[Paper-level Aggregated] PMCID: PMC2837563

Evidence Type(s): Functional

Summary: Mutation: A146T | Summary: The A146T mutation is shown to be in the active GTP-bound conformation and influences gene expression similarly to other activating mutations, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: G12V | Summary: The G12V mutation is identified as being in the active GTP-bound conformation and is part of a gene cluster that indicates it alters molecular function, as shown by transcription-profiling experiments.

Evidence Type: Functional Mutation: G12C | Summary: The G12C mutation is part of a gene cluster that shows similarity to wild-type K-Ras, indicating it may alter molecular function.

Evidence Type: Functional Mutation: G12D | Summary: The G12D mutation is included in a gene cluster that suggests it alters molecular function, as evidenced by transcription-profiling experiments.

Evidence Type: Functional Mutation: G13D | Summary: The G13D mutation is associated with distinct phenotypic characteristics and is described as an activating mutation that influences gene expression, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: K117N | Summary: The K117N mutation is confirmed to be in the active GTP-bound conformation, clusters with activating mutations, and influences gene expression, indicating a potential alteration in molecular function.

Evidence Type: Functional Mutation: L19F | Summary: The L19F mutation is demonstrated to be in the active GTP-bound conformation, is part of a subcluster that suggests it alters molecular function, and influences gene expression, albeit to a lesser extent than other activating mutations.

Evidence Type: Functional Mutation: R164Q | Summary: The R164Q mutation suggests an 'activating' phenotype and showed relatively few changes in gene expression or reduced pathway activation compared to other mutants, indicating a potential alteration in molecular function.

Evidence Type: Functional Mutation: Q61H | Summary: The Q61H mutation is characterized as an activating mutation that influences gene expression, indicating an alteration in molecular function.

Gene→Variant (gene-first): KRAS(3845):A146T KRAS(3845):G12V KRAS(3845):G12C KRAS(3845):G12D KRAS(3845):G13D KRAS(3845):K117N KRAS(3845):L19F KRAS(3845):R164Q KRAS(3845):Q61H

Genes: KRAS(3845)

Variants: A146T G12V G12C G12D G13D K117N L19F R164Q Q61H

[Paper-level Aggregated] PMCID: PMC2837563

Evidence Type(s): Oncogenic

Summary: Mutation: G57T | Summary: The G57T mutation is associated with tumor development or progression as it was found in a colorectal tumor.

Evidence Type: Oncogenic Mutation: Leu19Phe | Summary: The Leu19Phe mutation is associated with tumor development or progression as it was found in a colorectal tumor.

Evidence Type: Oncogenic Mutation: V600E | Summary: The V600E mutation is associated with tumor development or progression as it was found in a colorectal tumor and is known to contribute to tumor development or progression in colorectal tumors.

Evidence Type: Oncogenic Mutation: A to C (Lys to Asn at codon 117) | Summary: This K-Ras mutation is associated with tumor development or progression in colorectal tumors and exhibits phenotypes similar to hotspot mutations, suggesting its role in tumor development or progression.

Evidence Type: Oncogenic Mutation: G to A (Ala to Thr at codon 146) | Summary: This K-Ras mutation contributes to tumor development or progression in colorectal tumors and led to significant focus formation in NIH3T3 cells, suggesting its role in tumor development.

Evidence Type: Oncogenic Mutation: G to A (Arg to Gln at codon 164) | Summary: This K-Ras mutation is implicated in tumor development or progression in colorectal tumors and is phenotypically equivalent to wild-type K-Ras with no evidence of foci formation, indicating it does not contribute to tumor development.

Evidence Type: Oncogenic Mutation: G12V | Summary: The G12V mutation in K-Ras was associated with abundant foci formation in NIH3T3 cells, indicating its contribution to tumor development.

Evidence Type: Oncogenic Mutation: G12D | Summary: The G12D mutation in K-Ras demonstrated significant focus formation in NIH3T3 cells, suggesting its role in tumor progression.

Evidence Type: Oncogenic Mutation: G13D | Summary: The G13D mutation in K-Ras was linked to significant focus formation in NIH3T3 cells, indicating its oncogenic potential.

