[Paper-level Aggregated] PMCID: PMC10390864

Evidence Type(s): Functional

Summary: Mutation: A126T | Summary: The A126T mutation was assessed in a cell-based HDR assay, indicating its influence on RAD51C HR DNA repair activity. It is described as a neutral variant that coimmunoprecipitates with RAD51D and XRCC2, indicating it does not alter the molecular function of the RAD51C complexes.

Evidence Type: Functional Mutation: C135Y | Summary: The C135Y mutation was categorized as deleterious in the HDR assay, demonstrating its impact on RAD51C HR DNA repair activity. It introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Additionally, it exhibits dramatically reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response.

Evidence Type: Functional Mutation: D109Y | Summary: The D109Y variant induces RAD51 foci formation, indicating it alters molecular function related to DNA damage response. It is also a neutral variant that coimmunoprecipitates with RAD51D and XRCC2, suggesting it does not affect the molecular function of the RAD51C complexes.

Evidence Type: Functional Mutation: D159N | Summary: The D159N mutation was classified as intermediate in the HDR assay, suggesting it alters RAD51C HR DNA repair activity. It is classified as an intermediate variant that loses the ability to bind to XRCC3 but retains binding to RAD51D-XRCC2, indicating a change in molecular function.

Evidence Type: Functional Mutation: G125V | Summary: The G125V mutation was identified as deleterious in the HDR assay, indicating its effect on RAD51C HR DNA repair activity.

Evidence Type: Functional Mutation: G130R | Summary: The G130R variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. It introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Additionally, it alters molecular function by causing a significant decrease in RAD51 foci, indicating a disruption in homologous recombination repair.

Evidence Type: Functional Mutation: G153D | Summary: The G153D mutation was categorized as deleterious in the HDR assay, reflecting its influence on RAD51C HR DNA repair activity.

Evidence Type: Functional Mutation: G162E | Summary: The G162E variant is identified as a deleterious variant that loses the ability to bind to XRCC3 but can still bind to RAD51D-XRCC2, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: G264S | Summary: The G264S mutation was classified as neutral in the HDR assay, indicating it does not significantly alter RAD51C HR DNA repair activity.

Evidence Type: Functional Mutation: G264V | Summary: The G264V mutation was categorized as neutral in the HDR assay, suggesting it does not impact RAD51C HR DNA repair activity.

Evidence Type: Functional Mutation: G306R | Summary: The variant p.Gly306Arg (G306R) exhibits altered IC50 values for cisplatin and olaparib, suggesting a functional impact on drug response. It also exhibits partially reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response.

Evidence Type: Functional Mutation: K131I | Summary: The K131I variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. It leads to a significant decrease in RAD51 foci, which suggests a disruption in homologous recombination repair.

Evidence Type: Functional Mutation: L138F | Summary: The L138F variant is characterized as deleterious and shows reduced HDR activity in U2OS cells, indicating that it alters molecular function related to homologous recombination. It introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Additionally, it alters molecular function, as evidenced by a decrease in RAD51 foci, suggesting a disruption in homologous recombination repair.

Evidence Type: Functional Mutation: L219S | Summary: The L219S mutation was classified as neutral in the HDR assay, indicating it does not significantly alter RAD51C HR DNA repair activity.

Evidence Type: Functional Mutation: P21S | Summary: The P21S variant induces RAD51 foci formation, indicating it alters molecular function related to DNA damage response.

Evidence Type: Functional Mutation: R168G | Summary: The R168G variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. It impacts molecular function, leading to a significant decrease in RAD51 foci, indicating a disruption in homologous recombination repair. It also removes a positively charged residue that directly interacts with the negatively charged triphosphate group of ATP, influencing RAD51C function.

Evidence Type: Functional Mutation: R214C | Summary: The R214C mutation was reported as neutral in the HDR assay, indicating it does not affect RAD51C HR DNA repair activity.

Evidence Type: Functional Mutation: R258H | Summary: The R258H variant, observed as a homozygous variant in a FANCO patient, displays reduced binding for all complex members, indicating a change in molecular function. It was classified as intermediate in the HDR assay, suggesting it alters RAD51C HR DNA repair activity.

Evidence Type: Functional Mutation: R312W | Summary: The R312W variant was identified as deleterious in the HDR assay, demonstrating its effect on RAD51C HR DNA repair activity. It removes a positively charged residue that may weaken the interaction with the negatively charged gamma phosphate group of ATP, influencing RAD51C activity.

Evidence Type: Functional Mutation: T132R | Summary: The T132R variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. It affects molecular function, resulting in a significant decrease in RAD51 foci, indicating a disruption in homologous recombination repair. It introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function.

Evidence Type: Functional Mutation: T287A | Summary: The T287A mutation was categorized as neutral in the HDR assay, suggesting it does not impact RAD51C HR DNA repair activity.

Evidence Type: Functional Mutation: V140E | Summary: The V140E variant exhibits dramatically reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response. It introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function.

