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Ref Type Journal Article
PMID (36099300)
Authors Prakash R, Rawal Y, Sullivan MR, Grundy MK, Bret H, Mihalevic MJ, Rein HL, Baird JM, Darrah K, Zhang F, Wang R, Traina TA, Radke MR, Kaufmann SH, Swisher EM, Guérois R, Modesti M, Sung P, Jasin M, Bernstein KA
Title Homologous recombination-deficient mutation cluster in tumor suppressor RAD51C identified by comprehensive analysis of cancer variants.
Journal Vol Issue Date Pages Journal Short Title
Proceedings of the National Academy of Sciences of the United States of America 119 38 2022 Sep 20 e2202727119 Proc Natl Acad Sci U S A
URL
Abstract Text Mutations in homologous recombination (HR) genes, including BRCA1, BRCA2, and the RAD51 paralog RAD51C, predispose to tumorigenesis and sensitize cancers to DNA-damaging agents and poly(ADP ribose) polymerase inhibitors. However, ∼800 missense variants of unknown significance have been identified for RAD51C alone, impairing cancer risk assessment and therapeutic strategies. Here, we interrogated >50 RAD51C missense variants, finding that mutations in residues conserved with RAD51 strongly predicted HR deficiency and disrupted interactions with other RAD51 paralogs. A cluster of mutations was identified in and around the Walker A box that led to impairments in HR, interactions with three other RAD51 paralogs, binding to single-stranded DNA, and ATP hydrolysis. We generated structural models of the two RAD51 paralog complexes containing RAD51C, RAD51B-RAD51C-RAD51D-XRCC2 and RAD51C-XRCC3. Together with our functional and biochemical analyses, the structural models predict ATP binding at the interface of RAD51C interactions with other RAD51 paralogs, similar to interactions between monomers in RAD51 filaments, and explain the failure of RAD51C variants in binding multiple paralogs. Ovarian cancer patients with variants in this cluster showed exceptionally long survival, which may be relevant to the reversion potential of the variants. This comprehensive analysis provides a framework for RAD51C variant classification. Importantly, it also provides insight into the functioning of the RAD51 paralog complexes.

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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 A126T missense no effect RAD51C A126T lies within the Rad51b, Rad51d, and Xrcc3-interaction region of the Rad51c protein (UniProt.org). A126T demonstrates rescue of mitomycin C hypersensitivity and Rad51 foci formation similar to wild-type Rad51c in culture (PMID: 20400964), binds to Rad51b, Rad51d, and Xrcc3 to similar levels of wild-type protein in a yeast assay, and demonstrates homologous recombination activity similar to wild-type Rad51c in cultured cells (PMID: 36099300).
RAD51C A279V missense unknown RAD51C A279V does not lie within any known functional domains of the Rad51c protein (UniProt.org). A279V rescues survival of Rad51c-null cells in culture, however, results in decreased interaction with Rad51b, Rad51d, and Xrcc3 in a yeast assay and reduced homologous recombination activity compared to wild-type Rad51c in cultured cells (PMID: 36099300), and therefore, its effect on Rad51c protein function is unknown.
RAD51C A308S missense unknown RAD51C A308S does not lie within any known functional domains of the Rad51c protein (UniProt.org). A308S retains interaction with Rad51b, Rad51d, and Xrcc3 in a yeast assay (PMID: 36099300), but has not been fully biochemically characterized and therefore, its effect on Rad51c protein function is unknown.
RAD51C A308T missense unknown RAD51C A308T does not lie within any known functional domains of the Rad51c protein (UniProt.org). The functional effect of A308T is conflicting as it results in decreased interaction with Rad51d in a yeast assay and decreased homologous recombination (HR) activity in one cell line but demonstrates proficient HR activity in another cell line, rescues survival of RAD51C-null cells in culture, and retains interaction with Rad51b and Xrcc3 in a yeast assay (PMID: 36099300).
