[Paper-level Aggregated] PMCID: PMC7612117

Evidence Type(s): Functional

Summary: Mutation: p.L1363P | Summary: The Brca1 p.L1363P variant alters molecular or biochemical function by disrupting the interaction with PALB2, impairing homologous recombination repair (HRR), and leading to defects in RAD51 foci formation in response to gamma-radiation. It has been shown to cause general growth defects in embryos and is functionally important as it compromises BRCA1-mediated HRR.

Evidence Type: Functional Mutation: p.L1407P | Summary: The p.L1407P variant disrupts the interaction of BRCA1 with PALB2 and is predicted to disable the alpha-helical structure of the coiled-coil domain, indicating a functional alteration. It is analyzed in the context of its potential phenocopy of p.L1363P, suggesting it may also affect molecular interactions and functions related to BRCA1.

Gene→Variant (gene-first): TP53BP1(7158):p.L1363P BRCA1(672):p.L1407P

Genes: TP53BP1(7158) BRCA1(672)

Variants: p.L1363P p.L1407P

[Paper-level Aggregated] PMCID: PMC7612117

Evidence Type(s): Oncogenic

Summary: Mutation: p.L1363P | Summary: The homozygous Brca1 p.L1363P variant is associated with embryonic lethality and contributes to tumor development or progression, as evidenced by the absence of viable Brca1LP/LP mice, growth defects, and accelerated tumor formation in mouse models. It is implicated in mammary tumor suppression defects and is associated with mammary tumors exhibiting EMT-like phenotypes. Additionally, the p.L1363P variant is linked to the development of carcinosarcomas, indicating its role in oncogenesis and increasing the risk of developing breast cancer.

Gene→Variant (gene-first): TP53BP1(7158):p.L1363P

Genes: TP53BP1(7158)

Variants: p.L1363P

[Paper-level Aggregated] PMCID: PMC7612117

Evidence Type(s): Prognostic

Summary: Mutation: p.L1363P | Summary: The presence of the BRCA1 p.L1363P variant is associated with distinct histopathological features and stable DNA copy number profiles in tumors, which may correlate with disease outcome.

Gene→Variant (gene-first): TP53BP1(7158):p.L1363P

Genes: TP53BP1(7158)

Variants: p.L1363P

[Paper-level Aggregated] PMCID: PMC7612117

Evidence Type(s): Diagnostic

Summary: Mutation: L1363P | Summary: The presence of the KB1(L1363P)P mutation helps define and classify the tumors as carcinosarcomas, distinguishing them from adenocarcinomas based on their histological characteristics.

Gene→Variant (gene-first): TP53BP1(7158):L1363P

Genes: TP53BP1(7158)

Variants: L1363P

[Paper-level Aggregated] PMCID: PMC7612117

Evidence Type(s): Predictive

Summary: Mutation: p.L1363P | Summary: The mutation p.L1363P correlates with increased sensitivity to cisplatin and PARP inhibition, indicating a potential predictive value for therapy response. It is associated with a better response to cisplatin and the PARP inhibitor AZD2461 compared to other tumor types, further supporting its predictive value for therapy response.

Evidence Type: Predictive Mutation: p.L1407P | Summary: The analysis of p.L1407P in relation to p.L1363P implies a similar sensitivity to therapies, indicating a predictive aspect for treatment response.

Gene→Variant (gene-first): TP53BP1(7158):p.L1363P BRCA1(672):p.L1407P

Genes: TP53BP1(7158) BRCA1(672)

Variants: p.L1363P p.L1407P

[Paragraph-level] PMCID: PMC7612117 Section: ABSTRACT PassageIndex: 1

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

Summary: Evidence Type: Oncogenic | Mutation: p.L1363P | Summary: The BRCA1 p.L1363P variant contributes to tumor development, as it leads to the acceleration of mammary tumors in genetically engineered mice, indicating its role in cancer progression. Evidence Type: Functional | Mutation: p.L1363P | Summary: The BRCA1 p.L1363P variant disrupts the interaction with PALB2 and results in HRR incompetence, demonstrating an alteration in molecular function. Evidence Type: Predictive | Mutation: p.L1363P | Summary: The BRCA1 p.L1363P variant is responsive to cisplatin and PARP inhibition, indicating its potential correlation with treatment response. Evidence Type: Prognostic | Mutation: p.L1363P | Summary: The presence of the BRCA1 p.L1363P variant is associated with distinct histopathological features and stable DNA copy number profiles in tumors, which may correlate with disease outcome.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 15

