[Paper-level Aggregated] PMCID: PMC8008494

Evidence Type(s): Functional

Summary: Mutation: 2619 from Trp to Gly | Summary: Variants that change residue 2619 from Trp to Gly, Ser, or Cys all resulted in loss of function, indicating a critical role for this residue in molecular function.

Evidence Type: Functional Mutation: 2723 from Asp to Asn | Summary: Variants that change residue 2723 from Asp to Asn, His, Tyr, Ala, Gly, and Val consistently resulted in loss of function, suggesting a negatively charged amino acid is required at this position.

Evidence Type: Functional Mutation: Leu3180 | Summary: Differential effects on function were observed for two alterations in residue Leu3180, where a Pro substitution resulted in loss of function but an Arg substitution resulted in a functional protein.

Evidence Type: Functional Mutation: p.Gly2508Ser | Summary: The variant p.Gly2508Ser is associated with loss of function, indicating its critical role in the molecular function of the protein.

Evidence Type: Functional Mutation: p.Gly2508Arg | Summary: The variant p.Gly2508Arg is associated with loss of function, indicating its critical role in the molecular function of the protein.

Evidence Type: Functional Mutation: p.Ala2603Ser | Summary: The variant p.Ala2603Ser is associated with loss of function, indicating its critical role in the molecular function of the protein.

Evidence Type: Functional Mutation: p.Arg2625Lys | Summary: The variant p.Arg2625Lys is associated with loss of function, indicating its critical role in the molecular function of the protein.

Evidence Type: Functional Mutation: p.Ile2627Val | Summary: The variant p.Ile2627Val is associated with loss of function, indicating its critical role in the molecular function of the protein.

Evidence Type: Functional Mutation: p.Asn3124His | Summary: The variant p.Asn3124His is associated with loss of function, indicating its critical role in the molecular function of the protein.

Evidence Type: Functional Mutation: c.8723T>G | Summary: The variant c.8723T>G (p.Val2908Gly) was evaluated in a functional study and demonstrated sensitivity to multiple drugs, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: c.8905G>A | Summary: The variant c.8905G>A (p.Val2969Met) was also assessed in a functional study and showed consistent sensitivity to various drugs, reflecting a change in molecular function.

Gene→Variant (gene-first): NA:2619 from Trp to Gly BRCA2(675):2723 from Asp to Asn NA:Leu3180 BRCA2(675):p.Gly2508Ser APRT(353):p.Gly2508Arg BRCA2(675):p.Ala2603Ser BRCA2(675):p.Arg2625Lys BRCA2(675):p.Ile2627Val BRCA2(675):p.Asn3124His BRCA2(675):c.8723T>G BRCA2(675):c.8905G>A

Genes: NA BRCA2(675) APRT(353)

Variants: 2619 from Trp to Gly 2723 from Asp to Asn Leu3180 p.Gly2508Ser p.Gly2508Arg p.Ala2603Ser p.Arg2625Lys p.Ile2627Val p.Asn3124His c.8723T>G c.8905G>A

[Paragraph-level] PMCID: PMC8008494 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: c.8723T>G | Summary: The variant c.8723T>G (p.Val2908Gly) was evaluated in a functional study and demonstrated sensitivity to multiple drugs, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: c.8905G>A | Summary: The variant c.8905G>A (p.Val2969Met) was also assessed in a functional study and showed consistent sensitivity to various drugs, reflecting a change in molecular function.

Gene→Variant (gene-first): 675:c.8723T>G 675:c.8905G>A 675:p.Val2908Gly 675:p.Val2969Met