RAD51C A30E missense no effect - predicted RAD51C A30E lies within the region required for Holliday junction resolution activity of the Rad51c protein (UniProt.org). A30E binds to Rad51b, Rad51d, and Xrcc3 to similar levels as wild-type protein in a yeast assay and demonstrates homologous recombination activity similar to wild-type Rad51c in cultured cells (PMID: 36099300), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C A324T missense unknown RAD51C A324T does not lie within any known functional domains of the Rad51c protein (UniProt.org). The functional effect of A324T is conflicting as it demonstrates homologous recombination activity similar to wild-type Rad51c in one cell line but reduced activity in another cell line, results in variable binding to Rad51d and reduced binding to Rad51b but binds to Xrcc3 to similar levels of wild-type protein in yeast assays, and rescues survival in Rad51c-null cells in culture (PMID: 36099300), and therefore, its effect on Rad51c protein function is unknown.
RAD51C C135R missense loss of function RAD51C C135R lies within the Rad51b, Rad51d, and Xrcc3-interacting region of the Rad51c protein (UniProt.org). C135R demonstrates decreased interaction with Rad51b, Rad51d, and Xrcc3 in a yeast assay (PMID: 36099300, PMID: 28864920) and reduced homologous recombination activity compared to wild-type Rad51c in cultured cells (PMID: 36099300).
RAD51C C135Y missense loss of function RAD51C C135Y lies within the Rad51b, Rad51d, and Xrcc3-interaction region of the Rad51c protein (UniProt.org). C135Y confers a loss of function to the Rad51c protein as indicated by decreased Rad51 foci formation in cell culture (PMID: 22451500, PMID: 36099300), decreased interaction with Rad51b, Rad51d, Xrcc3, and DNA in in vitro assays, decreased ATPase activity in an in vitro assay, reduced homologous recombination activity in cultured cells, and failure to rescue survival in Rad51c-null cells in culture (PMID: 36099300).
RAD51C D108Y missense no effect - predicted RAD51C D108Y lies within the region required for Holliday junction resolution activity and the Rad51b, Rad51d, and Xrcc3-interacting region of the Rad51c protein (UniProt.org). D108Y results in variable interaction with Rad51b, Rad51d, and Xrcc3 in a yeast assay but demonstrates homologous recombination activity similar to wild-type Rad51c and rescues survival in Rad51c-null cells in culture (PMID: 36099300), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C D141G missense unknown RAD51C D141G does not lie within any known functional domains of the Rad51c protein (UniProt.org). D141G results in proficient interaction with Rad51b and Xrcc3 and reduced interaction with Rad51d in a yeast assay (PMID: 36099300), but has not been fully biochemically characterized and therefore, its effect on Rad51c protein function is unknown.
RAD51C D159N missense unknown RAD51C D159N does not lie within any known functional domains of the Rad51c protein (UniProt.org). D159N demonstrates partial rescue of mitomycin C hypersensitivity in chicken cells and Rad51 foci formation similar to wild-type Rad51c in human cells in culture (PMID: 20400964), but in another study results in decreased binding to Brca2, Palb2, Rad51 (PMID: 24141787), and Rad51d and demonstrates loss of interaction with Xrcc3 in cell culture (PMID: 37253112), and binds to Rad51b and Rad51c at reduced levels but to Xrcc3 similar to wild-type protein in a yeast assay (PMID: 36099300), and therefore, its effect on Rad51c protein function is unknown.
RAD51C D318E missense unknown RAD51C D318E does not lie within any known functional domains of the Rad51c protein (UniProt.org). D318E binds to Rad51b, Rad51d, and Xrcc3 to similar levels of wild-type protein in a yeast assay (PMID: 36099300), but has not been fully biochemically characterized and therefore, its effect on Rad51c protein function is unknown.
RAD51C E360Q missense unknown RAD51C E360Q does not lie within any known functional domains of the Rad51c protein (UniProt.org). E360Q binds to Rad51b, Rad51d, and Xrcc3 to similar levels of wild-type protein in a yeast assay (PMID: 36099300), but has not been fully biochemically characterized and therefore, its effect on Rad51c protein function is unknown.
