[Paper-level Aggregated] PMCID: PMC5111006

Evidence Type(s): Functional

Summary: Mutation: p.R474 | Summary: The variant p.R474 of CHEK2 shows high conservation in homologs, suggesting potential functional significance. It is involved in forming a salt bridge crucial for protein stability, indicating its role in altering molecular function.

Evidence Type: Functional Mutation: p.R474C | Summary: The mutation p.R474C disrupts the salt bridge with p.E394, leading to protein instability and poor activation in response to DNA damage. This alteration affects the molecular function of CHK2, indicating its functional importance.

Evidence Type: Functional Mutation: p.R210 | Summary: The mutation p.R210 is not well conserved and does not significantly affect the function or structure of the protein, particularly in its interaction with the immunoglobulin Fc fragment.

Evidence Type: Functional Mutation: p.R210Q | Summary: The mutation p.R210Q is not likely to affect the function and structure of the protein, indicating a focus on its molecular function.

Gene→Variant (gene-first): CHEK2(11200):p.R474 CHEK2(11200):p.R474C FCGRT(2217):p.R210 FCGRT(2217):p.R210Q

Genes: CHEK2(11200) FCGRT(2217)

Variants: p.R474 p.R474C p.R210 p.R210Q

[Paper-level Aggregated] PMCID: PMC5111006

Evidence Type(s): Oncogenic

Summary: Mutation: L858R | Summary: The L858R mutation in the EGFR gene is associated with tumor development in lung cancer, indicating its role as a somatic variant contributing to oncogenesis.

Evidence Type: Oncogenic Mutation: p.R474C | Summary: The variant p.R474C contributes to tumor development or progression by affecting the function of CHK2, a gene implicated in cell cycle regulation and DNA damage response. Additionally, the homozygous CHEK2 variant p.R474C is suggested to be contributory to familial cancer, as inactivation of CHEK2 in mice led to cancers in multiple organs.

Gene→Variant (gene-first): EGFR(1956):L858R CHEK2(11200):p.R474C

Genes: EGFR(1956) CHEK2(11200)

Variants: L858R p.R474C

[Paper-level Aggregated] PMCID: PMC5111006

Evidence Type(s): Predisposing

Summary: Mutation: rs1042522 | Summary: The variant rs1042522 (TP53, p.P72R) is associated with Li-Fraumeni syndrome, indicating a potential inherited risk for disease.

Evidence Type: Predisposing Mutation: rs169547 | Summary: The variant rs169547 (BRCA2, p.V2466A) is linked to hereditary breast/ovarian cancer, suggesting it may confer inherited risk for disease.

Gene→Variant (gene-first): TP53(7157):rs1042522 BRCA2(675):rs169547

Genes: TP53(7157) BRCA2(675)

Variants: rs1042522 rs169547

[Paper-level Aggregated] PMCID: PMC5111006

Evidence Type(s): Diagnostic

Summary: Mutation: rs757110 | Summary: The variant rs757110 in ABCC8 is associated with diabetes or insulin secretion, indicating its role in defining or classifying a disease.

Evidence Type: Diagnostic Mutation: rs5215 | Summary: The variant rs5215 in KCNJ11 is associated with diabetes or insulin secretion, indicating its role in defining or classifying a disease.

Evidence Type: Diagnostic Mutation: rs5219 | Summary: The variant rs5219 in KCNJ11 is associated with diabetes or insulin secretion, indicating its role in defining or classifying a disease.

Evidence Type: Diagnostic Mutation: rs2468844 | Summary: The variant rs2468844 in SAA2 is associated with carotid intima media thickness, indicating its role in defining or classifying a disease.

Evidence Type: Diagnostic Mutation: rs11703684 | Summary: The variant rs11703684 in PIWIL3 is associated with oligospermia, indicating its role in defining or classifying a disease.

Gene→Variant (gene-first): ABCC8(6833):rs757110 KCNJ11(3767):rs5215 KCNJ11(3767):rs5219 SAA2(6289):rs2468844 PIWIL3(440822):rs11703684

Genes: ABCC8(6833) KCNJ11(3767) SAA2(6289) PIWIL3(440822)

Variants: rs757110 rs5215 rs5219 rs2468844 rs11703684

[Paragraph-level] PMCID: PMC5111006 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.R474C | Summary: The CHEK2 mutation p.R474C alters the tertiary structure of CHK2 by disrupting the salt bridge between p.R474 and p.E394, indicating its functional importance. Evidence Type: Oncogenic | Mutation: p.R474C | Summary: The homozygous CHEK2 variant p.R474C is suggested to be contributory to familial cancer, as inactivation of CHEK2 in mice led to cancers in multiple organs.