Evidence Type(s): Predictive, Functional, Oncogenic

Summary: Evidence Type: Predictive | Mutation: L1363P | Summary: The L1363P mutation in BRCA1 is associated with a better response to cisplatin and the PARP inhibitor AZD2461 compared to other tumor types, indicating its predictive value for therapy response. Evidence Type: Functional | Mutation: L1363P | Summary: The L1363P mutation alters the molecular function of BRCA1, as evidenced by the compromised RAD51 foci formation in response to gamma-radiation, indicating a partial HRR defect. Evidence Type: Oncogenic | Mutation: L1363P | Summary: The BRCA1 L1363P variant is implicated in increasing the risk of developing breast cancer, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 7158:L1363P 7158:p.L1363P

Genes: 7158

Variants: L1363P p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 14

Evidence Type(s): Predictive, Oncogenic

Summary: Evidence Type: Predictive | Mutation: L1363P | Summary: The L1363P mutation is associated with a response to cisplatin and PARP inhibition in mammary tumors, indicating its predictive value for therapy response. Evidence Type: Oncogenic | Mutation: L1363P | Summary: The L1363P mutation contributes to tumor development or progression in mammary tumors, supporting its classification as an oncogenic variant.

Gene→Variant (gene-first): 7158:L1363P

Genes: 7158

Variants: L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 13

Evidence Type(s): Oncogenic, Diagnostic

Summary: Evidence Type: Oncogenic | Mutation: L1363P | Summary: The KB1(L1363P)P mutation is associated with the development of carcinosarcomas, indicating its contribution to tumor progression and classification as an oncogenic variant. Evidence Type: Diagnostic | Mutation: L1363P | Summary: The presence of the KB1(L1363P)P mutation helps define and classify the tumors as carcinosarcomas, distinguishing them from adenocarcinomas based on their histological characteristics.

Gene→Variant (gene-first): 7158:L1363P 7158:p.L1363P

Genes: 7158

Variants: L1363P p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: L1363P | Summary: The L1363P mutation is associated with mammary tumors exhibiting EMT-like phenotypes, indicating its contribution to tumor development or progression. Evidence Type: Functional | Mutation: L1363P | Summary: The L1363P mutation alters molecular or biochemical function, as suggested by the EMT-like phenotypes observed in the tumors.

Gene→Variant (gene-first): 7158:L1363P

Genes: 7158

Variants: L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.L1363P | Summary: The Brca1 p.L1363P variant is functionally important as it compromises BRCA1-mediated homologous recombination repair (HRR), indicating an alteration in molecular function. Evidence Type: Oncogenic | Mutation: p.L1363P | Summary: The Brca1 p.L1363P variant contributes to tumor development, as evidenced by the accelerated tumor formation in mouse models compared to controls, indicating its role in oncogenesis.

Gene→Variant (gene-first): 7158:L1363P 7158:p.L1363P

Genes: 7158

Variants: L1363P p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: p.L1363P | Summary: The variant p.L1363P in Brca1 is associated with a defect in mammary tumor suppression, indicating its role in tumor development or progression.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional, Predictive

Summary: Evidence Type: Functional | Mutation: p.L1363P | Summary: The mutation p.L1363P in Brca1 alters the binding interaction with PALB2, leading to defects in homologous recombination repair (HRR). Evidence Type: Predictive | Mutation: p.L1363P | Summary: The mutation p.L1363P correlates with increased sensitivity to cisplatin and PARP1 inhibition, indicating a potential predictive value for therapy response. Evidence Type: Functional | Mutation: p.L1407P | Summary: The mutation p.L1407P is analyzed in the context of its potential phenocopy of p.L1363P, suggesting it may also affect molecular interactions and functions related to BRCA1. Evidence Type: Predictive | Mutation: p.L1407P | Summary: The analysis of p.L1407P in relation to p.L1363P implies a similar sensitivity to therapies, indicating a predictive aspect for treatment response.