RAD51C F103V missense loss of function RAD51C F103V lies within the region required for Holliday junction resolution activity and the Rad51b, Rad51d, and Xrcc3-interacting region of the Rad51c protein (UniProt.org). F103V results in decreased interaction with Rad51b, Rad51d, and Xrcc3 in a yeast assay and reduced homologous recombination activity in cultured cells (PMID: 36099300).
RAD51C G112V missense unknown RAD51C G112V lies within the region required for Holliday junction resolution activity and the Rad51b, Rad51d, and Xrcc3-interacting region of the Rad51c protein (UniProt.org). G112V results in decreased interaction with Rad51b, Rad51c, and Xrcc3 in a yeast assay (PMID: 36099300), but has not been fully biochemically characterized and therefore, its effect on Rad51c protein function is unknown.
RAD51C G113S missense unknown RAD51C G113S lies within the region required for Holliday junction resolution activity and the Rad51b, Rad51d, and Xrcc3-interacting region of the Rad51c protein (UniProt.org). G113S retains binding with Xrcc3 but demonstrates decreased interaction with Rad51b and Rad51d in a yeast assay (PMID: 36099300), but has not been fully biochemically characterized and therefore, its effect on Rad51c protein function is unknown.
RAD51C G125S missense unknown RAD51C G125S lies within a region of the Rad51c protein required for Holliday junction resolution activity and the RAD51B, RAD51D, and XRCC3-interacting region (UniProt.org). The effect of G125S is conflicting as it results in decreased interaction with Rad51b, Rad51d, and Xrcc3 in a yeast assay and reduced homologous recombination (HR) activity in one cell line but proficient HR activity in another cell line, and rescues survival in RAD51C-null cells in culture (PMID: 36099300).
RAD51C G125V missense loss of function RAD51C G125V lies within a region of the Rad51c protein required for Holliday junction resolution activity and the RAD51B, RAD51D, and XRCC3-interacting region (UniProt.org). G125V confers a loss of function to the Rad51c protein as indicated by failure to rescue mitomycin C hypersensitivity, decreased Rad51 foci formation in cell culture (PMID: 20400964), decreased interaction with Rad51b, Rad51d, Xrcc3, and DNA in in vitro assays, reduced homologous recombination activity in cultured cells, and failure to rescue survival in Rad51c-null cells in culture (PMID: 36099300).
RAD51C G130A missense loss of function RAD51C G130A lies within the Rad51b, Rad51d, and Xrcc3-interaction region of the Rad51c protein (UniProt.org). G130A results in decreased interaction with Rad51b, Rad51d, and Xrcc3, intermediate DNA-binding and ATPase activity in in vitro assays, and reduced homologous recombination activity compared to wild-type Rad51c in cultured cells (PMID: 36099300).
RAD51C G153D missense unknown RAD51C G153D does not lie within any known functional domains of the Rad51c protein (UniProt.org). G153D results in reduced homologous recombination activity compared to wild-type Rad51c in cell culture (PMID: 36099300) and decreased interaction with Xrcc3, Rad51b, and Rad51d in a yeast assay but rescues survival in Rad51c-null cells in culture (PMID: 21980511, PMID: 36099300), and therefore, its effect on Rad51c protein function is unknown.
RAD51C G153S missense unknown RAD51C G153S does not lie within any known functional domains of the Rad51c protein (UniProt.org). G153S retains binding with Rad51b and Xrcc3 but demonstrates variable interaction with Rad51d in a yeast assay (PMID: 36099300), but has not been fully biochemically characterized and therefore, its effect on Rad51c protein function is unknown.
RAD51C G162E missense unknown RAD51C G162E does not lie within any known functional domains of the Rad51c protein (UniProt.org). G162E retains binding with Xrcc3 in a yeast assay and rescues survival of Rad51c-null cells in culture, however, results in decreased interaction with Rad51b and Rad51d in a yeast assay and reduced homologous recombination activity compared to wild-type Rad51c in cultured cells (PMID: 36099300), and therefore, its effect on Rad51c protein function is unknown.
RAD51C G162R missense unknown RAD51C G162R does not lie within any known functional domains of the Rad51c protein (UniProt.org). G162R results in decreased interaction with Rad51d, Rad51b, and Xrcc3 in a yeast assay (PMID: 36099300), but has not been fully biochemically characterized and therefore, its effect on Rad51c protein function is unknown.