Gene→Variant (gene-first): 11200:p.R474 11200:p.R474C

Genes: 11200

Variants: p.R474 p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 18

Evidence Type(s): Diagnostic

Summary: Evidence Type: Diagnostic | Mutation: rs757110 | Summary: The variant rs757110 in ABCC8 is associated with diabetes or insulin secretion, indicating its role in defining or classifying a disease. Evidence Type: Diagnostic | Mutation: rs5215 | Summary: The variant rs5215 in KCNJ11 is associated with diabetes or insulin secretion, indicating its role in defining or classifying a disease. Evidence Type: Diagnostic | Mutation: rs5219 | Summary: The variant rs5219 in KCNJ11 is associated with diabetes or insulin secretion, indicating its role in defining or classifying a disease. Evidence Type: Diagnostic | Mutation: rs2468844 | Summary: The variant rs2468844 in SAA2 is associated with carotid intima media thickness, indicating its role in defining or classifying a disease. Evidence Type: Diagnostic | Mutation: rs11703684 | Summary: The variant rs11703684 in PIWIL3 is associated with oligospermia, indicating its role in defining or classifying a disease.

Gene→Variant (gene-first): 440822:rs11703684 6289:rs2468844 3767:rs5215 3767:rs5219 6833:rs757110

Genes: 440822 6289 3767 6833

Variants: rs11703684 rs2468844 rs5215 rs5219 rs757110

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 17

Evidence Type(s): Predisposing

Summary: Evidence Type: Predisposing | Mutation: rs1042522 | Summary: The variant rs1042522 (TP53, p.P72R) is associated with Li-Fraumeni syndrome, indicating a potential inherited risk for disease. Evidence Type: Predisposing | Mutation: rs169547 | Summary: The variant rs169547 (BRCA2, p.V2466A) is linked to hereditary breast/ovarian cancer, suggesting it may confer inherited risk for disease.

Gene→Variant (gene-first): 7157:p.P72R 675:p.V2466A 7157:rs1042522 2956:rs1042821 4072:rs1126497 675:rs169547 5395:rs1805323 5395:rs2228006 4436:rs2303424

Genes: 7157 675 2956 4072 5395 4436

Variants: p.P72R p.V2466A rs1042522 rs1042821 rs1126497 rs169547 rs1805323 rs2228006 rs2303424

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.R474C | Summary: The variant p.R474C alters the molecular function of CHK2, resulting in instability and poor activation by DNA damage compared to wild-type CHK2. Evidence Type: Oncogenic | Mutation: p.R474C | Summary: The variant p.R474C contributes to tumor development or progression by affecting the function of CHK2, a gene implicated in cell cycle regulation and DNA damage response.

Gene→Variant (gene-first): 11200:p.R474C

Genes: 11200

Variants: p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: p.R474C | Summary: The mutation p.R474C in CHK2 is associated with altered molecular function, specifically indicating that the protein is poorly activated in response to DNA damage.

Gene→Variant (gene-first): 11200:p.R474C

Genes: 11200

Variants: p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: p.R210 | Summary: The mutation p.R210 is described in the context of its interaction with the immunoglobulin Fc fragment, but it is noted that it is not well conserved and does not significantly affect the function or structure of the protein. Evidence Type: Functional | Mutation: p.R210Q | Summary: The mutation p.R210Q is mentioned as not likely to affect the function and structure of the protein, indicating a focus on its molecular function.

Gene→Variant (gene-first): 2217:p.R210 2217:p.R210Q

Genes: 2217

Variants: p.R210 p.R210Q

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: p.R474 | Summary: The mutation p.R474 is involved in forming a salt bridge that is crucial for protein stability, indicating its role in altering molecular function. Evidence Type: Functional | Mutation: p.R474C | Summary: The mutation p.R474C disrupts the salt bridge with p.E394, likely leading to protein instability and altering its molecular function.

Gene→Variant (gene-first): 11200:p.R474 11200:p.R474C

Genes: 11200

Variants: p.R474 p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: p.R474 | Summary: The variant p.R474 of CHEK2 was analyzed for its impact on protein function, showing high conservation in homologs, which suggests a potential functional significance. Evidence Type: Functional | Mutation: p.R218 | Summary: The variant p.R218 of FCGRT was assessed for its effect on protein function, with lower conservation in homologs indicating a possible alteration in molecular function.