Evidence Type: Oncogenic Mutation: Q61H | Summary: The Q61H mutation in K-Ras showed focus formation in NIH3T3 cells, although it had a lesser transforming potential compared to codon 12 mutations.

Evidence Type: Oncogenic Mutation: L19F | Summary: The L19F mutation in K-Ras resulted in low but consistent numbers of isolated foci in NIH3T3 cells, suggesting its involvement in tumor development.

Evidence Type: Oncogenic Mutation: K117N | Summary: The K117N mutation in K-Ras was associated with significant focus formation in NIH3T3 cells, indicating its contribution to tumor progression.

Evidence Type: Oncogenic Mutation: R164Q | Summary: The R164Q mutation in K-Ras was phenotypically equivalent to wild-type K-Ras with no evidence of foci formation, indicating it does not contribute to tumor development.

Evidence Type: Oncogenic Mutation: Ala146Thr | Summary: The Ala146Thr mutation is associated with phenotypes similar to hotspot mutations, indicating its contribution to tumor development or progression.

Evidence Type: Oncogenic Mutation: Lys117Asn | Summary: The Lys117Asn mutation exhibits phenotypes similar to hotspot mutations, suggesting its role in tumor development or progression.

Evidence Type: Oncogenic Mutation: Arg164Gln | Summary: The Arg164Gln mutation is phenotypically equivalent to wild-type K-Ras, but its presence in tumors suggests a potential role in tumor development or progression.

Gene→Variant (gene-first): BRAF(673):G57T KRAS(3845):Leu19Phe BRAF(673):V600E NA:A to C (Lys to Asn at codon 117) NA:G to A (Ala to Thr at codon 146) NA:G to A (Arg to Gln at codon 164) KRAS(3845):G12V KRAS(3845):G12D KRAS(3845):G13D KRAS(3845):Q61H KRAS(3845):L19F KRAS(3845):K117N KRAS(3845):R164Q KRAS(3845):Ala146Thr KRAS(3845):Lys117Asn KRAS(3845):Arg164Gln

Genes: BRAF(673) KRAS(3845) NA

Variants: G57T Leu19Phe V600E A to C (Lys to Asn at codon 117) G to A (Ala to Thr at codon 146) G to A (Arg to Gln at codon 164) G12V G12D G13D Q61H L19F K117N R164Q Ala146Thr Lys117Asn Arg164Gln

[Paragraph-level] PMCID: PMC2837563 Section: ABSTRACT PassageIndex: 6

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: Ala146Thr | Summary: The Ala146Thr mutation is associated with phenotypes similar to hotspot mutations, indicating its contribution to tumor development or progression. Evidence Type: Oncogenic | Mutation: Lys117Asn | Summary: The Lys117Asn mutation exhibits phenotypes similar to hotspot mutations, suggesting its role in tumor development or progression. Evidence Type: Functional | Mutation: Leu19Phe | Summary: The Leu19Phe mutation is described as having an attenuated phenotype, indicating a potential alteration in molecular or biochemical function. Evidence Type: Oncogenic | Mutation: Arg164Gln | Summary: The Arg164Gln mutation is phenotypically equivalent to wild-type K-Ras, but its presence in tumors suggests a potential role in tumor development or progression.

Gene→Variant (gene-first): 3845:Ala146Thr 3845:Arg164Gln 3845:Leu19Phe 3845:Lys117Asn

Genes: 3845

Variants: Ala146Thr Arg164Gln Leu19Phe Lys117Asn

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: R164Q | Summary: The R164Q mutation showed relatively few changes in gene expression or reduced pathway activation compared to other mutants, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: A146T | Summary: The A146T mutation influenced gene expression similarly to other activating mutations, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: K117N | Summary: The K117N mutation clustered with other mutants and influenced gene expression, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: L19F | Summary: The L19F mutation influenced gene expression, albeit to a lesser extent than the other activating mutations, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: G13D | Summary: The G13D mutation is described as an activating mutation that influences gene expression, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: Q61H | Summary: The Q61H mutation is characterized as an activating mutation that influences gene expression, indicating an alteration in molecular function.