Gene→Variant (gene-first): 672:leucine to proline 7158:p.L1363P 672:p.L1407P

Genes: 672 7158

Variants: leucine to proline p.L1363P p.L1407P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.L1363P | Summary: The variant p.L1363P alters the molecular function of BRCA1 by impairing its ability to bind PALB2 and exhibiting reduced activity in homologous recombination repair (HRR). Evidence Type: Oncogenic | Mutation: p.L1363P | Summary: The inability of the p.L1363P variant to effectively participate in HRR suggests that it may contribute to tumor development or progression due to its compromised function in DNA repair.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: p.L1363P | Summary: The passage discusses the evaluation of the functional consequences of the Brca1 p.L1363P mutation in mouse embryonic fibroblasts, indicating that it alters molecular or biochemical function.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.L1363P | Summary: The p.L1363P variant in Brca1 was analyzed functionally in vivo, showing a general growth defect in embryos, indicating an alteration in molecular or biochemical function. Evidence Type: Oncogenic | Mutation: p.L1363P | Summary: The absence of viable Brca1LP/LP mice and the observed growth defects suggest that the p.L1363P variant contributes to tumor development or progression, similar to other pathogenic mutations in Brca1.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: p.L1363P | Summary: The homozygous Brca1 p.L1363P variant in mice is associated with embryonic lethality, indicating its role in tumor development or progression.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: 4220T>C; p.L1407P | Summary: The variant p.L1407P disrupts the interaction of BRCA1 with PALB2 and is predicted to disable the alpha-helical structure of the coiled-coil domain, indicating a functional alteration. Evidence Type: Functional | Mutation: p.L1363P | Summary: The murine equivalent variant p.L1363P is predicted to disable the alpha-helical structure of the coiled-coil domain, indicating a functional alteration.

Gene→Variant (gene-first): 672:4220T>C 7158:p.L1363P 672:p.L1407P

Genes: 672 7158

Variants: 4220T>C p.L1363P p.L1407P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 2

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: p.L1363P | Summary: The passage indicates the generation of Brca1 p.L1363P mice, suggesting that this variant may alter molecular or biochemical function related to the Brca1 gene.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paper-level Aggregated] PMCID: PMC7612117

Evidence Type(s): Oncogenic, Functional, Predisposing

Justification: Oncogenic: The evidence indicates that the BRCA1 p.L1363P variant disrupts the interaction with PALB2, leads to embryonic lethality, and accelerates the development of Trp53-deficient mammary tumors, suggesting its role in cancer development. Functional: The study demonstrates that Brca1 p.L1363P impairs homologous recombination repair (HRR) and affects BRCA1-PALB2 interaction, indicating a functional defect associated with this variant. Predisposing: The findings suggest that the BRCA1 p.L1363P variant increases the risk of developing breast cancer, as it leads to tumor formation in a mouse model.

Gene→Variant (gene-first): BRCA1(672):4220T>C TP53BP1(7158):p.L1363P BRCA1(672):p.L1407P TP53BP1(7158):L1363P BRCA1(672):leucine to proline

Genes: BRCA1(672) TP53BP1(7158)

Variants: 4220T>C p.L1363P p.L1407P L1363P leucine to proline

[Paragraph-level] PMCID: PMC7612117 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The variant p.L1363P is shown to disrupt the interaction with PALB2 and leads to the development of mammary tumors, indicating its contribution to tumor development. Predictive: The passage states that Brca1 p.L1363P mammary tumors are responsive to cisplatin and PARP inhibition, suggesting a correlation with treatment response.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 15

Evidence Type(s): Predictive, Oncogenic, Functional

Justification: Predictive: The passage discusses the response of KB1(L1363P)P mammary tumors to targeted therapies, indicating that these tumors responded significantly better to cisplatin and the PARP inhibitor AZD2461, which correlates the variant with treatment response. Oncogenic: The variant is associated with tumor development and progression, as it is discussed in the context of mammary tumors and their response to therapies, suggesting a role in cancer biology. Functional: The passage describes how the variant affects the ability of tumor cells to induce RAD51 foci in response to gamma-radiation, indicating an alteration in molecular function related to DNA repair mechanisms.