Gene→Variant (gene-first): 11200:p.R474

Genes: 11200

Variants: p.R474

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: L858R | Summary: The L858R mutation in the EGFR gene is associated with tumor development in lung cancer, indicating its role as a somatic variant contributing to oncogenesis.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paper-level Aggregated] PMCID: PMC5111006

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

Justification: Oncogenic: The mutation p.R474C in CHEK2 was shown to be unstable and poorly activated in response to DNA damage, suggesting a contributory role in familial cancer cases. Functional: The analysis indicated that p.R474C disrupts a salt bridge critical for protein stability and function, affecting the protein's activation upon DNA damage. Predisposing: The presence of the CHEK2 mutation in a familial context, along with the development of multiple primary cancers in the patients, suggests a predisposition to cancer associated with this variant. Predictive: The use of prediction models indicated that p.R474C was "disease causing" and likely interfered with protein function, supporting its predictive value in assessing cancer risk.

Gene→Variant (gene-first): EGFR(1956):L858R TP53(7157):p.P72R BRCA2(675):p.V2466A TP53(7157):rs1042522 MSH6(2956):rs1042821 EPCAM(4072):rs1126497 BRCA2(675):rs169547 PMS2(5395):rs1805323 PMS2(5395):rs2228006 MSH2(4436):rs2303424 FCGRT(2217):p.R210 FCGRT(2217):p.R210Q CHEK2(11200):p.R474 CHEK2(11200):p.R474C PIWIL3(440822):rs11703684 SAA2(6289):rs2468844 KCNJ11(3767):rs5215 KCNJ11(3767):rs5219 ABCC8(6833):rs757110

Genes: EGFR(1956) TP53(7157) BRCA2(675) MSH6(2956) EPCAM(4072) PMS2(5395) MSH2(4436) FCGRT(2217) CHEK2(11200) PIWIL3(440822) SAA2(6289) KCNJ11(3767) ABCC8(6833)

Variants: L858R p.P72R p.V2466A rs1042522 rs1042821 rs1126497 rs169547 rs1805323 rs2228006 rs2303424 p.R210 p.R210Q p.R474 p.R474C rs11703684 rs2468844 rs5215 rs5219 rs757110

[Paragraph-level] PMCID: PMC5111006 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage indicates that the homozygous CHEK2 variant p.R474C was contributory to familial cancer, and the inactivation of CHEK2 in mice led to cancers in multiple organs, suggesting a role in tumor development. Functional: The variant p.R474C alters the tertiary structure of the CHK2 protein by disrupting a salt bridge, and subsequent analysis showed that it was unstable and scarcely activated, indicating a change in molecular function.

Gene→Variant (gene-first): 11200:p.R474 11200:p.R474C

Genes: 11200

Variants: p.R474 p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 18

Evidence Type(s): Diagnostic, Predisposing

Justification: Diagnostic: The passage states that the variants are recorded as disease-associated variants, indicating their use in defining or classifying diseases such as diabetes, carotid intima media thickness, and oligospermia. Predisposing: The variants mentioned are associated with inherited conditions, suggesting they confer an inherited risk for developing diseases, although the germline nature is implied rather than explicitly stated.

Gene→Variant (gene-first): 440822:rs11703684 6289:rs2468844 3767:rs5215 3767:rs5219 6833:rs757110

Genes: 440822 6289 3767 6833

Variants: rs11703684 rs2468844 rs5215 rs5219 rs757110

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 17

Evidence Type(s): Predisposing, Diagnostic

Justification: Predisposing: The passage discusses variants in hereditary loci, specifically mentioning TP53 and BRCA2, which are associated with inherited cancer syndromes, indicating a potential inherited risk for developing disease. Diagnostic: The passage mentions the classification of variants as "Benign" or of "Uncertain significance," which relates to their use in defining or classifying disease risk or status.

Gene→Variant (gene-first): 7157:p.P72R 675:p.V2466A 7157:rs1042522 2956:rs1042821 4072:rs1126497 675:rs169547 5395:rs1805323 5395:rs2228006 4436:rs2303424

Genes: 7157 675 2956 4072 5395 4436

Variants: p.P72R p.V2466A rs1042522 rs1042821 rs1126497 rs169547 rs1805323 rs2228006 rs2303424

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the p.R474C variant alters the molecular function of the CHK2 protein, demonstrating that it is poorly expressed and activated by DNA damage compared to the wild-type protein. Oncogenic: The context implies that the p.R474C variant contributes to tumor development or progression by affecting the function of a cell cycle checkpoint regulator, which is critical in the context of cancer biology.

Gene→Variant (gene-first): 11200:p.R474C

Genes: 11200

Variants: p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Justification: Functional: The passage indicates that the p.R474C variant affects the activation of the CHK2 protein in response to DNA damage, suggesting an alteration in its molecular function.

Gene→Variant (gene-first): 11200:p.R474C

Genes: 11200

Variants: p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variant p.R210 and its substitution p.R210Q relate to the structure and potential function of the protein, indicating that p.R210Q is not likely to affect the function and structure of the protein.