Gene→Variant (gene-first): 3845:A146T 3845:G13D 3845:K117N 3845:L19F 3845:Q61H 3845:R164Q

Genes: 3845

Variants: A146T G13D K117N L19F Q61H R164Q

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A146T | Summary: The A146T mutation is associated with distinct phenotypic characteristics as indicated by transcription-profiling experiments, suggesting it alters molecular function. Evidence Type: Functional | Mutation: G12C | Summary: The G12C mutation is part of a gene cluster that shows similarity to wild-type K-Ras, indicating it may alter molecular function. Evidence Type: Functional | Mutation: G12D | Summary: The G12D mutation is included in a gene cluster that suggests it alters molecular function, as evidenced by transcription-profiling experiments. Evidence Type: Functional | Mutation: G12V | Summary: The G12V mutation is part of a gene cluster that indicates it alters molecular function, as shown by transcription-profiling experiments. Evidence Type: Functional | Mutation: G13D | Summary: The G13D mutation is associated with distinct phenotypic characteristics, suggesting it alters molecular function based on clustering analysis. Evidence Type: Functional | Mutation: K117N | Summary: The K117N mutation clusters with activating mutations, indicating it alters molecular function as suggested by transcription-profiling data. Evidence Type: Functional | Mutation: L19F | Summary: The L19F mutation is part of a subcluster that suggests it alters molecular function, consistent with Ras GTPase assay data. Evidence Type: Functional | Mutation: R164Q | Summary: The R164Q mutation, while initially surprising in its clustering, suggests an 'activating' phenotype, indicating it alters molecular function.

Gene→Variant (gene-first): 3845:A146T 3845:G12C 3845:G12D 3845:G12V 3845:G13D 3845:K117N 3845:L19F 3845:R164Q

Genes: 3845

Variants: A146T G12C G12D G12V G13D K117N L19F R164Q

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A146T | Summary: The A146T mutation is shown to be in the active GTP-bound conformation, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: G12V | Summary: The G12V mutation is identified as being in the active GTP-bound conformation, suggesting a change in molecular function. Evidence Type: Functional | Mutation: K117N | Summary: The K117N mutation is confirmed to be in the active GTP-bound conformation, reflecting an alteration in molecular function. Evidence Type: Functional | Mutation: L19F | Summary: The L19F mutation is demonstrated to be in the active GTP-bound conformation, indicating a change in molecular function.

Gene→Variant (gene-first): 3845:A146T 3845:G12V 3845:K117N 3845:L19F 3845:R164Q

Genes: 3845

Variants: A146T G12V K117N L19F R164Q

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: G12V | Summary: The G12V mutation in K-Ras was associated with abundant foci formation in NIH3T3 cells, indicating its contribution to tumor development. Evidence Type: Oncogenic | Mutation: G12D | Summary: The G12D mutation in K-Ras demonstrated significant focus formation in NIH3T3 cells, suggesting its role in tumor progression. Evidence Type: Oncogenic | Mutation: G13D | Summary: The G13D mutation in K-Ras was linked to significant focus formation in NIH3T3 cells, indicating its oncogenic potential. Evidence Type: Oncogenic | Mutation: Q61H | Summary: The Q61H mutation in K-Ras showed focus formation in NIH3T3 cells, although it had a lesser transforming potential compared to codon 12 mutations. Evidence Type: Oncogenic | Mutation: L19F | Summary: The L19F mutation in K-Ras resulted in low but consistent numbers of isolated foci in NIH3T3 cells, suggesting its involvement in tumor development. Evidence Type: Oncogenic | Mutation: K117N | Summary: The K117N mutation in K-Ras was associated with significant focus formation in NIH3T3 cells, indicating its contribution to tumor progression. Evidence Type: Oncogenic | Mutation: A146T | Summary: The A146T mutation in K-Ras led to significant focus formation in NIH3T3 cells, suggesting its role in tumor development. Evidence Type: Oncogenic | Mutation: R164Q | Summary: The R164Q mutation in K-Ras was phenotypically equivalent to wild-type K-Ras with no evidence of foci formation, indicating it does not contribute to tumor development.