Evidence Type: Functional Mutation: G302V | Summary: The G302V variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. It is identified as a deleterious variant that loses the ability to bind to XRCC3 but can still bind to RAD51D-XRCC2, indicating an alteration in molecular function. It disrupts a hydrophobic core and may interfere with RAD51C protomer formation, influencing RAD51C function.

Evidence Type: Functional Mutation: T336P | Summary: The T336P variant is a deleterious variant that binds only to XRCC3 and not to RAD51D-XRCC2, indicating a change in molecular function.

Evidence Type: Functional

Gene→Variant (gene-first): RAD51C(5889):A126T RAD51C(5889):C135Y RAD51C(5889):D109Y RAD51C(5889):D159N RAD51C(5889):G125V RAD51C(5889):G130R RAD51C(5889):G153D RAD51C(5889):G162E RAD51C(5889):G264S RAD51C(5889):G264V RAD51C(5889):G306R RAD51C(5889):K131I RAD51C(5889):L138F RAD51C(5889):L219S RAD51C(5889):P21S RAD51C(5889):R168G RAD51C(5889):R214C RAD51C(5889):R258H RAD51C(5889):R312W RAD51C(5889):T132R RAD51C(5889):T287A RAD51C(5889):V140E RAD51C(5889):G302V RAD51C(5889):T336P

Genes: RAD51C(5889)

Variants: A126T C135Y D109Y D159N G125V G130R G153D G162E G264S G264V G306R K131I L138F L219S P21S R168G R214C R258H R312W T132R T287A V140E G302V T336P

[Paper-level Aggregated] PMCID: PMC10390864

Evidence Type(s): Oncogenic

Summary: Mutation: L138F | Summary: The L138F variant is identified as a deleterious variant that fails to coimmunoprecipitate with RAD51D and XRCC2, indicating its contribution to tumor development or progression.

Gene→Variant (gene-first): RAD51C(5889):L138F

Genes: RAD51C(5889)

Variants: L138F

[Paper-level Aggregated] PMCID: PMC10390864

Evidence Type(s): Predictive

Summary: Mutation: E94K | Summary: The variant p.Glu94Lys (E94K) shows a significant reduction in sensitivity to cisplatin and a notable decrease in sensitivity to olaparib, indicating its potential role in predicting treatment response.

Evidence Type: Predictive Mutation: G306R | Summary: The variant p.Gly306Arg (G306R) demonstrates a marked reduction in sensitivity to both cisplatin and olaparib, suggesting its predictive value for treatment response.

Evidence Type: Predictive Mutation: G130R | Summary: The G130R variant showed sensitivity to olaparib compared with WT-complemented cells, indicating a correlation with response to therapy.

Evidence Type: Predictive Mutation: K131I | Summary: The K131I variant showed sensitivity to olaparib compared with WT-complemented cells, indicating a correlation with response to therapy.

Evidence Type: Predictive Mutation: T132R | Summary: The T132R variant showed sensitivity to olaparib compared with WT-complemented cells, indicating a correlation with response to therapy.

Evidence Type: Predictive Mutation: Q133E | Summary: The Q133E variant had intermediate effects on sensitivity to olaparib compared with WT-complemented cells, indicating a correlation with response to therapy.

Evidence Type: Predictive Mutation: G302V | Summary: The G302V variant had intermediate effects on sensitivity to olaparib compared with WT-complemented cells, indicating a correlation with response to therapy.

Evidence Type: Predictive Mutation: L138F | Summary: The L138F variant is associated with sensitivity to cisplatin and olaparib in CL-V4B cells, suggesting it may correlate with response to specific therapies.

Gene→Variant (gene-first): RAD51C(5889):E94K RAD51C(5889):G306R RAD51C(5889):G130R RAD51C(5889):K131I RAD51C(5889):T132R RAD51C(5889):Q133E RAD51C(5889):G302V RAD51C(5889):L138F

Genes: RAD51C(5889)

Variants: E94K G306R G130R K131I T132R Q133E G302V L138F

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K131 | Summary: The K131 variant removes a positively charged residue that directly interacts with the negatively charged triphosphate group of ATP, influencing RAD51C function. Evidence Type: Functional | Mutation: R168 | Summary: The R168 variant removes a positively charged residue that directly interacts with the negatively charged triphosphate group of ATP, influencing RAD51C function. Evidence Type: Functional | Mutation: Q133E | Summary: The Q133E variant introduces a negatively charged group that destabilizes the negatively charged triphosphate group of ATP, influencing RAD51C function. Evidence Type: Functional | Mutation: G130R | Summary: The G130R variant introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Evidence Type: Functional | Mutation: T132I | Summary: The T132I variant introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Evidence Type: Functional | Mutation: T132R | Summary: The T132R variant introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Evidence Type: Functional | Mutation: C135Y | Summary: The C135Y variant introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Evidence Type: Functional | Mutation: L138F | Summary: The L138F variant introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Evidence Type: Functional | Mutation: V140E | Summary: The V140E variant introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Evidence Type: Functional | Mutation: R312W | Summary: The R312W variant removes a positively charged residue that may weaken the interaction with the negatively charged gamma phosphate group of ATP, influencing RAD51C activity. Evidence Type: Functional | Mutation: G302V | Summary: The G302V variant disrupts a hydrophobic core and may interfere with RAD51C protomer formation, influencing RAD51C function.