Gene→Variant (gene-first): 2217:p.R210 2217:p.R210Q

Genes: 2217

Variants: p.R210 p.R210Q

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variant p.R474C alters the salt bridge formation and is likely to make the protein unstable, indicating an alteration in molecular function. Oncogenic: The variant p.R474C is described as "disease causing" and likely interferes with protein function, suggesting a role in tumor development or progression.

Gene→Variant (gene-first): 11200:p.R474 11200:p.R474C

Genes: 11200

Variants: p.R474 p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variant p.R474 in CHEK2 was analyzed for its effect on protein function based on evolutionary conservation, indicating that it alters molecular or biochemical function.

Gene→Variant (gene-first): 11200:p.R474

Genes: 11200

Variants: p.R474

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses the presence of the L858R mutation in the context of lung cancer, indicating its potential role in tumor development or progression.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC5111006 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage indicates that the homozygous CHEK2 variant p.R474C was contributory to familial cancer, and the inactivation of CHEK2 in mice led to cancers in multiple organs, suggesting a role in tumor development. Functional: The variant p.R474C alters the tertiary structure of the CHK2 protein by disrupting a salt bridge, and subsequent analysis showed that it was unstable and scarcely activated, indicating a change in molecular function.

Gene→Variant (gene-first): 11200:p.R474 11200:p.R474C

Genes: 11200

Variants: p.R474 p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 18

Evidence Type(s): Diagnostic, Predisposing

Justification: Diagnostic: The passage states that the variants are recorded as disease-associated variants, indicating their use in defining or classifying diseases such as diabetes, carotid intima media thickness, and oligospermia. Predisposing: The variants mentioned are associated with inherited conditions, suggesting they confer an inherited risk for developing diseases, although the germline nature is implied rather than explicitly stated.

Gene→Variant (gene-first): 440822:rs11703684 6289:rs2468844 3767:rs5215 3767:rs5219 6833:rs757110

Genes: 440822 6289 3767 6833

Variants: rs11703684 rs2468844 rs5215 rs5219 rs757110

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 17

Evidence Type(s): Predisposing, Diagnostic

Justification: Predisposing: The passage discusses variants in hereditary loci, specifically mentioning TP53 and BRCA2, which are associated with inherited cancer syndromes, indicating a potential inherited risk for developing disease. Diagnostic: The passage mentions the classification of variants as "Benign" or of "Uncertain significance," which relates to their use in defining or classifying disease risk or status.

Gene→Variant (gene-first): 7157:p.P72R 675:p.V2466A 7157:rs1042522 2956:rs1042821 4072:rs1126497 675:rs169547 5395:rs1805323 5395:rs2228006 4436:rs2303424

Genes: 7157 675 2956 4072 5395 4436

Variants: p.P72R p.V2466A rs1042522 rs1042821 rs1126497 rs169547 rs1805323 rs2228006 rs2303424

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the p.R474C variant alters the molecular function of the CHK2 protein, demonstrating that it is poorly expressed and activated by DNA damage compared to the wild-type protein. Oncogenic: The context implies that the p.R474C variant contributes to tumor development or progression by affecting the function of a cell cycle checkpoint regulator, which is critical in the context of cancer biology.

Gene→Variant (gene-first): 11200:p.R474C

Genes: 11200

Variants: p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Justification: Functional: The passage indicates that the p.R474C variant affects the activation of the CHK2 protein in response to DNA damage, suggesting an alteration in its molecular function.

Gene→Variant (gene-first): 11200:p.R474C

Genes: 11200

Variants: p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variant p.R210 and its substitution p.R210Q relate to the structure and potential function of the protein, indicating that p.R210Q is not likely to affect the function and structure of the protein.

Gene→Variant (gene-first): 2217:p.R210 2217:p.R210Q

Genes: 2217

Variants: p.R210 p.R210Q

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variant p.R474C alters the salt bridge formation and is likely to make the protein unstable, indicating an alteration in molecular function. Oncogenic: The variant p.R474C is described as "disease causing" and likely interferes with protein function, suggesting a role in tumor development or progression.

Gene→Variant (gene-first): 11200:p.R474 11200:p.R474C

Genes: 11200

Variants: p.R474 p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variant p.R474 in CHEK2 was analyzed for its effect on protein function based on evolutionary conservation, indicating that it alters molecular or biochemical function.

Gene→Variant (gene-first): 11200:p.R474

Genes: 11200

Variants: p.R474

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses the presence of the L858R mutation in the context of lung cancer, indicating its potential role in tumor development or progression.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R