Gene→Variant (gene-first): 3845:A146T 3845:G12D 3845:G12V 3845:G13D 3845:K117N 3845:L19F 3845:Q61H 3845:R164Q

Genes: 3845

Variants: A146T G12D G12V G13D K117N L19F Q61H R164Q

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: A to C (Lys to Asn at codon 117) | Summary: This K-Ras mutation is associated with tumor development or progression in colorectal tumors. Evidence Type: Oncogenic | Mutation: G to A (Ala to Thr at codon 146) | Summary: This K-Ras mutation contributes to tumor development or progression in colorectal tumors. Evidence Type: Oncogenic | Mutation: G to A (Arg to Gln at codon 164) | Summary: This K-Ras mutation is implicated in tumor development or progression in colorectal tumors. Evidence Type: Oncogenic | Mutation: V600E | Summary: The B-Raf V600E mutation is known to contribute to tumor development or progression in colorectal tumors.

Gene→Variant (gene-first): 3845:A to C 3845:Ala to Thr 3845:Arg to Gln 3845:C to T 3845:G to A 3845:Lys to Asn 673:V600E 3845:aspartic acid residue at codon 173

Genes: 3845 673

Variants: A to C Ala to Thr Arg to Gln C to T G to A Lys to Asn V600E aspartic acid residue at codon 173

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: G57T | Summary: The G57T mutation is associated with tumor development or progression as it was found in a colorectal tumor. Evidence Type: Oncogenic | Mutation: Leu19Phe | Summary: The Leu19Phe mutation is associated with tumor development or progression as it was found in a colorectal tumor. Evidence Type: Oncogenic | Mutation: V600E | Summary: The V600E mutation is associated with tumor development or progression as it was found in a colorectal tumor.

Gene→Variant (gene-first): 673:G57T 3845:Leu19Phe 673:V600E

Genes: 673 3845

Variants: G57T Leu19Phe V600E

[Paper-level Aggregated] PMCID: PMC2837563

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The K-Ras mutations, including G12V, G12D, G13D, Q61H, L19F, K117N, and A146T, were shown to have transforming potential in NIH3T3 cells, indicating their role in promoting oncogenesis. Functional: The study assessed the functional impact of K-Ras mutations through focus formation assays and GTPase activity, demonstrating that certain mutations are in the active GTP-bound conformation and influence gene expression. Predictive: The presence of specific K-Ras mutations, such as A146T and K117N, was associated with phenotypes similar to known activating mutations, suggesting their potential to predict tumor behavior and response to therapies.

Gene→Variant (gene-first): KRAS(3845):A to C KRAS(3845):Ala to Thr KRAS(3845):Arg to Gln KRAS(3845):C to T KRAS(3845):G to A KRAS(3845):Lys to Asn BRAF(673):V600E KRAS(3845):aspartic acid residue at codon 173 KRAS(3845):A146T KRAS(3845):G12C KRAS(3845):G12D KRAS(3845):G12V KRAS(3845):G13D KRAS(3845):K117N KRAS(3845):L19F KRAS(3845):R164Q KRAS(3845):Q61H KRAS(3845):Ala146Thr KRAS(3845):Arg164Gln KRAS(3845):Leu19Phe KRAS(3845):Lys117Asn BRAF(673):G57T

Genes: KRAS(3845) BRAF(673)

Variants: A to C Ala to Thr Arg to Gln C to T G to A Lys to Asn V600E aspartic acid residue at codon 173 A146T G12C G12D G12V G13D K117N L19F R164Q Q61H Ala146Thr Arg164Gln Leu19Phe Lys117Asn G57T

[Paragraph-level] PMCID: PMC2837563 Section: ABSTRACT PassageIndex: 6

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses K-Ras mutations identified in tumors, indicating that these variants contribute to tumor development or progression, particularly with reference to their phenotypes in the context of cancer. Functional: The passage describes the phenotypic effects of the K-Ras mutations, suggesting that they alter molecular or biochemical function, as evidenced by the comparison of their phenotypes to hotspot mutations and wild-type K-Ras.