Gene→Variant (gene-first): 7158:L1363P 7158:p.L1363P

Genes: 7158

Variants: L1363P p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 14

Evidence Type(s): Predictive

Justification: Predictive: The variant L1363P is associated with a response to cisplatin and PARP inhibition, indicating its correlation with treatment sensitivity.

Gene→Variant (gene-first): 7158:L1363P

Genes: 7158

Variants: L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 13

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses how KB1(L1363P)P mammary tumors are classified as predominantly carcinosarcomas, indicating that the variant is used to define and classify a specific tumor subtype. Oncogenic: The variant L1363P is associated with the development of carcinosarcomas, suggesting that it contributes to tumor progression and development, which aligns with oncogenic behavior.

Gene→Variant (gene-first): 7158:L1363P 7158:p.L1363P

Genes: 7158

Variants: L1363P p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage indicates that the variant L1363P is associated with mammary tumors exhibiting EMT-like phenotypes, suggesting a role in tumor development or progression.

Gene→Variant (gene-first): 7158:L1363P

Genes: 7158

Variants: L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the Brca1 p.L1363P variant contributes to tumor formation and accelerates tumor development in a mouse model, indicating its role in tumor progression. Functional: The passage indicates that the Brca1 p.L1363P variant has a functional defect that compromises BRCA1-mediated homologous recombination repair (HRR), suggesting an alteration in molecular function.

Gene→Variant (gene-first): 7158:L1363P 7158:p.L1363P

Genes: 7158

Variants: L1363P p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic

Justification: Oncogenic: The variant p.L1363P is associated with a defect in mammary tumor suppression, indicating its contribution to tumor development or progression.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses increased sensitivity to cisplatin and PARP1 inhibition in the context of the Brca1 p.L1363P variant, indicating a correlation with treatment response. Functional: The variant p.L1363P is shown to severely attenuate BRCA1-PALB2 binding, which alters the molecular function related to homologous recombination repair (HRR).

Gene→Variant (gene-first): 672:leucine to proline 7158:p.L1363P 672:p.L1407P

Genes: 672 7158

Variants: leucine to proline p.L1363P p.L1407P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional

Justification: Functional: The passage indicates that the variant p.L1363P alters the binding ability of BRCA1 to PALB2 and affects its activity in homologous recombination repair (HRR), demonstrating a change in molecular function.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional

Justification: Functional: The passage discusses the evaluation of the functional consequences of the Brca1 p.L1363P variant, indicating that it alters molecular or biochemical function.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses a functional analysis of the Brca1 p.L1363P variant, indicating that it alters embryonic development and leads to growth defects in mice, which demonstrates its impact on molecular or biochemical function. Oncogenic: The analysis of the Brca1 p.L1363P variant in the context of embryonic development and its comparison to Brca1-null mice suggests that it may contribute to tumor development or progression, as it is associated with severe phenotypes similar to pathogenic mutations in Brca1.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage indicates that the homozygous variant p.L1363P in Brca1 leads to embryonic lethality in mice, suggesting that it contributes to tumor development or progression.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variant p.L1407P disrupts the interaction of BRCA1 with PALB2 and predicts that it disables the alpha-helical structure of the coiled-coil domain, indicating an alteration in molecular function. Oncogenic: The use of CRISPR/Cas9 to model the BRCA1 variant in mice suggests that the variant contributes to tumor development or progression, as it is being studied in the context of a gene essential for embryonic development and cancer biology.

Gene→Variant (gene-first): 672:4220T>C 7158:p.L1363P 672:p.L1407P

Genes: 672 7158

Variants: 4220T>C p.L1363P p.L1407P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 2

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The variant p.L1363P is shown to disrupt the interaction with PALB2 and leads to the development of mammary tumors, indicating its contribution to tumor development. Predictive: The passage states that Brca1 p.L1363P mammary tumors are responsive to cisplatin and PARP inhibition, suggesting a correlation with treatment response.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 15

Evidence Type(s): Predictive, Oncogenic, Functional

Justification: Predictive: The passage discusses the response of KB1(L1363P)P mammary tumors to targeted therapies, indicating that these tumors responded significantly better to cisplatin and the PARP inhibitor AZD2461, which correlates the variant with treatment response. Oncogenic: The variant is associated with tumor development and progression, as it is discussed in the context of mammary tumors and their response to therapies, suggesting a role in cancer biology. Functional: The passage describes how the variant affects the ability of tumor cells to induce RAD51 foci in response to gamma-radiation, indicating an alteration in molecular function related to DNA repair mechanisms.