Genes: 675

Variants: c.8723T>G c.8905G>A p.Val2908Gly p.Val2969Met

[Paragraph-level] PMCID: PMC8008494 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: 2619 from Trp to Gly | Summary: Variants that change residue 2619 from Trp to Gly, Ser, or Cys all resulted in loss of function, indicating a critical role for this residue in molecular function. Evidence Type: Functional | Mutation: 2723 from Asp to Asn | Summary: Variants that change residue 2723 from Asp to Asn, His, Tyr, Ala, Gly, and Val consistently resulted in loss of function, suggesting a negatively charged amino acid is required at this position. Evidence Type: Functional | Mutation: Leu3180 | Summary: Differential effects on function were observed for two alterations in residue Leu3180, where a Pro substitution resulted in loss of function but an Arg substitution resulted in a functional protein. Evidence Type: Functional | Mutation: p.Gly2508Ser | Summary: The variant p.Gly2508Ser is associated with loss of function, indicating its critical role in the molecular function of the protein. Evidence Type: Functional | Mutation: p.Gly2508Arg | Summary: The variant p.Gly2508Arg is associated with loss of function, indicating its critical role in the molecular function of the protein. Evidence Type: Functional | Mutation: p.Ala2603Ser | Summary: The variant p.Ala2603Ser is associated with loss of function, indicating its critical role in the molecular function of the protein. Evidence Type: Functional | Mutation: p.Arg2625Lys | Summary: The variant p.Arg2625Lys is associated with loss of function, indicating its critical role in the molecular function of the protein. Evidence Type: Functional | Mutation: p.Ile2627Val | Summary: The variant p.Ile2627Val is associated with loss of function, indicating its critical role in the molecular function of the protein. Evidence Type: Functional | Mutation: p.Asn3124His | Summary: The variant p.Asn3124His is associated with loss of function, indicating its critical role in the molecular function of the protein.

Gene→Variant (gene-first): NA:2619 from Trp to Gly 675:2723 from Asp to Asn 353:7522G>A 353:7807G>T 353:7874G>A 353:7879A>G NA:Leu3180 353:Phe/Asn 353:c.7522G>C 675:c.7880T>A 675:c.9370A>C 675:c.9371A>T 675:c.9539T>C 675:p.Ala2603Ser 675:p.Arg2625Lys 675:p.Asn3124His 353:p.Gly2508Arg 675:p.Gly2508Ser 675:p.Ile2627Val

Genes: NA 675 353

Variants: 2619 from Trp to Gly 2723 from Asp to Asn 7522G>A 7807G>T 7874G>A 7879A>G Leu3180 Phe/Asn c.7522G>C c.7880T>A c.9370A>C c.9371A>T c.9539T>C p.Ala2603Ser p.Arg2625Lys p.Asn3124His p.Gly2508Arg p.Gly2508Ser p.Ile2627Val

[Paper-level Aggregated] PMCID: PMC8008494

Evidence Type(s): Functional, Oncogenic, Predictive

Justification: Functional: The text describes a functional assay (HDR) that evaluates the impact of various variants on protein function, indicating that certain variants resulted in loss of function or maintained functionality based on their HDR scores. Oncogenic: The mention of variants being associated with probabilities of pathogenicity >0.99 suggests that these variants may contribute to cancer development, indicating their potential oncogenic nature. Predictive: The text discusses the ability of certain variants to influence sensitivity to PARP inhibitors, which can be used to predict treatment responses in BRCA2-deficient cell lines.

Gene→Variant (gene-first): NA:2619 from Trp to Gly BRCA2(675):2723 from Asp to Asn APRT(353):7522G>A APRT(353):7807G>T APRT(353):7874G>A APRT(353):7879A>G NA:Leu3180 APRT(353):Phe/Asn APRT(353):c.7522G>C BRCA2(675):c.7880T>A BRCA2(675):c.9370A>C BRCA2(675):c.9371A>T BRCA2(675):c.9539T>C BRCA2(675):p.Ala2603Ser BRCA2(675):p.Arg2625Lys BRCA2(675):p.Asn3124His APRT(353):p.Gly2508Arg BRCA2(675):p.Gly2508Ser BRCA2(675):p.Ile2627Val BRCA2(675):c.8723T>G BRCA2(675):c.8905G>A BRCA2(675):p.Val2908Gly BRCA2(675):p.Val2969Met

Genes: NA BRCA2(675) APRT(353)