Gene→Variant (gene-first): 3845:Ala146Thr 3845:Arg164Gln 3845:Leu19Phe 3845:Lys117Asn

Genes: 3845

Variants: Ala146Thr Arg164Gln Leu19Phe Lys117Asn

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the introduction of the R164Q mutation led to changes in gene expression and pathway activation, indicating that the variant alters molecular function. Oncogenic: The mention of the A146T, K117N, G13D, and Q61H mutations clustering together and influencing gene expression suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 3845:A146T 3845:G13D 3845:K117N 3845:L19F 3845:Q61H 3845:R164Q

Genes: 3845

Variants: A146T G13D K117N L19F Q61H R164Q

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses transcription-profiling experiments and Ras GTPase assay data, indicating that the variants alter molecular or biochemical function, particularly in relation to their clustering and phenotypic characteristics. Oncogenic: The mention of the variants being associated with distinct phenotypes and their clustering suggests that these somatic mutations contribute to tumor development or progression.

Gene→Variant (gene-first): 3845:A146T 3845:G12C 3845:G12D 3845:G12V 3845:G13D 3845:K117N 3845:L19F 3845:R164Q

Genes: 3845

Variants: A146T G12C G12D G12V G13D K117N L19F R164Q

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how specific K-Ras mutations (G12V, L19F, K117N, A146T) are in the active GTP-bound conformation, indicating that these variants alter the molecular function of the K-Ras protein. Oncogenic: The mention of K-Ras mutations being in the active GTP-bound conformation suggests that these somatic variants contribute to tumor development or progression, as they are associated with active signaling pathways in cancer.

Gene→Variant (gene-first): 3845:A146T 3845:G12V 3845:K117N 3845:L19F 3845:R164Q

Genes: 3845

Variants: A146T G12V K117N L19F R164Q

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the transformation potential of various K-Ras mutations, indicating that these mutations contribute to tumor development as evidenced by the formation of foci in NIH3T3 cells after transfection. Functional: The study evaluates the molecular function of K-Ras mutations by assessing their ability to transform cells, which involves alterations in biochemical activity as demonstrated through focus formation assays.

Gene→Variant (gene-first): 3845:A146T 3845:G12D 3845:G12V 3845:G13D 3845:K117N 3845:L19F 3845:Q61H 3845:R164Q

Genes: 3845

Variants: A146T G12D G12V G13D K117N L19F Q61H R164Q

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 4

Evidence Type(s): Diagnostic, Oncogenic, Functional

Justification: Diagnostic: The passage discusses the identification and relative frequencies of K-Ras mutations in human colorectal tumors, indicating their association with the disease. Oncogenic: The mention of K-Ras mutations, including the V600E mutation, suggests their contribution to tumor development or progression, as they are associated with increased mutation frequency in the Ras pathway. Functional: The passage notes the predicted localization of each mutation in the functional domains of the K-Ras protein, indicating an alteration in molecular function.

Gene→Variant (gene-first): 3845:A to C 3845:Ala to Thr 3845:Arg to Gln 3845:C to T 3845:G to A 3845:Lys to Asn 673:V600E 3845:aspartic acid residue at codon 173

Genes: 3845 673

Variants: A to C Ala to Thr Arg to Gln C to T G to A Lys to Asn V600E aspartic acid residue at codon 173

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 3

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the detection of specific mutations in colorectal tumors, indicating their association with the disease, which supports their use in defining or classifying the disease. Oncogenic: The mention of mutations at codon 19 (G57T, Leu19Phe) and in B-Raf (V600E) suggests that these somatic variants may contribute to tumor development, as they are found in tumor samples.

Gene→Variant (gene-first): 673:G57T 3845:Leu19Phe 673:V600E

Genes: 673 3845

Variants: G57T Leu19Phe V600E

[Paragraph-level] PMCID: PMC2837563 Section: ABSTRACT PassageIndex: 6

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses K-Ras mutations identified in tumors, indicating that these variants contribute to tumor development or progression, particularly with reference to their phenotypes in the context of cancer. Functional: The passage describes the phenotypic effects of the K-Ras mutations, suggesting that they alter molecular or biochemical function, as evidenced by the comparison of their phenotypes to hotspot mutations and wild-type K-Ras.