RAD51C I144T missense unknown RAD51C I144T does not lie within any known functional domains of the Rad51c protein (UniProt.org). The functional effect of I144T is conflicting, as it demonstrates reduced homologous recombination activity in one cell line, but proficient activity in another, rescues survival in Rad51c-null cells in culture but results in variable interaction with Rad51b, Rad51d, and Xrcc3 in a yeast assay (PMID: 36099300), and therefore, its effect on Rad51c protein function is unknown.
RAD51C K26M missense unknown RAD51C K26M lies within the region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). K26M binds to Rad51b, Rad51d, and Xrcc3 to similar levels of wild-type protein in a yeast assay (PMID: 36099300), but has not been fully biochemically characterized and therefore, its effect on Rad51c protein function is unknown.
RAD51C L138F missense unknown RAD51C L138F does not lie within any known functional domains of the Rad51c protein (UniProt.org). L138F rescues survival in Rad51c-null cells and results in homologous recombination activity similar to wild-type Rad51c in one cell line but deficient activity in another in one study (PMID: 36099300), but demonstrates decreased homology-directed repair activity in another study (PMID: 37253112), decreased interaction with Xrcc2, Xrcc3, and Rad51d in culture (PMID: 37253112) and Rad51b, Rad51d, and Xrcc3 in a yeast assay (PMID: 36099300), decreased Rad51 foci formation (PMID: 20400964, PMID: 37253112), and fails to rescue mitomycin C hypersensitivity in culture (PMID: 20400964), and therefore, its effect on Rad51c protein function is unknown.
RAD51C L219S missense unknown RAD51C L219S does not lie within any known functional domains of the Rad51c protein (UniProt.org). L219S results in a loss of Rad51 foci formation in cell culture (PMID: 22451500) and decreased interaction with Rad51b, Rad51d, and Xrcc3 in a yeast assay, but results in homologous recombination activity similar to wild-type Rad51c and rescues survival in Rad51c-null cells in culture (PMID: 36099300), and therefore, its effect on Rad51c protein function is unknown.
RAD51C L226P missense loss of function RAD51C L226P does not lie within any known functional domains of the Rad51c protein (UniProt.org). L226P results in decreased interaction with Rad51b, Rad51d, and Xrcc3 in a yeast assay and reduced homologous recombination activity compared to wild-type Rad51c in cultured cells (PMID: 36099300).
RAD51C L257V missense unknown RAD51C L257V does not lie within any known functional domains of the Rad51c protein (UniProt.org). L257V binds to Rad51b, Rad51d, and Xrcc3 to similar levels of wild-type protein in a yeast assay (PMID: 36099300), but has not been fully biochemically characterized and therefore, its effect on Rad51c protein function is unknown.
RAD51C L262V missense unknown RAD51C L262V does not lie within any known functional domains of the Rad51c protein (UniProt.org). L262V retains binding with Rad51b and Xrcc3, but results in variable interaction with Rad51d in a yeast assay (PMID: 36099300), and therefore, its effect on Rad51c protein function is unknown.
RAD51C L27P missense loss of function - predicted RAD51C L27P lies within the region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). L27P binds to Rad51b, Rad51d, and Xrcc3 to similar levels as wild-type protein in a yeast assay (PMID: 36099300), however, results in loss of binding to Rad51d and Xrcc2 in cultured cells (PMID: 37253112) and reduced homologous recombination activity compared to wild-type Rad51c in cultured cells (PMID: 36099300), and therefore, is predicted to lead to a loss of Rad51c protein function.
RAD51C L91F missense no effect - predicted RAD51C L91F lies within the region required for Holliday junction resolution activity and the Rad51b, Rad51d, and Xrcc3-interacting region of the Rad51c protein (UniProt.org). L91F results in variable interaction with Rad51d but retains binding with Rad51b and Xrcc3 in a yeast assay and demonstrates homologous recombination activity similar to wild-type Rad51c in cultured cells (PMID: 36099300), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C M136L missense unknown RAD51C M136L lies within the Rad51b, Rad51d, and Xrcc3-interacting region of the Rad51c protein (UniProt.org). M136L binds to Rad51b, Rad51d, and Xrcc3 to similar levels of wild-type protein in a yeast assay (PMID: 36099300), but has not been fully biochemically characterized and therefore, its effect on Rad51c protein function is unknown.