Gene→Variant (gene-first): 5889:16 A 5889:C135Y 5889:E94K 5889:G130R 5889:G302V 5889:K131 5889:L138F 5889:P21S 5889:Q133E 5889:R168 5889:R168G 5889:R312 5889:R312W 5889:T132I 5889:T132R 5892:T86I 5889:V140E 5889:p.Cys135Tyr 5889:p.Thr132Ile 5889:p.Val140Glu

Genes: 5889 5892

Variants: 16 A C135Y E94K G130R G302V K131 L138F P21S Q133E R168 R168G R312 R312W T132I T132R T86I V140E p.Cys135Tyr p.Thr132Ile p.Val140Glu

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: A126T | Summary: The A126T variant is described as a neutral variant that coimmunoprecipitates with RAD51D and XRCC2, indicating it does not alter the molecular function of the RAD51C complexes. Evidence Type: Functional | Mutation: D109Y | Summary: The D109Y variant is also a neutral variant that coimmunoprecipitates with RAD51D and XRCC2, suggesting it does not affect the molecular function of the RAD51C complexes. Evidence Type: Oncogenic | Mutation: L138F | Summary: The L138F variant is identified as a deleterious variant that fails to coimmunoprecipitate with RAD51D and XRCC2, indicating its contribution to tumor development or progression. Evidence Type: Functional | Mutation: L27P | Summary: The L27P variant is classified as a deleterious variant that binds only to XRCC3 and not to RAD51D-XRCC2, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: T336P | Summary: The T336P variant is a deleterious variant that binds only to XRCC3 and not to RAD51D-XRCC2, indicating a change in molecular function. Evidence Type: Functional | Mutation: T86I | Summary: The T86I variant is described as an intermediate variant that binds only to XRCC3 and not to RAD51D-XRCC2, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: D159N | Summary: The D159N variant is classified as an intermediate variant that loses the ability to bind to XRCC3 but retains binding to RAD51D-XRCC2, indicating a change in molecular function. Evidence Type: Functional | Mutation: G162E | Summary: The G162E variant is identified as a deleterious variant that loses the ability to bind to XRCC3 but can still bind to RAD51D-XRCC2, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: S163R | Summary: The S163R variant is classified as a deleterious variant that loses the ability to bind to XRCC3 but retains binding to RAD51D-XRCC2, suggesting a change in molecular function. Evidence Type: Functional | Mutation: G302V | Summary: The G302V variant is identified as a deleterious variant that loses the ability to bind to XRCC3 but can still bind to RAD51D-XRCC2, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: R258H | Summary: The R258H variant, observed as a homozygous variant in a FANCO patient, displays reduced binding for all complex members, indicating a change in molecular function.

Gene→Variant (gene-first): 5889:A126T 5889:D109Y 5889:D159N 5889:G162E 5889:G302V 5889:L138F 5889:L27P 5889:Q133E 5889:R258H 5889:S163R 5889:T336P 5892:T86I 5889:p.Gly162Glu 5889:p.Ser163Arg 5889:p.Thr336Pro 5892:p.Thr86Ile

Genes: 5889 5892

Variants: A126T D109Y D159N G162E G302V L138F L27P Q133E R258H S163R T336P T86I p.Gly162Glu p.Ser163Arg p.Thr336Pro p.Thr86Ile

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G130R | Summary: The G130R variant alters molecular function by causing a significant decrease in RAD51 foci, indicating a disruption in homologous recombination repair. Evidence Type: Functional | Mutation: K131I | Summary: The K131I variant alters molecular function, leading to a significant decrease in RAD51 foci, which suggests a disruption in homologous recombination repair. Evidence Type: Functional | Mutation: T132R | Summary: The T132R variant affects molecular function, resulting in a significant decrease in RAD51 foci, indicating a disruption in homologous recombination repair. Evidence Type: Functional | Mutation: L138F | Summary: The L138F variant alters molecular function, as evidenced by a decrease in RAD51 foci, suggesting a disruption in homologous recombination repair. Evidence Type: Functional | Mutation: R168G | Summary: The R168G variant impacts molecular function, leading to a significant decrease in RAD51 foci, indicating a disruption in homologous recombination repair.

Gene→Variant (gene-first): 5889:G130R 5889:G302V 5889:K131I 5889:L138F 5889:Q133E 5889:R168G 5889:T132R

Genes: 5889

Variants: G130R G302V K131I L138F Q133E R168G T132R

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Predictive

Summary: Evidence Type: Functional | Mutation: L138F | Summary: The L138F variant is characterized as deleterious and shows reduced HDR activity in U2OS cells, indicating that it alters molecular function related to homologous recombination. Evidence Type: Predictive | Mutation: L138F | Summary: The L138F variant is associated with sensitivity to cisplatin and olaparib in CL-V4B cells, suggesting it may correlate with response to specific therapies.