Gene→Variant (gene-first): 3845:Ala146Thr 3845:Arg164Gln 3845:Leu19Phe 3845:Lys117Asn

Genes: 3845

Variants: Ala146Thr Arg164Gln Leu19Phe Lys117Asn

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the introduction of the R164Q mutation led to changes in gene expression and pathway activation, indicating that the variant alters molecular function. Oncogenic: The mention of the A146T, K117N, G13D, and Q61H mutations clustering together and influencing gene expression suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 3845:A146T 3845:G13D 3845:K117N 3845:L19F 3845:Q61H 3845:R164Q

Genes: 3845

Variants: A146T G13D K117N L19F Q61H R164Q

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses transcription-profiling experiments and Ras GTPase assay data, indicating that the variants alter molecular or biochemical function, particularly in relation to their clustering and phenotypic characteristics. Oncogenic: The mention of the variants being associated with distinct phenotypes and their clustering suggests that these somatic mutations contribute to tumor development or progression.

Gene→Variant (gene-first): 3845:A146T 3845:G12C 3845:G12D 3845:G12V 3845:G13D 3845:K117N 3845:L19F 3845:R164Q

Genes: 3845

Variants: A146T G12C G12D G12V G13D K117N L19F R164Q

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how specific K-Ras mutations (G12V, L19F, K117N, A146T) are in the active GTP-bound conformation, indicating that these variants alter the molecular function of the K-Ras protein. Oncogenic: The mention of K-Ras mutations being in the active GTP-bound conformation suggests that these somatic variants contribute to tumor development or progression, as they are associated with active signaling pathways in cancer.

Gene→Variant (gene-first): 3845:A146T 3845:G12V 3845:K117N 3845:L19F 3845:R164Q

Genes: 3845

Variants: A146T G12V K117N L19F R164Q

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the transformation potential of various K-Ras mutations, indicating that these mutations contribute to tumor development as evidenced by the formation of foci in NIH3T3 cells after transfection. Functional: The study evaluates the molecular function of K-Ras mutations by assessing their ability to transform cells, which involves alterations in biochemical activity as demonstrated through focus formation assays.

Gene→Variant (gene-first): 3845:A146T 3845:G12D 3845:G12V 3845:G13D 3845:K117N 3845:L19F 3845:Q61H 3845:R164Q

Genes: 3845

Variants: A146T G12D G12V G13D K117N L19F Q61H R164Q

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 4

Evidence Type(s): Diagnostic, Oncogenic, Functional

Justification: Diagnostic: The passage discusses the identification and relative frequencies of K-Ras mutations in human colorectal tumors, indicating their association with the disease. Oncogenic: The mention of K-Ras mutations, including the V600E mutation, suggests their contribution to tumor development or progression, as they are associated with increased mutation frequency in the Ras pathway. Functional: The passage notes the predicted localization of each mutation in the functional domains of the K-Ras protein, indicating an alteration in molecular function.

Gene→Variant (gene-first): 3845:A to C 3845:Ala to Thr 3845:Arg to Gln 3845:C to T 3845:G to A 3845:Lys to Asn 673:V600E 3845:aspartic acid residue at codon 173

Genes: 3845 673

Variants: A to C Ala to Thr Arg to Gln C to T G to A Lys to Asn V600E aspartic acid residue at codon 173

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 3

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the detection of specific mutations in colorectal tumors, indicating their association with the disease, which supports their use in defining or classifying the disease. Oncogenic: The mention of mutations at codon 19 (G57T, Leu19Phe) and in B-Raf (V600E) suggests that these somatic variants may contribute to tumor development, as they are found in tumor samples.

Gene→Variant (gene-first): 673:G57T 3845:Leu19Phe 673:V600E

Genes: 673 3845

Variants: G57T Leu19Phe V600E