RAD51C P21A missense no effect RAD51C P21A lies within a region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). P21A binds to Rad51b, Rad51d, and Xrcc3 to similar levels of wild-type protein in a yeast assay and demonstrates homologous recombination activity similar to wild-type Rad51c in cultured cells (PMID: 36099300).
RAD51C P21S missense no effect - predicted RAD51C P21S lies within a region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). P21S binds to Rad51b, Rad51d, and Xrcc3 to similar levels as wild-type protein in a yeast assay (PMID: 36099300) and retains the ability to induce foci formation in culture (PMID: 37253112), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C P21T missense unknown RAD51C P21T lies within a region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). P21T has been identified in the scientific literature (PMID: 36099300), but has not been biochemically characterized and therefore, its effect on Rad51c protein function is unknown (PubMed, Dec 2025).
RAD51C P247L missense unknown RAD51C P247L does not lie within any known functional domains of the Rad51c protein (UniProt.org). The functional effect of P247L is conflicting as it demonstrates homologous recombination activity similar to wild-type in one cell line but reduced in another, rescues survival in Rad51c-null cells in culture, and results in variable interaction with Rad51b, Rad51d, and Xrcc3 in a yeast assay (PMID: 36099300), and therefore, its effect on Rad51c protein function is unknown.
RAD51C P330H missense unknown RAD51C P330H does not lie within any known functional domains of the Rad51c protein (UniProt.org). P330H retains binding with Rad51b and Xrcc3 and rescues survival in Rad51c-null cells in culture, however, results in decreased binding with Rad51d in a yeast assay and reduced homologous recombination activity in cultured cells (PMID: 36099300), and therefore, its effect on Rad51c protein function is unknown.
RAD51C P43S missense no effect - predicted RAD51C P43S lies within the region required for Holliday junction resolution activity of the Rad51c protein (UniProt.org). P43S binds to Rad51b, Rad51d, and Xrcc3 at similar levels as wild-type protein in a yeast assay and demonstrates homologous recombination activity similar to wild-type Rad51c in cultured cells (PMID: 36099300), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C Q11R missense no effect RAD51C Q11R lies within the region required for Holliday junction resolution activity of the Rad51c protein (UniProt.org). Q11R binds to Rad51b, Rad51d, and Xrcc3 to similar levels of wild-type protein in a yeast assay and demonstrates homologous recombination activity similar to wild-type Rad51c in cultured cells (PMID: 36099300).
RAD51C Q133K missense loss of function RAD51C Q133K lies within the Rad51b, Rad51d, and Xrcc3-interacting region of the Rad51c protein (UniProt.org). Q133K results in decreased interaction with Rad51b, Rad51d, Xrcc3, and DNA in in vitro assays, decreased ATPase activity in an in vitro assay, and reduced homologous recombination activity compared to wild-type Rad51c in cultured cells (PMID: 36099300).
RAD51C Q143R missense loss of function RAD51C Q143R does not lie within any known functional domains of the Rad51c protein (UniProt.org). Q143R confers a loss of function to the Rad51c protein as indicated by decreased Rad51 foci formation in cell culture (PMID: 22451500) and decreased interaction with Rad51b, Rad51c, and Xrcc3 in a yeast assay (PMID: 36099300).
RAD51C R12W missense loss of function - predicted RAD51C R12W lies within a region of the Rad51c protein required for Holliday junction resolution activity (UniProt.org). R12W retains binding of Rad51d but results in decreased interaction with Rad51b and Xrcc3 in a yeast assay and decreased homologous recombination activity in culture (PMID: 36099300), and therefore, is predicted to lead to a loss of Rad51c protein function.