Gene→Variant (gene-first): 5889:L138F

Genes: 5889

Variants: L138F

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional, Predictive

Summary: Evidence Type: Functional | Mutation: G130R | Summary: The G130R variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. Evidence Type: Functional | Mutation: K131I | Summary: The K131I variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. Evidence Type: Functional | Mutation: T132R | Summary: The T132R variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. Evidence Type: Functional | Mutation: Q133E | Summary: The Q133E variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. Evidence Type: Functional | Mutation: L138F | Summary: The L138F variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. Evidence Type: Functional | Mutation: R168G | Summary: The R168G variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. Evidence Type: Functional | Mutation: G302V | Summary: The G302V variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. Evidence Type: Predictive | Mutation: G130R | Summary: The G130R variant showed sensitivity to olaparib compared with WT-complemented cells, indicating a correlation with response to therapy. Evidence Type: Predictive | Mutation: K131I | Summary: The K131I variant showed sensitivity to olaparib compared with WT-complemented cells, indicating a correlation with response to therapy. Evidence Type: Predictive | Mutation: T132R | Summary: The T132R variant showed sensitivity to olaparib compared with WT-complemented cells, indicating a correlation with response to therapy. Evidence Type: Predictive | Mutation: Q133E | Summary: The Q133E variant had intermediate effects on sensitivity to olaparib compared with WT-complemented cells, indicating a correlation with response to therapy. Evidence Type: Predictive | Mutation: G302V | Summary: The G302V variant had intermediate effects on sensitivity to olaparib compared with WT-complemented cells, indicating a correlation with response to therapy.

Gene→Variant (gene-first): 5889:G130R 5889:G302V 5889:K131I 5889:L138F 5889:Q133E 5889:R168G 5889:T132R

Genes: 5889

Variants: G130R G302V K131I L138F Q133E R168G T132R

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: P21S | Summary: The P21S variant induces RAD51 foci formation, indicating it alters molecular function related to DNA damage response. Evidence Type: Functional | Mutation: D109Y | Summary: The D109Y variant induces RAD51 foci formation, indicating it alters molecular function related to DNA damage response. Evidence Type: Functional | Mutation: C147Y | Summary: The C147Y variant induces RAD51 foci formation, indicating it alters molecular function related to DNA damage response. Evidence Type: Functional | Mutation: D108G | Summary: The D108G variant exhibits dramatically reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response. Evidence Type: Functional | Mutation: C135Y | Summary: The C135Y variant exhibits dramatically reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response. Evidence Type: Functional | Mutation: V140E | Summary: The V140E variant exhibits dramatically reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response. Evidence Type: Functional | Mutation: A155E | Summary: The A155E variant exhibits dramatically reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response. Evidence Type: Functional | Mutation: D159Y | Summary: The D159Y variant exhibits dramatically reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response. Evidence Type: Functional | Mutation: G306R | Summary: The G306R variant exhibits partially reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response.

Gene→Variant (gene-first): 5889:A155E 5889:C135Y 5889:C147Y 5888:D108G 5889:D109Y 5889:D159Y 5889:G306R 5889:P21S 5889:V140E 5889:p.Ala155Glu 5888:p.Asp108Gly 5889:p.Asp109Tyr 5889:p.Asp159Tyr 5889:p.Cys147Tyr 5889:p.Gly306Arg 5889:p.Pro21Ser 5889:p.Val140Glu

Genes: 5889 5888

Variants: A155E C135Y C147Y D108G D109Y D159Y G306R P21S V140E p.Ala155Glu p.Asp108Gly p.Asp109Tyr p.Asp159Tyr p.Cys147Tyr p.Gly306Arg p.Pro21Ser p.Val140Glu

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: E94K | Summary: The variant p.Glu94Lys (E94K) shows a significant reduction in sensitivity to cisplatin and a notable decrease in sensitivity to olaparib, indicating its potential role in predicting treatment response. Evidence Type: Predictive | Mutation: G306R | Summary: The variant p.Gly306Arg (G306R) demonstrates a marked reduction in sensitivity to both cisplatin and olaparib, suggesting its predictive value for treatment response. Evidence Type: Functional | Mutation: E94K | Summary: The variant p.Glu94Lys (E94K) is associated with altered IC50 values for cisplatin and olaparib, indicating a change in molecular function. Evidence Type: Functional | Mutation: G306R | Summary: The variant p.Gly306Arg (G306R) exhibits altered IC50 values for cisplatin and olaparib, suggesting a functional impact on drug response.