Variants: 2619 from Trp to Gly 2723 from Asp to Asn 7522G>A 7807G>T 7874G>A 7879A>G Leu3180 Phe/Asn c.7522G>C c.7880T>A c.9370A>C c.9371A>T c.9539T>C p.Ala2603Ser p.Arg2625Lys p.Asn3124His p.Gly2508Arg p.Gly2508Ser p.Ile2627Val c.8723T>G c.8905G>A p.Val2908Gly p.Val2969Met

[Paragraph-level] PMCID: PMC8008494 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the sensitivity of specific BRCA2 variants to PARP inhibitors, indicating a correlation with response to therapy. Functional: The passage describes how the BRCA2 variants influence the ability to restore survival in mouse embryonic stem cells and their functional classification based on drug sensitivity assays.

Gene→Variant (gene-first): 675:c.8723T>G 675:c.8905G>A 675:p.Val2908Gly 675:p.Val2969Met

Genes: 675

Variants: c.8723T>G c.8905G>A p.Val2908Gly p.Val2969Met

[Paragraph-level] PMCID: PMC8008494 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how specific variants alter the function of the protein, indicating that certain amino acid substitutions result in loss of function or maintain functionality, which is characteristic of functional evidence. Oncogenic: The context of the variants being associated with loss of function in a cancer-related gene (BRCA2) suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): NA:2619 from Trp to Gly 675:2723 from Asp to Asn 353:7522G>A 353:7807G>T 353:7874G>A 353:7879A>G NA:Leu3180 353:Phe/Asn 353:c.7522G>C 675:c.7880T>A 675:c.9370A>C 675:c.9371A>T 675:c.9539T>C 675:p.Ala2603Ser 675:p.Arg2625Lys 675:p.Asn3124His 353:p.Gly2508Arg 675:p.Gly2508Ser 675:p.Ile2627Val

Genes: NA 675 353

Variants: 2619 from Trp to Gly 2723 from Asp to Asn 7522G>A 7807G>T 7874G>A 7879A>G Leu3180 Phe/Asn c.7522G>C c.7880T>A c.9370A>C c.9371A>T c.9539T>C p.Ala2603Ser p.Arg2625Lys p.Asn3124His p.Gly2508Arg p.Gly2508Ser p.Ile2627Val

[Paragraph-level] PMCID: PMC8008494 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the sensitivity of specific BRCA2 variants to PARP inhibitors, indicating a correlation with response to therapy. Functional: The passage describes how the BRCA2 variants influence the ability to restore survival in mouse embryonic stem cells and their functional classification based on drug sensitivity assays.

Gene→Variant (gene-first): 675:c.8723T>G 675:c.8905G>A 675:p.Val2908Gly 675:p.Val2969Met

Genes: 675

Variants: c.8723T>G c.8905G>A p.Val2908Gly p.Val2969Met

[Paragraph-level] PMCID: PMC8008494 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how specific variants alter the function of the protein, indicating that certain amino acid substitutions result in loss of function or maintain functionality, which is characteristic of functional evidence. Oncogenic: The context of the variants being associated with loss of function in a cancer-related gene (BRCA2) suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): NA:2619 from Trp to Gly 675:2723 from Asp to Asn 353:7522G>A 353:7807G>T 353:7874G>A 353:7879A>G NA:Leu3180 353:Phe/Asn 353:c.7522G>C 675:c.7880T>A 675:c.9370A>C 675:c.9371A>T 675:c.9539T>C 675:p.Ala2603Ser 675:p.Arg2625Lys 675:p.Asn3124His 353:p.Gly2508Arg 675:p.Gly2508Ser 675:p.Ile2627Val

Genes: NA 675 353

Variants: 2619 from Trp to Gly 2723 from Asp to Asn 7522G>A 7807G>T 7874G>A 7879A>G Leu3180 Phe/Asn c.7522G>C c.7880T>A c.9370A>C c.9371A>T c.9539T>C p.Ala2603Ser p.Arg2625Lys p.Asn3124His p.Gly2508Arg p.Gly2508Ser p.Ile2627Val