RAD51C R212C missense unknown RAD51C R212C does not lie within any known functional domains of the Rad51c protein (UniProt.org). R212C binds to Rad51b, Rad51d, and Xrcc3 to similar levels of wild-type protein in a yeast assay (PMID: 36099300), but has not been fully biochemically characterized and therefore, its effect on Rad51c protein function is unknown.
RAD51C R214C missense unknown RAD51C R214C does not lie within any known functional domains of the Rad51c protein (UniProt.org). R214C results in decreased interaction with Xrcc3 and Rad51b in a yeast-two-hybrid assay in one study (PMID: 21980511), but in another study binds to Rad51b, Rad51d, and Xrcc3 to similar levels of wild-type protein in a yeast assay (PMID: 36099300) and demonstrates homology-directed repair activity in cultured cells (PMID: 37253112), and therefore, its effect on Rad51c protein function is unknown.
RAD51C R249C missense no effect - predicted RAD51C R249C does not lie within any known functional domains of the Rad51c protein (UniProt.org). R249C binds to Rad51b, Rad51d, and Xrcc3 at similar levels as wild-type protein in a yeast assay, demonstrates homologous recombination activity similar to wild-type Rad51c in cultured cells, and rescues survival in Rad51c-null cells in culture (PMID: 36099300), and therefore, is predicted to have no effect on Rad51c protein function.
RAD51C R249H missense unknown RAD51C R249H does not lie within any known functional domains of the Rad51c protein (UniProt.org). R249H binds to Rad51b, Rad51d, and Xrcc3 to similar levels of wild-type protein in a yeast assay (PMID: 36099300), but has not been fully biochemically characterized and therefore, its effect on Rad51c protein function is unknown.
RAD51C R258H missense loss of function RAD51C R258H does not lie within any known functional domains of the Rad51c protein (UniProt.org). R258H rescues survival in Rad51c-null cells in culture (PMID: 36099300), however, results in variable interaction with Rad51b, Rad51d, and Xrcc3 in a yeast assay (PMID: 36099300), defects in cell cycle progression at the G2/M transition (PMID: 22167183, PMID: 20400963), decreased sensitivity to mitomycin in cell culture, and reduced homologous recombination activity in a reporter assay (PMID: 22167183) and in cell culture (PMID: 36099300).
RAD51C R260W missense unknown RAD51C R260W does not lie within any known functional domains of the Rad51c protein (UniProt.org). R260W binds to Rad51b, Rad51d, and Xrcc3 to similar levels of wild-type protein in a yeast assay (PMID: 36099300), but has not been biochemically characterized and therefore, its effect on Rad51c protein function is unknown.
RAD51C R312W missense loss of function RAD51C R312W does not lie within any known functional domains of the Rad51c protein (UniProt.org). R312W retains binding with Rad51b and Xrcc3, however, results in a loss of Rad51c function as indicated by failure to rescue mitomycin C hypersensitivity and cell cycle arrest (PMID: 28829762), defects in homologous recombination repair (PMID: 28829762, PMID: 36099300), and failure to rescue survival in Rad51c-null cells in culture (PMID: 36099300).
RAD51C R366Q missense loss of function - predicted RAD51C R366Q does not lie within any known functional domains of the Rad51c protein (UniProt.org). R366Q results in Chk2 activation and Rad51 foci formation similar to wild-type (PMID: 20400964), and complements sensitivity to DNA damage and homologous recombination repair activity in RAD51C-null cells in culture (PMID: 37253112), and similar interaction with Rad51b, Rad51d, and Xrcc3 to wild-type Rad51c in yeast assays (PMID: 36099300), but moderately increased chromosomal aberrations, reduced G2/M accumulation and DNA synthesis in cultured cells, and decreased homologous recombination activity in a reporter assay (PMID: 22167183) and in culture (PMID: 25292178), and therefore, is predicted to lead to a loss of Rad51c protein function.
RAD51C T121R missense loss of function RAD51C T121R lies within the region required for Holliday junction resolution activity and the Rad51b, Rad51d, and Xrcc3-interacting region of the Rad51c protein (UniProt.org). T121R results in decreased interaction with Rad51b, Rad51d, and Xrcc3 in a yeast assay, reduced homologous recombination activity, and decreased Rad51 foci formation in culture, and failure to rescue survival in Rad51c-null cells or complement sensitivity to DNA damage in Rad51c-null cells in culture (PMID: 36099300).