Gene→Variant (gene-first): 5889:E94K 5889:G306R 5889:p.Glu94Lys 5889:p.Gly306Arg

Genes: 5889

Variants: E94K G306R p.Glu94Lys p.Gly306Arg

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A126T | Summary: The A126T mutation was assessed in a cell-based HDR assay, indicating its influence on RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: C135Y | Summary: The C135Y mutation was categorized as deleterious in the HDR assay, demonstrating its impact on RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: D159N | Summary: The D159N mutation was classified as intermediate in the HDR assay, suggesting it alters RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: G125V | Summary: The G125V mutation was identified as deleterious in the HDR assay, indicating its effect on RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: G153D | Summary: The G153D mutation was categorized as deleterious in the HDR assay, reflecting its influence on RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: G264S | Summary: The G264S mutation was classified as neutral in the HDR assay, indicating it does not significantly alter RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: G264V | Summary: The G264V mutation was categorized as neutral in the HDR assay, suggesting it does not impact RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: G3R | Summary: The G3R mutation was reported as neutral in the HDR assay, indicating it does not affect RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: L138F | Summary: The L138F mutation was identified as deleterious in the HDR assay, demonstrating its effect on RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: L219S | Summary: The L219S mutation was classified as neutral in the HDR assay, indicating it does not significantly alter RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: Q143R | Summary: The Q143R mutation was categorized as neutral in the HDR assay, suggesting it does not impact RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: R214C | Summary: The R214C mutation was reported as neutral in the HDR assay, indicating it does not affect RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: R258H | Summary: The R258H mutation was classified as intermediate in the HDR assay, suggesting it alters RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: R312W | Summary: The R312W mutation was identified as deleterious in the HDR assay, demonstrating its effect on RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: R366Q | Summary: The R366Q mutation was reported as neutral in the HDR assay, indicating it does not significantly alter RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: T287A | Summary: The T287A mutation was categorized as neutral in the HDR assay, suggesting it does not impact RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: V169A | Summary: The V169A mutation was reported as neutral in the HDR assay, indicating it does not affect RAD51C HR DNA repair activity.

Gene→Variant (gene-first): 5889:A126T 5889:C135Y 5889:D159N 5889:G125V 5889:G153D 5889:G264S 5889:G264V 5889:G3R 5889:L138F 5889:L219S 5889:Q143R 5889:R214C 5889:R258H 5889:R312W 5889:R366Q 5889:T287A 5889:V169A 5889:p.Arg214Cys 5889:p.Arg258His 5889:p.Arg312Trp 5889:p.Arg366Gln 5889:p.Asp159Asn 5889:p.Gln143Arg 5889:p.Gly125Val 5889:p.Gly153Asp 5889:p.Gly264Ser 5889:p.Gly264Val 5889:p.Gly3Arg 5889:p.Leu219Ser 5889:p.Thr287Ala 5889:p.Val169Ala

Genes: 5889

Variants: A126T C135Y D159N G125V G153D G264S G264V G3R L138F L219S Q143R R214C R258H R312W R366Q T287A V169A p.Arg214Cys p.Arg258His p.Arg312Trp p.Arg366Gln p.Asp159Asn p.Gln143Arg p.Gly125Val p.Gly153Asp p.Gly264Ser p.Gly264Val p.Gly3Arg p.Leu219Ser p.Thr287Ala p.Val169Ala

[Paper-level Aggregated] PMCID: PMC10390864

Evidence Type(s): Functional, Oncogenic, Predictive, Prognostic

Justification: Functional: The study assessed the influence of various RAD51C missense mutations on HDR DNA repair activity, categorizing them as deleterious, hypomorphic, or neutral based on their effects on HDR scores, indicating their functional impact on DNA repair mechanisms. Oncogenic: The loss of RAD51C function promotes HR deficiency and sensitizes cells to cisplatin and olaparib, suggesting that variants affecting RAD51C function may contribute to oncogenic processes by impairing DNA repair and influencing drug sensitivity in cancer cells. Predictive: The study evaluated the sensitivity of cells with different RAD51C variants to cisplatin and olaparib, indicating that specific variants can predict responses to these drugs, which is crucial for therapeutic decision-making in cancer treatment. Prognostic: The correlation between RAD51C variant status and drug response (IC50 values) suggests that these variants may serve as prognostic markers for treatment outcomes in patients receiving cisplatin or olaparib.

