional homology-directed DNA repair activity in cell culture reporter assays (PMID: 42625895, PMID: 37253112) and binding to Rad51d and Xrcc3 similar to wild-type Rad51c in a yeast assay (PMID: 42625895), and therefore, is predicted to have no effect on Rad51c protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RAD51C R212H Advanced Solid Tumor no benefit Saruparib Preclinical - Cell culture Actionable In a preclinical study, Saruparib (AZD5305) treatment did not inhibit colony formation in cells expressing RAD51C R212H in culture (PMID: 42625895). 42625895
RAD51C D141H Advanced Solid Tumor sensitive Ceralasertib + Saruparib Preclinical - Cell culture Actionable In a preclinical study, Ceralasertib (AZD6738) and Saruparib (AZD5305) synergistically inhibited colony formation in cell lines expressing RAD51C D141H in culture (PMID: 42625895). 42625895
RAD51C D141H Advanced Solid Tumor no benefit Ceralasertib Preclinical - Cell culture Actionable In a preclinical study, Ceralasertib (AZD6738) treatment did not inhibit colony formation in cells expressing RAD51C D141H in culture (PMID: 42625895). 42625895
RAD51C G113S Advanced Solid Tumor no benefit Ceralasertib Preclinical - Cell culture Actionable In a preclinical study, Ceralasertib (AZD6738) treatment did not inhibit colony formation in cells expressing RAD51C G113S in culture (PMID: 42625895). 42625895
RAD51C R212H Advanced Solid Tumor no benefit Ceralasertib Preclinical - Cell culture Actionable In a preclinical study, Ceralasertib (AZD6738) treatment did not inhibit colony formation in cells expressing RAD51C R212H in culture (PMID: 42625895). 42625895
RAD51C G113S Advanced Solid Tumor no benefit Saruparib Preclinical - Cell culture Actionable In a preclinical study, Saruparib (AZD5305) treatment did not inhibit colony formation in cells expressing RAD51C G113S in culture (PMID: 42625895). 42625895
RAD51C L230F Advanced Solid Tumor sensitive Ceralasertib + Saruparib Preclinical - Cell culture Actionable In a preclinical study, Ceralasertib (AZD6738) and Saruparib (AZD5305) synergistically inhibited colony formation in cell lines expressing RAD51C L230F in culture (PMID: 42625895). 42625895
RAD51C D141H Advanced Solid Tumor no benefit Saruparib Preclinical - Cell culture Actionable In a preclinical study, Saruparib (AZD5305) treatment did not inhibit colony formation in cells expressing RAD51C D141H in culture (PMID: 42625895). 42625895
RAD51C I341M Advanced Solid Tumor sensitive Ceralasertib + Saruparib Preclinical - Cell culture Actionable In a preclinical study, Ceralasertib (AZD6738) and Saruparib (AZD5305) synergistically inhibited colony formation in cell lines expressing RAD51C I341M in culture (PMID: 42625895). 42625895