Gene→Variant (gene-first): 7158:L1363P 7158:p.L1363P

Genes: 7158

Variants: L1363P p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 14

Evidence Type(s): Predictive

Justification: Predictive: The variant L1363P is associated with a response to cisplatin and PARP inhibition, indicating its correlation with treatment sensitivity.

Gene→Variant (gene-first): 7158:L1363P

Genes: 7158

Variants: L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 13

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses how KB1(L1363P)P mammary tumors are classified as predominantly carcinosarcomas, indicating that the variant is used to define and classify a specific tumor subtype. Oncogenic: The variant L1363P is associated with the development of carcinosarcomas, suggesting that it contributes to tumor progression and development, which aligns with oncogenic behavior.

Gene→Variant (gene-first): 7158:L1363P 7158:p.L1363P

Genes: 7158

Variants: L1363P p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage indicates that the variant L1363P is associated with mammary tumors exhibiting EMT-like phenotypes, suggesting a role in tumor development or progression.

Gene→Variant (gene-first): 7158:L1363P

Genes: 7158

Variants: L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the Brca1 p.L1363P variant contributes to tumor formation and accelerates tumor development in a mouse model, indicating its role in tumor progression. Functional: The passage indicates that the Brca1 p.L1363P variant has a functional defect that compromises BRCA1-mediated homologous recombination repair (HRR), suggesting an alteration in molecular function.

Gene→Variant (gene-first): 7158:L1363P 7158:p.L1363P

Genes: 7158

Variants: L1363P p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic

Justification: Oncogenic: The variant p.L1363P is associated with a defect in mammary tumor suppression, indicating its contribution to tumor development or progression.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses increased sensitivity to cisplatin and PARP1 inhibition in the context of the Brca1 p.L1363P variant, indicating a correlation with treatment response. Functional: The variant p.L1363P is shown to severely attenuate BRCA1-PALB2 binding, which alters the molecular function related to homologous recombination repair (HRR).

Gene→Variant (gene-first): 672:leucine to proline 7158:p.L1363P 672:p.L1407P

Genes: 672 7158

Variants: leucine to proline p.L1363P p.L1407P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional

Justification: Functional: The passage indicates that the variant p.L1363P alters the binding ability of BRCA1 to PALB2 and affects its activity in homologous recombination repair (HRR), demonstrating a change in molecular function.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional

Justification: Functional: The passage discusses the evaluation of the functional consequences of the Brca1 p.L1363P variant, indicating that it alters molecular or biochemical function.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses a functional analysis of the Brca1 p.L1363P variant, indicating that it alters embryonic development and leads to growth defects in mice, which demonstrates its impact on molecular or biochemical function. Oncogenic: The analysis of the Brca1 p.L1363P variant in the context of embryonic development and its comparison to Brca1-null mice suggests that it may contribute to tumor development or progression, as it is associated with severe phenotypes similar to pathogenic mutations in Brca1.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage indicates that the homozygous variant p.L1363P in Brca1 leads to embryonic lethality in mice, suggesting that it contributes to tumor development or progression.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variant p.L1407P disrupts the interaction of BRCA1 with PALB2 and predicts that it disables the alpha-helical structure of the coiled-coil domain, indicating an alteration in molecular function. Oncogenic: The use of CRISPR/Cas9 to model the BRCA1 variant in mice suggests that the variant contributes to tumor development or progression, as it is being studied in the context of a gene essential for embryonic development and cancer biology.

Gene→Variant (gene-first): 672:4220T>C 7158:p.L1363P 672:p.L1407P

Genes: 672 7158

Variants: 4220T>C p.L1363P p.L1407P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 2

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P