Gene→Variant (gene-first): RAD51C(5889):16 A RAD51C(5889):C135Y RAD51C(5889):E94K RAD51C(5889):G130R RAD51C(5889):G302V RAD51C(5889):K131 RAD51C(5889):L138F RAD51C(5889):P21S RAD51C(5889):Q133E RAD51C(5889):R168 RAD51C(5889):R168G RAD51C(5889):R312 RAD51C(5889):R312W RAD51C(5889):T132I RAD51C(5889):T132R RAD51D(5892):T86I RAD51C(5889):V140E RAD51C(5889):p.Cys135Tyr RAD51C(5889):p.Thr132Ile RAD51C(5889):p.Val140Glu RAD51C(5889):A126T RAD51C(5889):D159N RAD51C(5889):G125V RAD51C(5889):G153D RAD51C(5889):G264S RAD51C(5889):G264V RAD51C(5889):G3R RAD51C(5889):L219S RAD51C(5889):Q143R RAD51C(5889):R214C RAD51C(5889):R258H RAD51C(5889):R366Q RAD51C(5889):T287A RAD51C(5889):V169A RAD51C(5889):p.Arg214Cys RAD51C(5889):p.Arg258His RAD51C(5889):p.Arg312Trp RAD51C(5889):p.Arg366Gln RAD51C(5889):p.Asp159Asn RAD51C(5889):p.Gln143Arg RAD51C(5889):p.Gly125Val RAD51C(5889):p.Gly153Asp RAD51C(5889):p.Gly264Ser RAD51C(5889):p.Gly264Val RAD51C(5889):p.Gly3Arg RAD51C(5889):p.Leu219Ser RAD51C(5889):p.Thr287Ala RAD51C(5889):p.Val169Ala RAD51C(5889):D109Y RAD51C(5889):G162E RAD51C(5889):L27P RAD51C(5889):S163R RAD51C(5889):T336P RAD51C(5889):p.Gly162Glu RAD51C(5889):p.Ser163Arg RAD51C(5889):p.Thr336Pro RAD51D(5892):p.Thr86Ile RAD51C(5889):A155E RAD51C(5889):C147Y RAD51(5888):D108G RAD51C(5889):D159Y RAD51C(5889):G306R RAD51C(5889):p.Ala155Glu RAD51(5888):p.Asp108Gly RAD51C(5889):p.Asp109Tyr RAD51C(5889):p.Asp159Tyr RAD51C(5889):p.Cys147Tyr RAD51C(5889):p.Gly306Arg RAD51C(5889):p.Pro21Ser RAD51C(5889):p.Glu94Lys RAD51C(5889):K131I

Genes: RAD51C(5889) RAD51D(5892) RAD51(5888)

Variants: 16 A C135Y E94K G130R G302V K131 L138F P21S Q133E R168 R168G R312 R312W T132I T132R T86I V140E p.Cys135Tyr p.Thr132Ile p.Val140Glu A126T D159N G125V G153D G264S G264V G3R L219S Q143R R214C R258H R366Q T287A V169A p.Arg214Cys p.Arg258His p.Arg312Trp p.Arg366Gln p.Asp159Asn p.Gln143Arg p.Gly125Val p.Gly153Asp p.Gly264Ser p.Gly264Val p.Gly3Arg p.Leu219Ser p.Thr287Ala p.Val169Ala D109Y G162E L27P S163R T336P p.Gly162Glu p.Ser163Arg p.Thr336Pro p.Thr86Ile A155E C147Y D108G D159Y G306R p.Ala155Glu p.Asp108Gly p.Asp109Tyr p.Asp159Tyr p.Cys147Tyr p.Gly306Arg p.Pro21Ser p.Glu94Lys K131I

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how several variants, including K131, R168G, G130R, and others, alter the molecular function of RAD51C by disrupting the ATP-binding site and influencing RAD51C activity, as demonstrated in HDR assays. Oncogenic: The passage indicates that the variants are deleterious and influence RAD51C function, which is relevant to tumor development or progression, particularly in the context of HDR assays.

Gene→Variant (gene-first): 5889:16 A 5889:C135Y 5889:E94K 5889:G130R 5889:G302V 5889:K131 5889:L138F 5889:P21S 5889:Q133E 5889:R168 5889:R168G 5889:R312 5889:R312W 5889:T132I 5889:T132R 5892:T86I 5889:V140E 5889:p.Cys135Tyr 5889:p.Thr132Ile 5889:p.Val140Glu

Genes: 5889 5892

Variants: 16 A C135Y E94K G130R G302V K131 L138F P21S Q133E R168 R168G R312 R312W T132I T132R T86I V140E p.Cys135Tyr p.Thr132Ile p.Val140Glu

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how various RAD51C variants affect the ability to form protein complexes involved in DNA damage repair, indicating that these variants alter molecular function. Oncogenic: The mention of deleterious variants that lose the ability to form complexes suggests a role in tumor development or progression, as these variants are associated with impaired DNA repair mechanisms.

Gene→Variant (gene-first): 5889:A126T 5889:D109Y 5889:D159N 5889:G162E 5889:G302V 5889:L138F 5889:L27P 5889:Q133E 5889:R258H 5889:S163R 5889:T336P 5892:T86I 5889:p.Gly162Glu 5889:p.Ser163Arg 5889:p.Thr336Pro 5892:p.Thr86Ile

Genes: 5889 5892

Variants: A126T D109Y D159N G162E G302V L138F L27P Q133E R258H S163R T336P T86I p.Gly162Glu p.Ser163Arg p.Thr336Pro p.Thr86Ile

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how RAD51C variants alter cell proliferation and the formation of RAD51 foci in response to ionizing radiation, indicating changes in molecular function related to DNA damage signaling and repair. Oncogenic: The variants are implicated in a proliferation defect and disruption of homologous recombination (HR) repair, suggesting their role in tumor development or progression.

Gene→Variant (gene-first): 5889:G130R 5889:G302V 5889:K131I 5889:L138F 5889:Q133E 5889:R168G 5889:T132R

Genes: 5889

Variants: G130R G302V K131I L138F Q133E R168G T132R

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the L138F variant alters HDR activity in different cell lines, indicating a change in molecular function. Predictive: The passage mentions the sensitivity of variants, including L138F, to cisplatin and olaparib, suggesting a correlation with response to these therapies.