RAD51C T132P missense loss of function RAD51C T132P lies within the Rad51b, Rad51d, and Xrcc3-interacting region of the Rad51c protein (UniProt.org). T132P retains binding to Rad51b, Rad51c, and Xrcc2 but not Xrcc3 in an in vitro assay in one study (PMID: 33832919), but demonstrates reduced interaction with Rad51b, Rad51d, and Xrcc3 in a yeast assay in another study (PMID: 36099300), results in loss of DNA binding in in vitro assays, reduced homologous recombination activity compared to wild-type Rad51c in cultured cells, fails to rescue survival of Rad51c-null cells, and results in decreased Rad51 foci formation in cell culture (PMID: 33832919, PMID: 36099300).
RAD51C T287A missense unknown RAD51C T287A does not lie within any known functional domains of the Rad51c protein (UniProt.org). T287A is conflicting as it demonstrates homologous recombination activity similar to wild-type Rad51c in cultured cells, rescues survival in Rad51c-null cells in culture, and results in variable interaction with Rad51b, Rad51d, and Xrcc3 in one study (PMID: 36099300), but demonstrates a partial defect in homologous recombination (PMID: 22167183, PMID: 21980511, PMID: 25292178) and decreased association with Xrcc3 in other studies (PMID: 22167183, PMID: 21980511), and therefore, its effect on Rad51c protein function is unknown.
RAD51C T336P missense loss of function - predicted RAD51C T336P does not lie within any known functional domains of the Rad51c protein (UniProt.org). T336P retains binding with Rad51b and Xrcc3 (PMID: 36099300, PMID: 37253112), but results in variable interaction with Rad51d in a yeast assay (PMID: 36099300), demonstrates lack of binding to Rad51d and Xrcc2 and results in decreased homology-directed DNA repair activity compared to wild-type Rad51c in culture (PMID: 37253112), and therefore, is predicted to lead to a loss of Rad51c protein function.
RAD51C V140G missense loss of function RAD51C V140G does not lie within any known functional domains of the Rad51c protein (UniProt.org). V140G results in decreased interaction with Rad51b, Rad51d, and Xrcc3 in a yeast assay and reduced homologous recombination activity compared to wild-type Rad51c in cultured cells (PMID: 36099300).
RAD51C Y224H missense no effect - predicted RAD51C Y224H does not lie within any known functional domains of the Rad51c protein (UniProt.org). Y224H binds to Rad51b, Rad51d, and Xrcc3 at similar levels as wild-type Rad51c in a yeast assay (PMID: 36099300) 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 T121R osteosarcoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment inhibited viability of an osteosarcoma cell line expressing RAD51C T121R in culture (PMID: 36099300). 36099300
RAD51C T121R osteosarcoma sensitive Cisplatin Preclinical - Cell culture Actionable In a preclinical study, Platinol (cisplatin) treatment inhibited viability of an osteosarcoma cell line expressing RAD51C T121R in culture (PMID: 36099300). 36099300
RAD51C C135Y osteosarcoma sensitive Cisplatin Preclinical - Cell culture Actionable In a preclinical study, Platinol (cisplatin) treatment inhibited viability of an osteosarcoma cell line expressing RAD51C C135Y in culture (PMID: 36099300). 36099300
RAD51C T132P osteosarcoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment inhibited viability of an osteosarcoma cell line expressing RAD51C T132P in culture (PMID: 36099300). 36099300
RAD51C T132P osteosarcoma sensitive Cisplatin Preclinical - Cell culture Actionable In a preclinical study, Platinol (cisplatin) treatment inhibited viability of an osteosarcoma cell line expressing RAD51C T132P in culture (PMID: 36099300). 36099300
RAD51C C135Y osteosarcoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment inhibited viability of an osteosarcoma cell line expressing RAD51C C135Y in culture (PMID: 36099300). 36099300