Gene→Variant (gene-first): 5889:L138F

Genes: 5889

Variants: L138F

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the sensitivity of specific RAD51C variants (G130R, K131I, T132R, Q133E, and G302V) to olaparib, indicating a correlation with response to therapy. Functional: The passage describes the introduction of RAD51C variants into a cell line and assesses their effects on homologous recombination repair (HDR), indicating that these variants alter molecular function.

Gene→Variant (gene-first): 5889:G130R 5889:G302V 5889:K131I 5889:L138F 5889:Q133E 5889:R168G 5889:T132R

Genes: 5889

Variants: G130R G302V K131I L138F Q133E R168G T132R

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how RAD51C missense variants alter RAD51 foci formation in response to DNA damage, indicating a change in molecular function related to DNA repair mechanisms. Predictive: The mention of "drug response findings" suggests that the variants may correlate with sensitivity or resistance to a specific therapy, indicating predictive evidence.

Gene→Variant (gene-first): 5889:A155E 5889:C135Y 5889:C147Y 5888:D108G 5889:D109Y 5889:D159Y 5889:G306R 5889:P21S 5889:V140E 5889:p.Ala155Glu 5888:p.Asp108Gly 5889:p.Asp109Tyr 5889:p.Asp159Tyr 5889:p.Cys147Tyr 5889:p.Gly306Arg 5889:p.Pro21Ser 5889:p.Val140Glu

Genes: 5889 5888

Variants: A155E C135Y C147Y D108G D109Y D159Y G306R P21S V140E p.Ala155Glu p.Asp108Gly p.Asp109Tyr p.Asp159Tyr p.Cys147Tyr p.Gly306Arg p.Pro21Ser p.Val140Glu

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the influence of RAD51C missense variants on the response to cisplatin and olaparib, indicating a correlation between the variants and treatment sensitivity. Functional: The passage describes how the variants affect IC50 values in the HDR assay, suggesting that they alter molecular function related to drug response.

Gene→Variant (gene-first): 5889:E94K 5889:G306R 5889:p.Glu94Lys 5889:p.Gly306Arg

Genes: 5889

Variants: E94K G306R p.Glu94Lys p.Gly306Arg

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the influence of missense mutations on RAD51C HR DNA repair activity, indicating that the variants alter molecular function as assessed by HDR activity in a cell-based assay. Oncogenic: The mention of deleterious variants categorized based on their impact on HDR activity suggests that these somatic variants contribute to tumor development or progression through their effects on DNA repair mechanisms.

Gene→Variant (gene-first): 5889:A126T 5889:C135Y 5889:D159N 5889:G125V 5889:G153D 5889:G264S 5889:G264V 5889:G3R 5889:L138F 5889:L219S 5889:Q143R 5889:R214C 5889:R258H 5889:R312W 5889:R366Q 5889:T287A 5889:V169A 5889:p.Arg214Cys 5889:p.Arg258His 5889:p.Arg312Trp 5889:p.Arg366Gln 5889:p.Asp159Asn 5889:p.Gln143Arg 5889:p.Gly125Val 5889:p.Gly153Asp 5889:p.Gly264Ser 5889:p.Gly264Val 5889:p.Gly3Arg 5889:p.Leu219Ser 5889:p.Thr287Ala 5889:p.Val169Ala

Genes: 5889

Variants: A126T C135Y D159N G125V G153D G264S G264V G3R L138F L219S Q143R R214C R258H R312W R366Q T287A V169A p.Arg214Cys p.Arg258His p.Arg312Trp p.Arg366Gln p.Asp159Asn p.Gln143Arg p.Gly125Val p.Gly153Asp p.Gly264Ser p.Gly264Val p.Gly3Arg p.Leu219Ser p.Thr287Ala p.Val169Ala

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how several variants, including K131, R168G, G130R, and others, alter the molecular function of RAD51C by disrupting the ATP-binding site and influencing RAD51C activity, as demonstrated in HDR assays. Oncogenic: The passage indicates that the variants are deleterious and influence RAD51C function, which is relevant to tumor development or progression, particularly in the context of HDR assays.

Gene→Variant (gene-first): 5889:16 A 5889:C135Y 5889:E94K 5889:G130R 5889:G302V 5889:K131 5889:L138F 5889:P21S 5889:Q133E 5889:R168 5889:R168G 5889:R312 5889:R312W 5889:T132I 5889:T132R 5892:T86I 5889:V140E 5889:p.Cys135Tyr 5889:p.Thr132Ile 5889:p.Val140Glu

Genes: 5889 5892

Variants: 16 A C135Y E94K G130R G302V K131 L138F P21S Q133E R168 R168G R312 R312W T132I T132R T86I V140E p.Cys135Tyr p.Thr132Ile p.Val140Glu

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how various RAD51C variants affect the ability to form protein complexes involved in DNA damage repair, indicating that these variants alter molecular function. Oncogenic: The mention of deleterious variants that lose the ability to form complexes suggests a role in tumor development or progression, as these variants are associated with impaired DNA repair mechanisms.

Gene→Variant (gene-first): 5889:A126T 5889:D109Y 5889:D159N 5889:G162E 5889:G302V 5889:L138F 5889:L27P 5889:Q133E 5889:R258H 5889:S163R 5889:T336P 5892:T86I 5889:p.Gly162Glu 5889:p.Ser163Arg 5889:p.Thr336Pro 5892:p.Thr86Ile

Genes: 5889 5892

Variants: A126T D109Y D159N G162E G302V L138F L27P Q133E R258H S163R T336P T86I p.Gly162Glu p.Ser163Arg p.Thr336Pro p.Thr86Ile

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how RAD51C variants alter cell proliferation and the formation of RAD51 foci in response to ionizing radiation, indicating changes in molecular function related to DNA damage signaling and repair. Oncogenic: The variants are implicated in a proliferation defect and disruption of homologous recombination (HR) repair, suggesting their role in tumor development or progression.

Gene→Variant (gene-first): 5889:G130R 5889:G302V 5889:K131I 5889:L138F 5889:Q133E 5889:R168G 5889:T132R

Genes: 5889

Variants: G130R G302V K131I L138F Q133E R168G T132R

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the L138F variant alters HDR activity in different cell lines, indicating a change in molecular function. Predictive: The passage mentions the sensitivity of variants, including L138F, to cisplatin and olaparib, suggesting a correlation with response to these therapies.

Gene→Variant (gene-first): 5889:L138F

Genes: 5889

Variants: L138F

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the sensitivity of specific RAD51C variants (G130R, K131I, T132R, Q133E, and G302V) to olaparib, indicating a correlation with response to therapy. Functional: The passage describes the introduction of RAD51C variants into a cell line and assesses their effects on homologous recombination repair (HDR), indicating that these variants alter molecular function.

Gene→Variant (gene-first): 5889:G130R 5889:G302V 5889:K131I 5889:L138F 5889:Q133E 5889:R168G 5889:T132R

Genes: 5889

Variants: G130R G302V K131I L138F Q133E R168G T132R

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how RAD51C missense variants alter RAD51 foci formation in response to DNA damage, indicating a change in molecular function related to DNA repair mechanisms. Predictive: The mention of "drug response findings" suggests that the variants may correlate with sensitivity or resistance to a specific therapy, indicating predictive evidence.

Gene→Variant (gene-first): 5889:A155E 5889:C135Y 5889:C147Y 5888:D108G 5889:D109Y 5889:D159Y 5889:G306R 5889:P21S 5889:V140E 5889:p.Ala155Glu 5888:p.Asp108Gly 5889:p.Asp109Tyr 5889:p.Asp159Tyr 5889:p.Cys147Tyr 5889:p.Gly306Arg 5889:p.Pro21Ser 5889:p.Val140Glu

Genes: 5889 5888

Variants: A155E C135Y C147Y D108G D109Y D159Y G306R P21S V140E p.Ala155Glu p.Asp108Gly p.Asp109Tyr p.Asp159Tyr p.Cys147Tyr p.Gly306Arg p.Pro21Ser p.Val140Glu

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the influence of RAD51C missense variants on the response to cisplatin and olaparib, indicating a correlation between the variants and treatment sensitivity. Functional: The passage describes how the variants affect IC50 values in the HDR assay, suggesting that they alter molecular function related to drug response.

Gene→Variant (gene-first): 5889:E94K 5889:G306R 5889:p.Glu94Lys 5889:p.Gly306Arg

Genes: 5889

Variants: E94K G306R p.Glu94Lys p.Gly306Arg

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the influence of missense mutations on RAD51C HR DNA repair activity, indicating that the variants alter molecular function as assessed by HDR activity in a cell-based assay. Oncogenic: The mention of deleterious variants categorized based on their impact on HDR activity suggests that these somatic variants contribute to tumor development or progression through their effects on DNA repair mechanisms.

Gene→Variant (gene-first): 5889:A126T 5889:C135Y 5889:D159N 5889:G125V 5889:G153D 5889:G264S 5889:G264V 5889:G3R 5889:L138F 5889:L219S 5889:Q143R 5889:R214C 5889:R258H 5889:R312W 5889:R366Q 5889:T287A 5889:V169A 5889:p.Arg214Cys 5889:p.Arg258His 5889:p.Arg312Trp 5889:p.Arg366Gln 5889:p.Asp159Asn 5889:p.Gln143Arg 5889:p.Gly125Val 5889:p.Gly153Asp 5889:p.Gly264Ser 5889:p.Gly264Val 5889:p.Gly3Arg 5889:p.Leu219Ser 5889:p.Thr287Ala 5889:p.Val169Ala

Genes: 5889

Variants: A126T C135Y D159N G125V G153D G264S G264V G3R L138F L219S Q143R R214C R258H R312W R366Q T287A V169A p.Arg214Cys p.Arg258His p.Arg312Trp p.Arg366Gln p.Asp159Asn p.Gln143Arg p.Gly125Val p.Gly153Asp p.Gly264Ser p.Gly264Val p.Gly3Arg p.Leu219Ser p.Thr287Ala p.Val169Ala